Monograph

Transcription

Monograph

Monograph
22 November 2000
Benzoic acid
Volume 1
Report and
Proposed Decision
Rapporteur Member State: Germany
-iBenzoic acid – Contents
22 November 2000
Contents
1
Statement of subject matter and purpose for which the monograph was
prepared ...................................................................................................................... 3
1.1
1.2
1.5.1
1.5.2
1.5.3
1.5.4
Purpose for which the monograph was prepared (Dossier Document A).................... 3
Summary and assessment of information relating to collective provision of
dossiers (Dossier Document B).................................................................................... 3
Identity of the active substance (Annex IIA 1) (Dossier Documents J, K-II and
L-II) .............................................................................................................................. 3
Name and address of applicant(s) for inclusion of the active substance in
Annex I (Annex IIA 1.1) .............................................................................................. 3
Common name and synonyms (Annex IIA 1.3)........................................................... 3
Chemical name (Annex IIA 1.4) .................................................................................. 3
Manufacturer's development code number (Annex IIA 1.5)........................................ 3
CAS, EEC and CIPAC numbers (Annex IIA 1.6) ....................................................... 4
Molecular and structural formulae, molecular mass (Annex IIA 1.7) ......................... 4
Manufacturer or manufacturers of the active substance (Annex IIA 1.2) .................... 4
Method or methods of manufacture (Annex IIA 1.8) .................................................. 4
Specification of purity of the active substance (Annex IIA 1. 9)................................. 5
Identity of isomers, impurities and additives (Annex IIA 1.10)................................... 5
Analytical profile of batches (Annex IIA 1.11)............................................................ 5
Identity of the plant protection product (Annex IIA 3.1; Annex IIIA 1) (Dossier
Documents J, K-II, L-II, K-III, and L- III) (to be included for each preparation
for which an Annex III dossier was submitted) ........................................................... 6
Current, former and proposed trade names and development code numbers
(Annex IIIA 1.3)........................................................................................................... 6
Manufacturer or manufacturers of the plant protection product (Annex IIIA 1.2) ...... 6
Type of the preparation and code (Annex IIIA 1.5) ..................................................... 6
Function (Annex IIA 3.1; Annex IIIA 1.6) .................................................................. 6
Composition of the preparation (Annex IIIA 1.4)........................................................ 6
Use of the plant protection product (Annex IIA 3.2 to 3.4; Annex IIIA 3.1 to
3.7, 3.9, 12.1) (Dossier Documents C, D, and E) (to be included for each
preparation for which an Annex III dossier was submitted) ........................................ 7
Field of use (Annex IIA 3.3; Annex IIIA 3.1).............................................................. 7
Effects on harmful organisms (Annex IIA 3.2; Annex IIIA 3.2) ................................. 7
Summary of intended uses (Annex IIA 3.4; Annex IIIA 3.3 to 3. 7, 3.9) .................... 7
Information on authorizations in EU Member States (Annex IIIA 12.1)................... 10
2
Reasoned statement of the overall conclusions...................................................... 13
2.1
2.1.1
2.1.2
2.1.3
2.1.3.1
2.1.3.2
2.1.4
2.2
2.2.1
Identity ....................................................................................................................... 13
Identity ....................................................................................................................... 13
Physical and chemical properties ............................................................................... 13
Details of uses and further information...................................................................... 13
Details of uses ............................................................................................................ 13
Further information .................................................................................................... 13
Classification and labelling........................................................................................ 14
Methods of Analysis .................................................................................................. 14
Analytical methods for analysis of the active substance as manufactured................. 14
1.3
1.3.1
1.3.2
1.3.3
1.3.4
1.3.5
1.3.6
1.3.7
1.3.8
1.3.9
1.3.10
1.3.11
1.4
1.4.1
1.4.2
1.4.3
1.4.4
1.4.5
1.5
- ii Benzoic acid – Contents
2.2.2
2.2.3
2.3
2.3.1
2.3.2
2.3.3
2.3.4
2.3.5
2.3.6
2.4
2.4.1
2.4.2
2.4.3
2.4.4
2.4.5
2.4.6
2.5
2.5.1
2.5.2
2.5.3
2.5.4
2.6
2.6.1
2.6.2
2.6.3
2.6.3.1
2.6.3.2
2.6.4
2.6.5
2.6.6
2.6.7
2.7
2.7.1
2.7.2
2.7.3
2.8
2.8.1
2.8.2
2.8.3
2.8.3.1
2.8.3.2
2.8.3.3
2.8.3.4
22 November 2000
Analytical methods for formulation analysis ............................................................. 14
Analytical methods for residue analysis..................................................................... 15
Impact on human and animal health .......................................................................... 15
Effects having relevance to human and animal health arising from exposure to
the active substance or to impurities contained in the active substance or to
their transformation products ..................................................................................... 15
ADI............................................................................................................................. 20
ARfD (acute reference dose)...................................................................................... 20
AOEL ......................................................................................................................... 20
Drinking water limit................................................................................................... 21
Impact on human or animal health arising from exposure to the active
substance or to impurities contained in it................................................................... 21
Residues ..................................................................................................................... 21
Definition of the residues relevant to MRLs.............................................................. 21
Residues relevant to consumer safety ........................................................................ 22
Residues relevant to worker safety............................................................................. 22
Proposed EU MRLs and compliance with existing MRLs ........................................ 22
Proposed EU import tolerances and compliance with existing import tolerances..... 22
Basis for differences, if any, in conclusion reached having regard to established
or proposed CAC MRLs ............................................................................................ 22
Fate and behaviour in the environment ...................................................................... 22
Definition of the residues relevant to the environment .............................................. 22
Fate and behaviour in soil .......................................................................................... 23
Fate and behaviour in water ....................................................................................... 23
Fate and behaviour in air............................................................................................ 24
Effects on non-target species...................................................................................... 24
Effects on terrestrial vertebrates................................................................................. 24
Effects on aquatic species .......................................................................................... 24
Effects on bees and other arthropod species .............................................................. 24
Effects on bees ........................................................................................................... 24
Effects on other arthropod species ............................................................................. 24
Effects on earthworms and other soil macro-organisms ............................................ 25
Effects on soil micro-organisms................................................................................. 25
Effects on other non-target organisms (flora and fauna)............................................ 25
Effects on biological methods of sewage treatment................................................... 25
Overall conclusion (metabolism schemes)................................................................. 26
Toxicology (laboratory animals) ................................................................................ 26
Residues (plant, plant products, livestock animals) ................................................... 26
Fate and behaviour in the environment (soil, water, air) ........................................... 26
Appendices................................................................................................................. 29
Appendix I: Standard terms and abbreviations .......................................................... 29
Appendix II: Specific terms and abbreviations .......................................................... 41
Appendix III: Listing of end points............................................................................ 45
Appendix III.1: Chapter 1(identity, physical and chemical properties, details of
uses, further information, classification and labelling) .............................................. 45
Appendix III.4: Chapter 4 (residues).......................................................................... 53
Appendix III.5: Chapter 5 (fate and behaviour in the environment).......................... 55
Appendix III.6: Chapter 6 (effects on non-target species) ......................................... 60
- iii Benzoic acid – Contents
22 November 2000
3
Proposed decision with respect to the application for inclusion of the active
substance in Annex I ................................................................................................ 65
3.1
3.2
3.3
Background to the proposed decision ........................................................................ 65
Proposed decision concerning inclusion in Annex I .................................................. 65
Rational for the postponement of the decision to include the active substance in
Annex I, or for the conditions and restrictions to be associated with a proposed
inclusion in Annex I, as appropriate .......................................................................... 66
4
Further information to permit a decision to be made, or to support a
review of the conditions and restrictions associated with the proposed
inclusion in Annex I ................................................................................................. 69
4.1
4.2
4.3
4.3.1
4.3.2
4.4
4.5
4.5.1
4.5.2
4.6
4.7
4.8
4.9
Identity of the active substance .................................................................................. 69
Physical and chemical properties of the active substance.......................................... 69
Data on application and further information.............................................................. 69
Data on application .................................................................................................... 69
Further information .................................................................................................... 69
Classification, packaging and labelling...................................................................... 69
Methods of analysis.................................................................................................... 69
Analytical methods for formulation analysis ............................................................. 69
Analytical methods for residue analysis..................................................................... 69
Toxicology and metabolism ....................................................................................... 69
Residue data ............................................................................................................... 70
Environmental fate and behaviour ............................................................................. 70
Ecotoxicology ............................................................................................................ 70
Level 1
Benzoic acid
Statement of Subject Matter and
Purpose of Monograph
-3Benzoic acid – Level 1: Statement of subject matter and purpose for which the monograph was prepared
22 November 2000
1
Statement of subject matter and purpose for which the monograph was
prepared
1.1 Purpose for which the monograph was prepared (Dossier Document
A)
This monograph is submitted to support first inclusion of the new active substance benzoic
acid in Annex I of the Council Directive 91/414/EEC, according to Commission Regulations
(EEC) No 3600/92 and (EC) No 993/94.
1.2 Summary and assessment of information relating to collective
provision of dossiers (Dossier Document B)
As MENNO is the only notifier of the new active ingredient Benzoesäure, there is no
relevance.
1.3 Identity of the active substance (Annex IIA 1) (Dossier Documents J,
K-II and L-II)
1.3.1 Name and address of applicant(s) for inclusion of the active substance in Annex I
(Annex IIA 1.1)
Menno Chemie-Vertriebs-Ges.mbH
Langer Kamp 104
D-22850 Norderstedt
Germany
Contact person: Jan Nevermann
Tel No.: +49 40 5253024
Fax No.: +49 40 5253027
1.3.2 Common name and synonyms (Annex IIA 1.3)
Common name (ISO, accepted): benzoic acid
1.3.3 Chemical name (Annex IIA 1.4)
Chemical name IUPAC: benzoic acid
Chemical name CA:
benzoic acid
1.3.4 Manufacturer's development code number (Annex IIA 1.5)
Benzoic acid
22 November 2000
1.3.5 CAS, EEC and CIPAC numbers (Annex IIA 1.6)
CAS:
CIPAC:
EINECS:
ELINCS:
65-85-0
622
2006182
not available
1.3.6 Molecular and structural formulae, molecular mass (Annex IIA 1.7)
Molecular formula:
Structural formula:
C7H6O2
O
OH
Molecular mass:
122.12
1.3.7 Manufacturer or manufacturers of the active substance (Annex IIA 1.2)
CVH Chemie-Vertrieb GmbH & Co. Hannover KG
Podbielskistr. 22
D-30163 Hannover
Germany
Phone:
Fax:
0049-511-628151
0049-511-625334
1.3.8 Method or methods of manufacture (Annex IIA 1.8)
Benzoic acid is manufactured by liquid-phase oxidation of toluene employing various cobalt
catalysts. Figure 1.3-1 gives a general flow diagram. The syntheses conditions are: 308 to
790 kPa and 130 to 160 °C. The by-products water, formic acid, acetic acid and CO2 are volatile at these conditions and could be distilled like excess toluene. Benzoic acid is crystallised
with a yield over 90 % and a purity over 99 %. The substance is used for pharmaceutical formulations.
22 November 2000
H2O
formic acid
acetic acid
toluene
CO2
air
toluene
cobalt
liquid phase reactor
308-790 kPa
130-160 °C
toluene
recycle
distillation
and/or
crystallization
benzoic acid
tar
Figure 1.3-1:
General flow diagram of liquid-phase toluene oxidation (Williams,
1978)
1.3.9 Specification of purity of the active substance (Annex IIA 1. 9)
The active substance benzoic acid has pharmaceutic quality. The purity as well as the limits of
the impurities are defined by the German pharmacopoeia (current revision DAB 10, 1991):
Purity:
99.0-100.5 %
1.3.10 Identity of isomers, impurities and additives (Annex IIA 1.10)
Isomers:
None
Impurities: Cinnamic acid:
Sum of heavy metals:
Ash:
Organic and inorganic chloride:
Additives: None
max. 0.1%
max. 0.001%
max. 0.1%
not detectable
1.3.11 Analytical profile of batches (Annex IIA 1.11)
Analytical profiles of batches are not required, because the maximum content of impurities
does not exceed 1 g/kg. The active substance has pharmaceutic quality. The purity as well as
the limits of the impurities are defined by the German pharmacopoeia (current revision DAB
10, 1991):
Purity:
Cinnamic acid:
99.0-100.5 %
max. 0.1 %
max. 0.001 %
22 November 2000
Ash:
max. 0.1 %
Organic and inorganic chloride: not detectable
1.4 Identity of the plant protection product (Annex IIA 3.1; Annex IIIA 1)
(Dossier Documents J, K-II, L-II, K-III, and L- III) (to be included for
each preparation for which an Annex III dossier was submitted)
1.4.1 Current, former and proposed trade names and development code numbers
(Annex IIIA 1.3)
Proposed trade names:
Menno-Florades
M&ENNO-Florades
1.4.2 Manufacturer or manufacturers of the plant protection product (Annex IIIA 1.2)
A.F.P. GmbH
Otto Brenner-Str. 16
D-21337 Lueneburg
Phone: +49 4131 55085
Fax: +49 4131 81131
Contact person: Dr. W. Hahn
1.4.3 Type of the preparation and code (Annex IIIA 1.5)
Soluble liquid (SL)
1.4.4 Function (Annex IIA 3.1; Annex IIIA 1.6)
Bactericide, virucide, viroicide, fungicide
1.4.5 Composition of the preparation (Annex IIIA 1.4)
Confidential information, see Annex C.
22 November 2000
1.5 Use of the plant protection product (Annex IIA 3.2 to 3.4; Annex IIIA
3.1 to 3.7, 3.9, 12.1) (Dossier Documents C, D, and E) (to be included
for each preparation for which an Annex III dossier was submitted)
1.5.1 Field of use (Annex IIA 3.3; Annex IIIA 3.1)
The active substance benzoic acid is intended to be used in horticulture (floriculture) for the
control of fungi, bacteria, viruses and viroids (by disinfection). It is proposed to be used in
glasshouses and similarly protected cultivation areas.
1.5.2 Effects on harmful organisms (Annex IIA 3.2; Annex IIIA 3.2)
Benzoic acid acts by contact as a fungicide, bactericide, virucide and viroicide and thus is
used for disinfection. The mode of action is not quite clear. Benzoic acid is known to inhibit
the bacteria cell multiplication (Verschueren, 1977). The cellular uptake of for example
amino-acids, organic acids and phosphate is inhibited and results in uncoupling of both
substrate transport and oxidative phosphorylation from the electron transport system (Freese et
al., 1973). Furthermore, the citric acid cycle is inhibited. Effective is the undissociated acid
(low pH).
1.5.3 Summary of intended uses (Annex IIA 3.4; Annex IIIA 3.3 to 3. 7, 3.9)
The intended uses for benzoic acid are listed in the following table. It is proposed to use plant
protection products based on benzoic acid for disinfection of surfaces (i.e. the surfaces on
which plants in pots or other culture vessels stand; e.g. sand beds, fleece mats, ebb- and flood
benches, including culture- and storerooms), culture vessels and equipment (e.g. knives) in
glasshouses or similarly protected areas. Disinfection of surfaces will be done by watering
after the last use. For ebb- and flood benches 0,2 l/m² of the ready for use solution are
necessary, for other surfaces up to 2 l/m². Equipment is dipped before, culture vessels soaked
after use in the solution of the plant production product. The concentration of the dip depends
on the pests to be controlled. The period of the treatment is 16 hours for surfaces and culture
vessels and three minutes for equipment respectively.
22 November 2000
List of uses supported by available data
Crop and/
or situation
(a)
Member
State
or
Country
Product
name
F
G
or
I
(b)
Pests or
Group of pests
controlled
(c)
Formulation
Type
Application
(d-f)
Conc
of as
(i)
method
kind
(f-h)
growth
stage &
season
(j)
after the
last use
number
Application rate per treatment
min max
(k)
1
interval
between
applications
(min)
n.a.
Surfaces
Germany
Menno
Florades
G
+
I
Virus
(ArMV, PFBV,
PLCV, PLPV,
TBRV, TSWV)
SL
90 g/l
watering
Surfaces
Germany
Menno
Florades
G
+
I
Virus
(TMV, ToMV)
SL
90 g/l
watering
after the
last use
1
Culture vessels
Germany
Menno
Florades
G
+
I
Virus
(ArMV, PFBV,
PLCV, PLPV,
TBRV, TSWV)
SL
90 g/l
soaking
after the
last use
Culture vessels
Germany
Menno
Florades
G
+
I
Virus
(TMV, ToMV)
SL
90 g/l
soaking
Equipment (eg
knives)
Germany
Menno
Florades
G
+
I
Virus
(ArMV, PFBV,
PLCV, PLPV,
TBRV, TSWV)
SL
90 g/l
Equipment (eg
knives)
Germany
Menno
Florades
G
+
I
Virus
(TMV, ToMV)
SL
90 g/l
kg as/hl
min max
water
l/ha
min max
PHI
(days)
(l)
Remarks
(m)
kg as/ha
min max
0.09 kg
(1 % solution)
2000 20000
1.8 - 18 kg n.a.
watering (16 h)
ebb/flood benches:
0.2 l/m2
other surfaces:
2.0 l/m2
n.a.
0.36 kg
(4 % solution)
2000 20000
7.2 - 72 kg n.a.
watering (16 h)
ebb/flood benches:
0.2 l/m2
other surfaces:
2.0 l/m2
n.a.
n.a.
0.09 kg
(1 % solution)
n.a.
n.a.
n.a.
soaking (16 h)
after the
last use
n.a.
n.a.
0.36 kg
(4 % solution)
n.a.
n.a.
n.a.
soaking (16 h)
dipping
before
the use
n.a.
n.a.
0.18 kg
(2 % solution)
n.a.
n.a.
n.a.
dipping
(3 minutes)
dipping
before
the use
n.a.
n.a.
0.27 kg
(3 % solution)
n.a.
n.a.
n.a.
dipping
(3 minutes)
22 November 2000
Crop and/
or situation
(a)
Member
State
or
Country
Product
name
F
G
or
I
(b)
Pests or
Group of pests
controlled
(c)
Formulation
Type
Application
(d-f)
Conc
of as
(i)
method
kind
(f-h)
growth
stage &
season
(j)
after the
last use
number
min max
(k)
1
interval
between
applications
(min)
n.a.
Surfaces
Germany
Menno
Florades
G
+
I
Bacteria and fungi
SL
90 g/l
watering
Culture vessels
Germany
Menno
Florades
G
+
I
Bacteria and fungi
SL
90 g/l
soaking
after the
last use
n.a.
Equipment (eg
knives)
Germany
Menno
Florades
G
+
I
Bacteria and fungi
SL
90 g/l
dipping
before
the use
Equipment (eg
knives)
Germany
Menno
Florades
G
+
I
Viroids
SL
90 g/l
dipping
before
the use
kg as/hl
min max
water
l/ha
min max
PHI
(days)
(l)
Remarks
(m)
kg as/ha
min max
0.09 kg
(1 % solution)
2000 20000
1.8 - 18 kg n.a.
watering (16 h)
ebb/flood benches:
0.2 l/m2
other surfaces:
2.0 l/m2
n.a.
0.09 kg
(1 % solution)
n.a.
n.a.
n.a.
soaking (16 h)
n.a.
n.a.
0.09 kg
(1 % solution)
n.a.
n.a.
n.a.
dipping
(3 minutes)
n.a.
n.a.
0.09 kg
(1 % solution)
n.a.
n.a.
n.a.
dipping
(3 minutes)
n.a. = not applicable
(a) For crops, the EU and Codex classifications (both) should be used; where relevant, the use situation
should be described (e.g. fumigation of a structure)
(c) e.g. biting and suckling insects, soil born insects, foliar fungi, weeds
(e) GCPF Codes - GIFAP Technical Monograph No 2, 1989
(g) Method, e.g. high volume spraying, low volume spraying, spreading, dusting, drench
(i) g/kg or g/l
(k) Indicate the minimum and maximum number of application possible under practical conditions of use
(m) Remarks may include: Extent of use/economic importance/restrictions
(b) Outdoor or field use (F), glasshouse application (G) or indoor application (I)
(d) e.g. wettable powder (WP), emulsifiable concentrate (EC), granule (GR)
(f) All abbreviations used must be explained
(h) Kind, e.g. overall, broadcast, aerial spraying, row, individual plant, between the plant - type of equipment
used must be indicated
(j) Growth stage at last treatment (BBCH Monograph, Growth Stages of Plants, 1997, Blackwell, ISBN 38263-3152-4), including where relevant, information on season at time of application
(l) PHI - minimum pre-harvest interval
- 10 Benzoic acid – Level 1: Statement of subject matter and purpose for which the monograph was prepared
22 November 2000
1.5.4 Information on authorizations in EU Member States (Annex IIIA 12.1)
The plant protection product “MENNO-Florades” containing benzoic acid, is authorized in
Germany for use in floriculture. It is used for disinfection of equipment (like knives), culture
vessels and surfaces in glasshouses and similarly protected areas. The conditions of
application correspond to the ones of the intended uses (chapter 1.5.3).
Level 2
Benzoic acid
Overall Conclusions
- 13 Benzoic acid – Level 2: Reasoned statement of the overall conclusion
2
22 November 2000
Reasoned statement of the overall conclusions
2.1 Identity
2.1.1 Identity
All points (Annex II and III) have been addressed and the information supplied is acceptable.
2.1.2 Physical and chemical properties
Benzoic acid is a crystalline white odourless solid with a melting point of 122 °C and a
boiling point of 249 °C. The density is 1.321 g/cm3. The vapour pressure of benzoic acid is
reported to be 0.11 – 0.53 Pa (20 °C), Henry’s Law constant was calculated to be 0.00460.022 Pa m3 mol-1. Solubility in distilled water is 2.9 g/l (pH = 2.94). Benzoic acid is less
soluble under acidic conditions (free acis) and more soluble under alkaline conditions (as
salt). The active substance is soluble in polar organic solvents as acetone, methanol, ethyl
ether and ethanol in the range of 41-72 g/100 g. The solubility decreases in non-polar solvents
like toluene (10.6 g/100 g) or n-hexane (0.94 g/100 g). The log POW values is 1.87. Taking
account of the chemical structure (aromatic monocarbon acid) hydrolysis at pH 5 – 9 will not
occur. The active substance has no explosive or oxidising properties. When benzoic acid is
heated to 370 °C, it is irreversible decomposed to benzene and carbon dioxide, with a small
fraction (2-8 %) decomposing into phenol and carbon monoxide.
The preparation Menno-Florades is a clear slightly amber coloured liquid, which can be diluted with water to the required application concentration of 1 to 4%.
Due to the content of organic solvents the preparation is flammable with a flash point of
28 °C. The preparation is stable after storage at low and high temperatures and has a shelf live
of at least 2 years. Its technical properties indicate no particular problems when used as recommended.
2.1.3 Details of uses and further information
2.1.3.1 Details of uses
Benzoic acid is an active substance with fungicidal, bactericidal, virucidal and viroicidal
properties and thus serves for disinfection. It is proposed to be used in horticulture
(floriculture) for disinfection of surfaces (i.e. the surfaces on which plants in culture vessels
stand inculuding culture- and storerooms), equipment and culture vessels in glasshouses and
other similarly protected cultivation areas.
2.1.3.2 Further information
Information of packaging, procedures for cleaning, handling, storage, transport or fire, destruction or decontamination, emergency measures for the active substance as manufactured
and the soluble liquid have been supplied and are acceptable.
22 November 2000
2.1.4 Classification and labelling
A proposal in accordance with the latest classification and labelling guidance under Directive
67/548/EEC (i.e. in the 18th ATP published as Directive 93/21/EEC) is not possible because
not all of the original studies are available. The proposal is made on the basis of all respective
data available.
Benzoic acid
Hazard symbol:
Indication of danger:
Xi
Irritant
Risk phrases:
R 41
Risk of serious damage to eyes.
Menno-Florades
The following is proposed in accordance with Directive 78/631/EEC in combination with the
latest classification and labelling guidance under Directive 67/548/EEC (i.e. in the 18th ATP
published as Directive 93/21/EEC):
Hazard symbol:
Xi
Irritant
Risk phrases:
R 41
Remarks
Concerning the possible sensitizing properties, no test was performed. It is considered not
nessecary on the basis of the available information about the active substance, the
preparation and the intended uses.
Persons who react sensitive to pseudoallergic substances have to check for benzoic
acid/benzoates. If these are the causative substances in their individual case they should
avoid contact with them.
2.2 Methods of Analysis
2.2.1 Analytical methods for analysis of the active substance as manufactured
The active substance is determined by isocratic HPLC on a reversed phase stationary phase
(Spherisorb 5 ODS). Mobile phase: methanol/0.03 mol/l H3PO4 (50:50, V/V) with UV detection (245 nm). The method is validated.
2.2.2 Analytical methods for formulation analysis
Analytical methodology is available for the determination of the as in the SL-preparation.
22 November 2000
2.2.3 Analytical methods for residue analysis
Relevant residues in food and the environmental compartments arising from the application of
benzoic acid according to the GAP are not expected to occur, MRL are not to be set (cf.
Point 2.4.1, Definition of residues relevant to MRL; Point 2.4.4, Proposed EU MRL and
compliance with existing MRL; Point 2.5.1, Definition of the residue relevant to the
environment). Therefore, residue analytical methods for the determination of the active
substance in food of plant and animal origin for enforcement purposes as well as for soil,
water and air are not required.
2.3 Impact on human and animal health
2.3.1 Effects having relevance to human and animal health arising from exposure to
the active substance or to impurities contained in the active substance or to their
transformation products
Bridging concept
In this monograph, benzoic acid and its salts - showing a great similarity of the toxicological
profile - were considered together because a considerable part of data was generated with
benzoates.
The evaluation of the active ingredient is almost exclusively based on original publications,
cited to some extent in other reviews. The cited literature had often to be traced back for the
actual results which were in fact elaborated in many cases decades or even a century ago.
Even if the literature is very heterogeneous, the assessment of the toxicological properties of
benzoic acid and benzoates is possible. Taking into account the natural occurrence of these
substances in the environment and the long and extensive experience with the use of benzoic
acid/benzoates as dietary supplement, further testing is not necessary.
Regarding the overall conclusions on the toxicological properties of benzoic acid/benzoates in
this monograph, they resemble those drawn in other evaluations (e.g. JECFA, 1974, 1983,
1996). The decision of FDA (1972) to accept benzoic acid as a GRAS (Generally Recognized
As Safe) direct food substance is absolutely agreed.
Biokinetics and metabolism
Information regarding the absorption, distribution, excretion and metabolism of benzoic
acid/sodium benzoate is derived from investigations with very different objectives (e.g.
perfusion experiments with different organs, elucidation of basic metabolism principles,
special absorption phenomenas). In these investigations, a great variety of animal species has
been studied. A comprehensive ADME (absorption, distribution, metabolism, excretion) study
based on a current guideline (e.g. EU, OECD or EPA) is not available.
22 November 2000
Benzoic acid/sodium benzoate is rapidly and virtually completely absorbed after oral ingestion
in many animal species and man. It is rapidly excreted to a high rate via urine after oral,
intraperitoneal and subcutaneous administration (80% to 99% within 24 hours). The fecal
excretion is only a minor route of elimination.
The percutaneous absorption in humans accounts for approximately 40%. However, for
practical reasons and due to the heterogeneous results in different species, an overall dermal
absorption of 100% was assumed and taken for operator calculations.
Data regarding the pulmonary absorption are not available.
Because of the high rate and extent of elimination, accumulation of incorporated benzoic
acid/sodium benzoate in organs and tissues is not to be expected. In contrast benzoic acid
itself can also be generated in intermediary metabolism.
The main metabolite of benzoic acid/sodium benzoate is hippuric acid (up to 100%, e.g. in
humans) followed by benzoyl-glucuronic acid (0% to ca 20%). These metabolites result from
conjugation reactions of benzoic acid with glycine or glucuronic acid. Major sites of the
conjugation reactions are the liver and the kidney. Marked species differences exist in the rate
and extent of benzoate metabolism in both organs.
Important factors which affect the tolerance for the benzoates are the incorporated amount of
these substances, the availability of an adequate glycine concentration for the conjugation
process and the velocity rate for both the conjugation reactions and the excretory process.
In plants, benzoic acid serves as defensive substance and as basic intermediate for secondary
plant products.
Acute toxicity
Acute toxicity testing with benzoic acid / benzoic salts was performed in several animals
species - often at the turn of the century and it is occasionally not absolutely clear which
benzoic compound was used then.
Benzoic acid is of moderate to low toxicity:
630 mg/kg bw (cat) to 3040 mg/kg bw (rat),
LD50, oral:
LD50, dermal:
> 5000 mg/kg bw (rabbit) and
> 0.026 mg/l (1 h, rat).
LC50, inhalative:
All respective data summarized, benzoic acid is not irritating to the skin but due to its acidic
property irritating to the eyes (R 41, according to the EU-Directive 67/548/EEC) and not
sensitizing. The picture of poisoning is characterized by convulsions, hyperaesthesia,
disturbed respiration and changed body temperature.
Sodium benzoate is of low toxicity. The LD50 (oral) values are in the range from 2000 to 4000
mg/kg bw. It is not irritating to skin and eyes. No data on sensitizing effects were available.
Short-term toxicity
In the short-term toxicity studies benzoic acid and/or sodium benzoate were tested in the rat,
mouse, cat, guinea-pig and dog. The predominant aim in most experiments was to
demonstrate effects and not to find out a NOEL/NOAEL. Therefore, the noted NOELs were
mostly derived by the rapporteur.
In all experiments, the application route was oral, except in one inhalation study.
22 November 2000
The range of tested doses was from 0.5% up to 8% benzoic acid/sodium benzoate in the diet
or in the drinking water.
At high oral doses, mortality occurred preceded by acute symptoms like aggressiveness,
hypersensitivity, tremor, convulsions, uncoordinated movement and depression, indicating
disturbances in the central nervous system.
Body weight gain and food consumption, parameters almost in all studies measured, were
decreased.
In some experiments, development of tolerance to benzoic acid after prolonged application
was observed.
Overall, the main target organs were liver, kidney and brain, partly supported by biochemical
and/or pathohistological findings. However, in spite of pronounced symptoms of toxicity in
the cat at high doses, no adverse histological findings in the brain were evident.
The overall NOEL has to be derived from all relevant short-term and chronic rat studies
together, i.e. 1% benzoic acid in the diet corresponding to ca 500 mg/kg bw/d. This NOEL can
serve for the calculation of the ADI and AOEL.
Genotoxicity
A large number of genotoxicity studies with benzoic acid or sodium benzoate, including the
main end points, is available.
Although there are some positive results in vitro, most of the in vitro and all the in vivo tests
were negative. The following conclusion is drawn:
From the available literature, no mutagenic properties of benzoic acid or sodium benzoate are
evident.
Chronic toxicity/carcinogenicity
Only two relevant chronic toxicity studies in rats are available. The tested doses are 0.5%, 1%
and 1.5% benzoic acid in the diet.
No target organ was found out. At 1.5% mortality and decreased body weight gain and food
consumption occurred.
At 0.5% a considerable prolongation of life was observed.
Under the aspect of carcinogenicity, two relevant studies were performed, one in rats with 1%
and 2% sodium benzoate in the diet, the other in mice with 2% sodium benzoate in the
drinking water.
No adverse effects were evident.
Including the results from the chronic toxicity studies, the conclusion can be drawn that no
carcinogenic effect is evident for benzoic acid or sodium benzoate from the available
literature.
The overall NOEL - 1% benzoic acid in the diet corresponding to ca 500 mg/kg bw/d - has to
be derived from all relevant short-term and chronic toxicity/carcinogenicity studies together
since no single study according to a current test guideline is available. This NOEL can serve
for the calculation of the ADI and AOEL. Most of these studies and relevant studies on other
species are summarized in table B.6.10-1.
Reproductive/developmental toxicity
Only one reproduction study is available. The combined chronic/reproductive toxicity study
was performed in rats with dose levels of 0.5% and 1% benzoic acid in the diet, including 4
22 November 2000
generations with varying test periods. No adverse effect on reproduction or other parameters
was evident. This study is one of the relevant studies for deriving the ADI.
According to a summarizing review, no adverse teratogenic effects were observed in rats,
rabbits, mice and hamsters up to the highest tested doses of 175, 250, 175 and 300 mg/kg
bw/d, respectively. However, these doses seem to be very low for drawing conclusions on
these species.
For the assessment of the teratogenic potential in rats, three original publications (application
during the whole gestation period in two studies, only at day 9 in the other one) and one
abstract were available. The tested doses were in a range from 50 to 4000 mg/kg bw/d.
In one experiment, at 2000 and 4000 mg/kg bw/d, abnormalities/malformations of the eye,
kidney and brain occurred at severe maternaltoxic effects (mortality, reduction of body weight
and food consumption).
Taken together all teratogenic investigations, at a dose of ca 500 mg/kg bw/d neither
maternaltoxic nor adverse effects on fetuses and offspring were evident. This is the same
magnitude as the overall NOEL in short-term and chronic toxicity studies (basis for ADI).
Table 2.3-1:
Relevant oral short-term and long-term/carcinogenicity, reproduction
and developmental toxicity studies taken for risk assessment
Study
Short-term studies
Rat, 10 days, SB
Rat, 1-5 days,
1, 2, 5 weeks, BA
NOEL
1.81% (ca 1358 mg/kg
bw/d)
no NOEL at 1.1% (5
weeks)
Rat, 4 weeks, SB
Rat, 4 weeks, BA
Remark
Fujitani, 1993
1.1%: decreased body
weight change and food
consumption only
authors stated 1% as
threshold
2%: lowest dose tested
no NOEL at 2%
7600 ppm (ca 648 mg/kg
bw/d)
Rat, 4-5 weeks, SB
1.0% (ca 500 mg/kg bw/d) development of tolerance
to SB
Rat, 40 days, SB
1.5% (ca 750 mg/kg bw/d)
Rat, 10 weeks, SB
1.5% (ca 750 mg/kg bw/d)
Mouse, 10 days, SB
2.08% (ca 3012 mg/kg
bw/d)
Cat, 3, 4, 15, 23 days, BA 200 mg/kg bw/d (15 days) lowest NOEL*
Dog, up to 250 days, SB
Long-term studies
Rat, 72 weeks, BA
Rat, combined
chronic/reproduction
study, 4 generations, BA
Rat, carcinogenicity
study, 18-24 months, SB
Mouse, carcinogenicity,
life-long, drinking water,
SB
Reference
Kreis et al., 1967
Fanelli & Halliday, 1963
Bio-Fax, 1973
Harshbarger, 1942
Griffith, 1929
Kramer & Tarjan, 1962
Fujitani, 1993
Bedford & Clarke, 1972
800 mg/kg bw/d
NOEL for the most
sensitive dog
Rost et al., 1913
no NOEL at 1.5% (ca
1125 mg/kg bw/d)
1% (ca 750 mg/kg bw/d)
this dose tested only
Marquardt, 1960
2% (ca 1000 mg/kg bw/d)
2% in the drinking water
(ca 120 mg/mouse/d)
significant prolongation of Kieckebusch & Lang,
life at 0.5%
1960
No evidence of
carcinogenicity at this
dose (highest dose tested)
No evidence of
carcinogenicity,
(only this dose tested)
Sodemoto & Enomoto,
1980
Toth, 1984
22 November 2000
Study
NOEL
Remark
Reference
Developmental toxicity studies
Rat, appl. at day 9 of
510 mg/kg bw/d
only this dose tested
Kimmel, 1971
gestation, BA
Rat, appl. during whole
Onodera et al., 1978
gestation, SB
Crane & Lachance, 1985
gestation, SB
BA: benzoic acid; SB: sodium benzoate
* This investigation on one species with a peculiar metabolism, performed without a guideline is not suitable for
deriving a reference dose.
Neurotoxicity
Neurotoxicity studies including testing of delayed neurotoxicity according to current
guidelines are not available. They are not indicated by results in other studies. In one study
examining the neuroexcitation potential of benzoic acid no neuroexcitation or changes in EEG
were found.
Further data
It would be beyond the scope of this monograph to refer to the multitude of studies biochemical studies, certain biological tests etc - with benzoic acid/benzoates.
Computer-optimized molecular parametric analysis of chemical toxicity (“COMPACT”)
indicated benzoic acid as being a potential substrate of cytochrome P450 IIE. Because the
detoxication of benzoic acid/benzoates requires glycine, ATP and coenzyme A, metabolic
processes in which these physiological substances are involved might be affected by
benzoates. Benzoate did not uncouple the oxidative phosphorylation from respiration at
concentrations of 0.5 to 2.0 mmolar in isolated rat liver mitochondria.
Medical data
In man, the tolerance for benzoic acid/benzoates appears to vary in a wide range. Volunteers
tolerated oral doses of 3 to 42 g at single administration and doses of 0.5 to 6 g per day in
subacute studies. However, in two classic experiments, symptoms of discomfort were reported
at lower doses already.
Poisoning with benzoates at excessive doses is comparable to salicylate poisoning which is
related to disturbances in the acid-base equilibrium rather than to tissue damage.
Benzoic acid was therapeutically used for the treatment of rheumatic arthritis (4 to 25 g per
day) and is now administered (125 to 500 mg/kg bw/day) to patients suffering from different
forms of hyperammonemia.
Benzoic acid and its salts are known to cause pseudoallergic reactions (e.g. urticaria, asthma
and rhinitis) which mimic signs and symptoms of allergic disorders but without underlying
immunologic mechanisms, therefore also termed as non-immune immediate contact reactions
(NIICRs). In the general population, 0.003% to 0.15% (estimated) react sensitively to
pseudoallergic substances including benzoic acid/benzoates in food. Sensitivity to benzoates
in cosmetics or at occupational exposure was occasionally reported too.
In a maximization test - developed for humans - benzoic acid and related compounds did not
show a sensitization reaction in volunteers.
Intensive testing (skin tests and oral provocation tests) has been carried out with benzoates in
patients with a known or suspected sensitivity to pseudoallergic (or allergic) substances. The
number of patients reacting and the strength of reaction depend on a variety of factors as the
22 November 2000
kind of test, the study design, the number of patients and the criteria for judging the reactions.
Therefore an overall frequency of positive reactions in these tests cannot be given.
2.3.2 ADI
Considering the toxicological profile of benzoic acid and benzoates, a risk for the consumer in
terms of acute toxicity, organtoxicity, genotoxicity, carcinogenicity and reproductive/
developmental toxicity is not discernable. There is no evidence of bioaccumulation.
According to the principles of Annex VI to Directive 91/414 EEC, the acceptable daily intake
should be established on the basis of the highest dose at which no adverse effect is observed
(NOAEL) in relevant studies in the most sensitive species.
be derived from all relevant short-term, chronic toxicity/carcinogenicity and
reproduction/developmental studies on rats together since no single study according to a
current test guideline is available. Considering the overall low toxicity of benzoic acid and
benzoates, an assessment factor of 100 is proposed and an ADI value of 5.0 mg/kg bw/d is
calculated.
The ADI derived in this monograph is in agreement with the ADI of JECFA (FAO, WHO
1974, 1996).
2.3.3 ARfD (acute reference dose)
Benzoic acid and its salts are widely spread natural compounds in the environment. No
residues in harvest products occur from the intended use. There is no relevant exposure of
operators, bystanders and workers. Therefore allocation of an ARfD is not nessecary.
2.3.4 AOEL
According to the principles of Annex VI to Directive 91/414 EEC, the proposed acceptable
operator exposure level should be established on the basis of the highest dose at which no
adverse effect is observed (NOAEL) in relevant studies in the most sensitive species.
For the risk assessment of the user, applicator and producer as well as for the calculation of
the AOEL, the results of the short-term toxicity and/or reproduction/developmental toxicity
studies are considered to be most relevant.
current test guideline is available.
Due to the high level of gastrointestinal absorption, an additional correction factor is not
required.
Considering the overall low toxicity of benzoic acid and benzoates, an assessment factor of
100 is proposed and a systemic AOEL of 5.0 mg/kg bw/d is calculated.
22 November 2000
2.3.5 Drinking water limit
The determination of a MAC value is not necessary, because according to Directive
91/414/EC only the ADI and AOEL values have to be determined. Therefore, the
establishment of a maximum admissible concentration for drinking water from an ADI value
is not yet confirmed by a harmonized EU proposal. In addition to that, the maximum
admissible concentration of an active substance is 0.1 µg/l, as established by the Directive
89/778/EEC.
2.3.6 Impact on human or animal health arising from exposure to the active substance
or to impurities contained in it
According to the toxicological properties of benzoic acid, harmful effects on the health of
operators, bystanders, workers or consumers are not to be expected if the preparation is used
in accordance with good plant protection practice. The available data for benzoic
acid/benzoates do not support any evidence of genotoxic, carcinogenic and the fertility or
development damaging properties of the active substance.
Benzoic acid and its salts are widely spread natural compounds in the environment. From the
use of benzoic acid as disinfectant in horticulture, residues in harvest products do not occur.
Any additional exposure of the general population can be excluded and a risk assessment for
consumers is not necessary.
For the intended use of Menno-Florades, it was tried to estimate a possible operator exposure.
Although benzoic acid is assumed to be absorbed dermally to a high extend, the results using
parts of the German model as well as the EASE model for workplace assessment, indicate
exposures clear below the AOEL even if no PPE is worn. Nevertheless, taking into account
the relatively high intake of benzoic acid from non pesticide sources and the possible local
effects, PPE should be used when handling the undiluted product to minimize the exposure. In
view of the recommended uses, it is not likely that bystanders will be exposed to relevant
quantities.
acid/benzoates. If these are the causative substances in their individual case they should avoid
contact with them.
In view of the recommended uses and application techniques, harmful effects on the health of
domestic or wild animals are not to be expected.
2.4 Residues
2.4.1 Definition of the residues relevant to MRLs
Benzoic acid is applied as a disinfectant for deposit areas and gardening tools in floriculture
and horticulture. Neither plants nor soil will be treated with the compound. Since there are no
residues to be monitored, a residue definition is not necessary.
22 November 2000
2.4.2 Residues relevant to consumer safety
Due to its use as a disinfectant, no residues of benzoic acid will occur in plants (cf. 2.4.1). The
field of use covers ornamentals rather than edible crops. Since benzoic acid is also approved
and extensively used as a preservative for food, its application in floriculture and horticulture
does not present a risk to consumers’ health.
2.4.3 Residues relevant to worker safety
A residue definition relevant to worker safety is not necessary (see 2.4.1).
acid/benzoates. If these are the causative substances in their individual case they should avoid
contact with them.
2.4.4 Proposed EU MRLs and compliance with existing MRLs
As mentioned above, there will be no dietary exposition to benzoic acid due to its use in
floriculture and horticulture. Setting of MRLs is therefore not necessary for this compound.
2.4.5 Proposed EU import tolerances and compliance with existing import tolerances
There are no EU Import tolerances applied for by the notifier.
2.4.6 Basis for differences, if any, in conclusion reached having regard to established
or proposed CAC MRLs
No CAC MRLs are set for benzoic acid.
2.5 Fate and behaviour in the environment
2.5.1 Definition of the residues relevant to the environment
As outlined in the chapters considering fate and behaviour in the environment the active
substance is naturally occurring in the environment. Contamination of soil following
application according to the GAP is not expectecd. Benzoic acid is readily biodegradable in
aquatic systems. Furthermore, it will not be possible to discriminate by residue analytical
means between the species applied as a plant protection product and those due to industrial
emissions (e.g. production/processing of benzoic acid and phthalic acid anhydride) or natural
occurence.
With regard to toxicity to human beings and ecotoxicology there are no specific concerns
arising from the fate and behaviour of benzoic acid in soil, water and air following application
according to the GAP. It is therefore concluded that a relevant residue of concern in the
environmental compartments needs not to be defined.
22 November 2000
2.5.2 Fate and behaviour in soil
Taking into account the kind of application the contamination of soil following use as a disinfectant of equipment (watering of surfaces on which plants in pots or other culture vessels
stand, soaking of culture vessels, dipping of tools like knives etc.) according to the GAP is not
expected.
The active substance is a compound naturally occurring in soil and plants. In soil under aerobic conditions rapid degradation was reported. Benzoic acid can be regarded as readily biodegradable.
Benzoic acid has to be assessed as mobile in soil. Since contamination of soil is not expected
and the active substance is a natural component of soils which is readily degraded a risk of
ground water contamination resulting from application of benzoic acid according to the GAP
is not expected.
arising from the fate and behaviour of benzoic acid in soil following application according to
the GAP. It is therefore deemed acceptable that studies addressing route and rate of degradation in soil were not submitted and further data requirements with regard to fate and behaviour
of the active substance in soil are waived.
2.5.3 Fate and behaviour in water
The active substance is a compound naturally occurring in soil and plants. Apart from its natural occurrence findings of benzoic acid in the aquatic environment may be due to industrial
and other anthropogenic emissions.
The active substance can be regarded as readily biodegradable. Easy degradation is reported
from several studies some of them using special conditions like degradation under anaerobic
conditions, degradation in sea water or rain water. Due to this property sodium benzoate can
be used as reference compound in order to check the activity of the inoculum for the investigation of ready biodegradability of chemical substances according to OECD guideline 301.
As the plant protection product is applied as a disinfectant of horticulture equipment (watering
of surfaces on which plants in pots or other culture vessels stand, soaking of culture vessels,
dipping of tools like knives etc.) a direct contamination of surface water via spray drift or runoff can be excluded. Thus, the only possible entry route into water bodies is via disposal into
waste water. It can be anticipated that rapid degradation as well as considerable dilution in the
waste water conduit and in the waterbody receiving effluent from waste water treatment will
lead to a decline of the concentration of benzoic acid by several orders of magnitude. Roughly
estimated, the environmental concentration expected in aquatic ecosystems (river receiving
effluent from waste water treatment) will be in the range << 100 µg/l which will add to benzoic acid due to natural or non-agricultural anthropogenic sources.
Taking account of the kind of application and the ready biodegradability of the active substance it can be assumed that the use of the plant protection product Menno Florades according to the GAP will not lead to an additional relevant load of benzoic acid in the aquatic environment. With regard to toxicity to human beings and ecotoxicology there are no specific concerns arising from the fate and behaviour of benzoic acid in water following application according to the GAP. It is therefore deemed acceptable that studies addressing route and rate of
degradation in aquatic systems were not submitted and that the data requirements with regard
to fate and behaviour of the active substance in water are waived.
22 November 2000
2.5.4 Fate and behaviour in air
The plant protection product Menno Florades is used as a disinfectant of equipment (watering
dipping of tools like knives etc.). Taking into account the type of formulation and the kind of
application contamination of air following use according to the GAP is not expected. It is
therefore deemed acceptable that further data requirements with regard to fate and behaviour
of the active substance in air are waived.
2.6 Effects on non-target species
2.6.1 Effects on terrestrial vertebrates
Benzoic acid is used for the disinfection of culture vessels and equipment on deposit areas.
Therefore mammals and birds will normally not come into contact with the active substance.
In exceptional cases individuals may traverse treated spots respectively perch on treated
objects and thus are subject to dermal exposure. However the ready-to-use fluid contains only
3.6 g as/l and thus the magnitude of exposure is low. Taking into account that benzoic acid as
well as the preparation Menno-Florades is of low toxicity to mammals (oral and dermal LD50
>2000 mg/kg bw in rats) there is no risk to mammals and birds.
2.6.2 Effects on aquatic species
According to the intended uses the formulated product Menno-Florades (9 % benzoic acid)
will be used exclusively in glass houses. A contamination of surface water therefore is
unlikely to occur. The test results with fish, daphnia and algae indicate a low toxicity.
Furthermore, benzoic acid is a natural compound of the environment. No adverse effects have
been reported so far in the literature. The overall risk to aquatic organisms is considered to be
low.
2.6.3 Effects on bees and other arthropod species
2.6.3.1 Effects on bees
Because of the application of the product Menno Florades (desinfection of mats, vessels and
gardening equipment) an exposure of bees to the active substance benzoic can be excluded.
2.6.3.2 Effects on other arthropod species
The intended uses for formulated benzoic acid cover disinfection of culture vessels and
equipment on deposit areas, only. Therefore the exposure of non-target arthropods to the
active substance is not likely and consequently unacceptable risks to non-target arthropods are
most unlikely to occur. No data are required.
22 November 2000
2.6.4 Effects on earthworms and other soil macro-organisms
Therefore earthworms and other non-target macro-organisms will normally not come into
contact with the active substance.
2.6.5 Effects on soil micro-organisms
Because of the intended uses of benzoic acid soil microorganisms will normally not come into
contact with the active substance. Therefore, no studies on effects on activities of soil
microorganisms are required.
2.6.6 Effects on other non-target organisms (flora and fauna)
Therefore non-target terrestrial plants will normally not come into contact with the active
substance.
2.6.7 Effects on biological methods of sewage treatment
A study has not been provided. However, it can be assumed from published literature, that
benzoic acid serves as substrate to the microflora. Data available from the national
authorisation procedure indicate a 3h-EC50 > 1000 mg/l (pH 7.5).
22 November 2000
2.7 Overall conclusion (metabolism schemes)
2.7.1 Toxicology (laboratory animals)
Figure B.6.1-1
Conjugation reactions of Benzoic acid
COOH
Gly
Benzoic acid
ATP
CoA
H 2O
Gly
C
O
Hippuric acid
Gluc
UTP
H 2O
Gluc
C
O
Benzoyl-glucuronic acid
Gly : Glycine
Gluc: Glucuronic acid
Abbildung 2.7-1:
2.7.2 Residues (plant, plant products, livestock animals)
Not applicable
2.7.3 Fate and behaviour in the environment (soil, water, air)
Not relevant
Appendix 1
Benzoic acid
Standard Terms and Abbreviations
Appendix 1 – Standard Terms and Abbreviations
22 November 2000
2.8 Appendices
2.8.1 Appendix I: Standard terms and abbreviations
Part 1 Technical Terms
A
ACH
AChE
ADI
ADP
AE
AFID
A/G
ai
ALD50
ALT
AMD
ANOVA
AOEL
AP
approx
ARC
ARfD
as
AST
ASV
ATP
BCF
bfa
BOD
bp
BSAF
BSE
BSP
Bt
Bti
Btk
Btt
BUN
bw
c
°C
CA
CAD
CADDY
ampere
acetylcholine
acetylcholinesterase
acceptable daily intake
adenosin diphosphate
acid equivalent
alkali flame-ionization detector or detection
albumin/globulin ratio
active ingredient
approximate median lethal dose, 50 %
alanine amitrotransferase (SGPT)
automatic multiple development
analysis of variance
acceptable operator exposure level
alkaline phosphatase
approximate
anticipated residue contribution
acute reference dose
active substance
aspartate aminotransferase (SGOT)
air saturation value
adenosine triphosphate
bioconcentration factor
body fluid assay
biological oxygen demand
boiling point
biota-sediment accumulation factor
bovine spongiform encephalopathie
bromosulfophthalein
bacillus thuringiensis
bacillus thuringiensis israelensis
bacillus thuringiensis kurstaki
bacillus thuringiensis tenebrionis
blood urea nitrogen
body weight
centi- (x 10-2)
degree celsius (centigrade)
controlled atmosphere
computer aided design
computer aided dossier and data supply (an electronic dossier
interchange and archiving format)
cd
CDA
cDNA
CEC
cf
CFU
ChE
CI
CL
cm
CNS
COD
CPK
cv
Cv
CXL
d
DES
DFR
DMSO
DNA
dna
DO
DOC
dpi
DRES
DT50
DT90
dw
DWQG
ε
EC50
ECD
ECU
ED50
EDI
ELISA
e-mail
EMDI
EPMA
ERC
ERL
F
F0
F1
F2
FIA
FID
FOB
22 November 2000
candela
controlled drop(let) application
complementary DNA
cation exchange capacity
confer, compare to
colony forming units
cholinesterase
confidence interval
confidence limits
centimetre
central nervous system
chemical oxygen demand
creatinine phosphatase
coeficient of variation
ceiling value
Codex Maximum Residue Limit (Codex MRL)
day
diethylstilboestrol
dislodgeable foliar residue
dimethylsulfoxide
deoxyribonucleic acid
designated national authority
dissolved oxygen
dissolved organic carbon
days pot inoculation
dietary risk evaluation system
period required for 50 percent dissipation (define method of estimation)
dry weight
drinking water quality guidelines
decadic molar extinction coefficient
effective concentration
electron capture detector
European currency unit
median effective dose
estimated daily intake
enzyme linked immunosorbent assay
electronic mail
estimated maximum daily intake
electron probe micro analysis
environmentally relevant concentration
extraneous residue limit
field
parental generation
filial generation, first
filial generation, second
fluorescence immuno assay
flame ionization detector
functional observation battery
fp
FPD
FPLC
g
G
GAP
GC
GC-EC
GC-FID
GC-MS
GC-MSD
GEP
GFP
GGT
GI
GIT
GL
GLC
GLP
GM
GMO
GMM
GPC
GPPP
GPS
GSH
GV
h
H
ha
Hb
HCG
Hct
HDT
hL
HEED
HID
HPAEC
HPLC
HPLC-MS
HPPLC
HPTLC
HRGC
Hs
Ht
I
I50
IC50
22 November 2000
freezing point
flame photometric detector
fast protein liquid chromatography
gram
glasshouse
good agricultural practice
gas chromatography
gas chromatography with electron capture detector
gas chromatography with flame ionization detector
gas chromatography-mass spectrometry
gas chromatography with mass-selective detection
good experimental practice
good field practice
gamma glutamyl transferase
gastro-intestinal
gastro-intestinal tract
guideline level
gas liquid chromatography
good laboratory practice
geometric mean
genetically modified organism
genetically modified micro-organism
gel-permeation chromatography
good plant protection practice
global positioning system
glutathion
granulosevirus
hour(s)
Henry`s Law constant (calculated as a unitless value) (see also K)
hectare
haemoglobin
human chorionic gonadotropin
haematocrit
highest dose tested
hectolitre
high energy electron diffraction
helium ionization detector
high performance anion exchange chromatography
high pressure liquid chromatography or high performance liquid
chromatography
high pressure liquid chromatography – mass spectrometry
high pressure planar liquid chromatography
high performance thin layer chromatography
high resolution gaschromatography
Shannon-Weaver index
haematocrit
indoor
inhibitory dose, 50 %
median immobilization concentration
ICM
ID
IEDI
IGR
im
inh
ip
IPM
IR
ISBN
ISSN
iv
IVF
k
K
Kads
Kdes
Koc
Kom
kg
L
LAN
LASER
LBC
LC
LC-MS
LC50
LCA
LCLo
LC-MS-MS
LD50
LDLo
LDH
LOAEC
LOAEL
LOD
LOEC
LOEL
LOQ
LPLC
LSC
LSD
LSS
LT
m
M
µm
MC
22 November 2000
integrated crop management
ionization detector
international estimated daily intake
insect growth regulator
intramuscular
inhalation
intraperitoneal
integrated pest management
infrared
international standard book number
international standard serial number
intravenous
in vitro fertilization
kilo
Kelvin or Henry`s Law constant (in athmospheres per cubic meter per
mole) (see also H)13
adsorption constant
apparent desorption coefficient
organic carbon adsortion coefficient
organic matter adsorption coefficient
kilogram
litre
local area network
light amplification by stimulated emission
loosely bound capacity
liquid chromatography
liquid chromatography-mass spectrometry
lethal concentration, median
life cycle analysis
lethal concentration low
liquid chromatography with tandem mass spectrometry
lethal dose, median; dosis letalis media
lethal dose low
lactate dehydrogenase
lowest observable adverse effect concentration
lowest observable adverse effect level
limit of determination
lowest observable effect concentration
lowest observable effect level
limit of quantification (determination)
low pressure liquid chromatography
liquid scintillation counting or counter
least squared denominator multiple range test
liquid scintillation spectrometry
lethal threshold
metre
molar
micrometer (micron)
moisture content
MCH
MCHC
MCV
MDL
MFO
µg
mg
MHC
min
mL
MLT
MLD
mm
mo
mol
MOS
mp
MRE
MRL
mRNA
MS
MSDS
MTD
n
NAEL
nd
NEDI
NEL
NERL
ng
nm
NMR
no
NOAEC
NOAEL
NOEC
NOED
NOEL
NOIS
NPD
NPV
NR
NTE
OC
OCR
ODP
ODS
OM
op
mean corpuscular haemoglobin
mean corpuscular haemoglobin concentratin
mean corpuscular volume
method detection limit
mixed function oxidase
microgram
milligram
moisture holding capacity
minute(s)
millilitre
median lethal time
minimum lethal dose
millimetre
month(s)
Mol
margin of safety
melting point
maximum residue expected
maximum residue limit or level
messenger ribonucleic acid
mass spectrometry
material safety data sheet
maximum tolerated dose
normal (defining isomeric configuration)
no adverse effect level
not detected
no effect daily intake (mg/kg body wt/day)
no effect level
no effect residue level
nanogram
nanometer
nuclear magnetic resonance
number
no observed adverse effect concentration
no observed adverse effect level
no observed effect concentration
no observed effect dose
no observed effect level
notice of intend to suspend
nitrogen-phosphorus detector or detection
nuclear polyhedrosis virus
not reported
neurotoxic target esterase
organic carbon content
optical character recognition
ozone-depleting potential
ozone-depleting substances
organic matter content
organophosphorus pesticide
22 November 2000
Pa
PAD
2-PAM
pc
PC
PCV
PEC
PECA
PECS
PECSW
PECGW
PED
pH
PHED
PHI
PIC
pic
PIXE
pKa
PNEC
po
Pow
POP
ppb
PPE
ppm
ppp
ppq
ppt
PSP
PrT
PRL
PT
PTDI
PTT
QSAR
r
r2
RBC
REI
Rf
RfD
RH
RL50
RNA
RP
rpm
rRNA
RRT
22 November 2000
pascal
pulsed amperometric detection
2-pralidoxime
paper chromatography
personal computer
haematocrit (packed corpuscular volume)
predicted environmental concentration
predicted environmental concentration in air
predicted environmental concentration in soil
predicted environmental concentration in surface water
predicted environmental concentration in ground water
plasma-emissions-detektor
pH-value
pesticide handler`s exposure data
pre-harvest interval
prior informed consent
phage inhibition capacity
proton inducted X-ray emission
negative logarithm (to the base 10) of the dissociation constant)
predicted no effect concentration
by mouth (per os)
partition coefficient between n-octanol and water
persistent organic pollutants
parts per billion (10-9)
personal protective equipment
parts per million (10-6)
plant protection product
parts per quadrillion (10-24)
parts per trillion (10-12)
phenolsulfophthalein
prothrombin time
practical residue limit
prothrombin time
provisional tolerable daily intake
partial thromboplastin time
quantitative structure-activity relationship
correlation coefficient
coefficient of determination
red blood cell
restricted entry interval
ratio of fronts
reference dose
relative humidity
residual lifetime
ribonucleic acid
reversed phase
reversed phase material
ribosomal ribonucleic acic
relative retention time
RSD
s
SAC
SAP
SAR
SBLC
sc
sce
SD
SE
SEM
SEP
SF
SFC
SFE
SIMS
SOP
sp
SPE
SPF
spp
sq
SSD
SSMS
STEL
STMR
t
t1/2
T3
T4
TADI
TBC
TCD
TCLo
TID
TDLo
TDR
TER
TERI
TERST
TERLT
tert
TEP
TGGE
TIFF
TLC
Tlm
TLV
TMDI
relative standard deviation
second
strong adsorption capacity
serum alkaline phosphatase
structure/activity relationship
shallow bed liquid chromatography
subcutaneous
sister chromatid exchange
standard deviation
standard error
standard error of the mean
standard evaluation procedure
safety factor
supercritical fluid chromatography
supercritical fluid extraction
secondary ion mass spectroscopy
standard operating procedures
species (only after a generic name)
solid phase extraction
specific pathogene free
subspecies
square
sulfur specific detector
spark source mass spectrometry
short term exposure limit
supervised trials median residue
tonne (metric ton)
half-life (define method of estimination)
tri-iodothyroxine
thyroxine
temporary acceptable daily tntake
tightly bound capacity
thermal conductivity detector
toxic concentration low
thermionic detector, alkali flame detector
toxic dose low
time domain reflectrometry
toxicity exposure ration
toxicity exposure ration for initial exposure
toxicity exposure ration following repeated exposure
toxicity exposure ration following chronic exposure
tertiary (in a chemical name)
typical end-use product
temperature gradient gel electrophoresis
tag image file format
thin layer chromatography
median tolerance limit
threshold limit value
theoretical maximum daily intake
22 November 2000
TMRC
TMRL
TOC
Tremcard
tRNA
TSH
TWA
UDS
UF
ULV
UV
v/v
WBC
wk
wt
w/v
w/w
XRFA
yr
<
≤
>
≥
22 November 2000
theoretical maximum residue contribution
temporary maximum residue limit
total organic chlorine
Transport emergency card
transfer riboncleic acid
thyroid stimulating hormone (thyrotropin)
time weighted average
unscheduled DNA synthesis
uncertainly factor (safety factor)
ultra low volume
ultraviolet
volume ratio (volume per volume)
white blood cell
week
weight
weight per volume
weight per weight
X-ray fluorescence analysis
year
less than
less than or equal to
greater than
greater than or equal to
Part 2 Organisations and Publications
ACPA
ACTM
BA
BART
CA
CAB
CAC
CAS
CCFAC
CCGP
CCPR
CCRVDF
CE
CIPAC
COREPER
EC
ECB
ECCA
ECDIN
ECDIS
American Crop Protection Association
American Society for Testing and Materials
Biological Abstracts (Philadelphia)
Beneficial Arthropod Registration Testing Group
Chemical Abstracts
Centre for Agriculture and Biosciences International
Codex Alimentarius Commission
Chemical Abstracts Service
Codex Committee on Food Additives and Contaminants
Codex Committee on General Principles
Codex Committee on Pesticide Residues
Codex Committee on Residues of Veterinary Drugs in Food
Council of Europe
Collaborative International Pesticides Analytical
Council Ltd
Comite des Representants Permanents
European Commission
European Chemical Bureau
European Crop Care Association
Environmental Chemicals Data and Information of the European
Communities
European Environmental Chemicals Data and Information System
ECE
ECETOC
ECLO
ECMWF
ECPA
EDEXIM
EHC (number)
EHCD
EINECS
ELINCS
EMIC
EPA
EPO
EPPO
ESCORT
EU
EUPHIDS
EUROPOEM
FAO
FOCUS
FRAC
GATT
GAW
GCOS
GCPF
GEDD
GEMS
GIEWS
GIFAP
GRIN
HRAC
IARC
IATS
IBT
ICBB
ICBP
ICES
ICPBR
ILO
IMO
IOBC
IPCS
IRAC
IRC
ISCO
ISO
IUPAC
22 November 2000
Economic Commission for Europe
European Chemical Industry Ecology and Toxicology Centre
Emergency Centre for Locust Operations
European Centre for Medium Range Weather Forecasting
European Crop Protection Association
European Database on Export an Import of Dangerous Chemicals
Environment Health Criteria (number)
Environmental Health Criteria Document
European Inventory of Existing Commercial Chemical Substances
European List of New Chemical Substances
Environmental Mutagens Information Centre
Environmental Protection Agency
European Patent Office
European and Mediterranean Plant Protection Organization
European Standard Characteristics of Beneficials Regulatory Testing
European Union
European Pesticide Hazard Information and Decision Support System
European Predictive Operator Exposure Model
Food and Agriculture Organization of the UN
Forum for the Co-ordination of Pesticide Fate Models and their Use
Fungicide Resistance Action Committee
General Agreement on Tariffs and Trade
Global Atmosphere Watch
Global Climate Observing System
Global Crop Protection Federation (formerly known as GIFAP)
Global Environmental Data Directory
Global Environmental Monotoring System
Global Information and Early Warning System for Food and Agriculture
Groupement International des Association Nationales de Fabricants de
Produits Agrochimiques (now known as GCPF)
Germplasm Resources Information Network
Herbicide Resistance Action Committee
International Agency for Research on Cancer
International Academy of Toxicological Science
Industrial Bio-Test Laboratories
International Commissin of Bee Botany
International Council for Bird Preservation
International Council for the Exploration of the Seas
International Commissin for Plant-Bee Relationships
International Labour Organization
International Maritime Organisation
International Organization for Biological Control of noxious Animals
and Plants
International Programme on Chemical Safety
Insecticide Restistance Action Committee
International Rice Commission
International Soil Conservation Orginazation
International Organization for Standardization
International Union of Pure and Applied Chemistry
JECFA
JFCMP
JMP
JMPR
NATO
NAFTA
NCI
NCTR
NGO
NTP
OECD
OLIS
PAN
RNN
RTECS
SCPH
SETAC
SI
SITC
TOXLINE
UN
UNEP
WCDP
WCP
WCRP
WFP
WHO
WTO
WWF
22 November 2000
FAO/WHO Joint Expert Committee on Food Additives
Joint FAO/WHO Food and Animal Feed Contamination Monitoring
Programme
Joint Meeting on Pesticdes (WHO/FAO)
Joint Meeting of the FAO Panel of Experts on Pesticide Residues in
Food and the Environment and the WHO Expert Group on Pesticide
Residues (Joint Meeting on Pesticide Residues)
North Atlantic Treaty Organisation
North American Free Trade Agreement
National Cancer Institute (USA)
National Center for Toxicological Research (USA)
non-governmental organization
National Toxicology Programme (USA)
Organization for Economic Cooperation and Development
On-line Information Service of OECD
Pesticides Action Network
Re-registration Notification Network
Registry of Toxic Effects of Chemical Substances (USA)
Standing Committee on Plant Health
Society of Environmental Toxicology and Chemistry
Systeme International d`Unites
Standard International Trade Classification
Toxicology Information On-line
United Nations
United Nations Environment Programme
World Climate Data Programmme
Workd Climate Programme
World Climate Research Programme
World Food Programme
World Health Organization
World Trade Organization
World Wide Fund for Nature
Appendix 2
Benzoic acid
Specific Terms and Abbreviations
Appendix 2 -Specific Terms and Abbreviations
2.8.2 Appendix II: Specific terms and abbreviations
BA
EbC50
ErC50
PAS
SB
TAS
benzoic acid
effective concentration (biomass)
effective concentration (growth rate)
pure active substance
sodium benzoate
technical active substance
22 November 2000
Appendix 3
Benzoic acid
List of End-Points
Appendix 3 – List of End Points
22 November 2000
2.8.3 Appendix III: Listing of end points
2.8.3.1 Appendix III.1: Chapter 1(identity, physical and chemical properties, details of
uses, further information, classification and labelling)
Active substance (ISO Common Name)
benzoic acid
Function (e.g. fungicide)
fungicide, bactericide, virucide, viroicide
Rapporteur Member State
Germany
Identity (Annex IIA, point 1)
Chemical name (IUPAC)
benzoic acid
Chemical name (CA)
benzoic acid
CIPAC No
622
CAS No
65-85-0
EEC No (EINECS or ELINCS)
EINECS: 2006182
FAO Specification (including year of publication)
not available
Minimum purity of the active substance as manu-
99 %
factured (g/kg)
Identity of relevant impurities (of toxicological,
no relevant impurities
environmental and/or other significance) in the
active substance as manufactured (g/kg)
Molecular formula
C7H6O2
Molecular mass
122.12
Structural formula
O
OH
22 November 2000
Physical-chemical properties (Annex IIA, point 2)
Melting point (state purity)
122.4 °C
Boiling point (state purity)
249.2 °C
Temperature of decomposition
Begin of sublimation at > 100 °C
at app. 150 °C formation of anhydride
at app. 370 °C decarboxylation
Appearance (state purity)
white odourless crystalline solid
Relative density (state purity)
1.312 g/cm3
Surface tension
31 ± 1.3 mN/m (130 °C)
Vapour pressure (in Pa, state temperature)
3
-1
0.11 – 0.53 Pa (20 °C)
Henry’s law constant (Pa m mol )
0.0046 – 0.022 Pa m³ mol-1 (20 °C)
Solubility in water (20 °C)
pH 2.9:
Solubility in organic solvents (20 °C)
2.9 g/l
pH 5:
5 g/l
pH 9:
15 g/l
acetone:
556 g/kg
benzene:
121.7 g/kg
CCl4:
chloroform:
41.4 g/kg
150.2 g/kg
ethanol:
584 g/kg
ethyl ether
408 g/kg
hexane:
9.4 g/kg (17 °C)
methanol:
715 g/kg (23 °C)
toluene:
106 g/kg
Partition co-efficient (log POW) (state pH and tem-
log Pow = 1.87 (The effect of pH on the n-octanol/water
perature)
partition coefficient was not determined because the
pKa-value is over 2)
Hydrolytic stability (DT50) (state pH and tempera-
stable
ture)
Dissociation constant
pKa = 4.2
UV/VIS absorption (max.) (if absorption > 290 nm
not relevant
state ε at wavelength)
Photostability (DT50) (aqueous, sunlight, state pH)
not relevant
Quantum yield of direct phototransformation in
not relevant
water at λ > 290 nm
Flammability
Ignition temperature in air: 573 °C
Explosive properties
not explosive
22 November 2000
Crop and/
or situation
(a)
Member
State
or
Country
Product
name
F
G
or
I
(b)
Pests or
Group of pests
controlled
(c)
Formulation
Type
Application
(d-f)
Conc
of as
(i)
method
kind
(f-h)
growth
stage &
season
(j)
after the
last use
number
min max
(k)
1
interval
between
applications
(min)
n.a.
Surfaces
Germany
Menno
Florades
G
+
I
Virus
(ArMV, PFBV,
PLCV, PLPV,
TBRV, TSWV)
SL
90 g/l
watering
Surfaces
Germany
Menno
Florades
G
+
I
Virus
(TMV, ToMV)
SL
90 g/l
watering
after the
last use
1
Culture vessels
Germany
Menno
Florades
G
+
I
Virus
(ArMV, PFBV,
PLCV, PLPV,
TBRV, TSWV)
SL
90 g/l
soaking
after the
last use
Culture vessels
Germany
Menno
Florades
G
+
I
Virus
(TMV, ToMV)
SL
90 g/l
soaking
Equipment (eg
knives)
Germany
Menno
Florades
G
+
I
Virus
(ArMV, PFBV,
PLCV, PLPV,
TBRV, TSWV)
SL
90 g/l
Equipment (eg
knives)
Germany
Menno
Florades
G
+
I
Virus
(TMV, ToMV)
SL
90 g/l
kg as/hl
min max
water
l/ha
min max
PHI
(days)
(l)
Remarks
(m)
kg as/ha
min max
0.09 kg
(1 % solution)
2000 20000
1.8 - 18 kg n.a.
watering (16 h)
ebb/flood benches:
0.2 l/m2
other surfaces:
2.0 l/m2
n.a.
0.36 kg
(4 % solution)
2000 20000
7.2 - 72 kg n.a.
watering (16 h)
ebb/flood benches:
0.2 l/m2
other surfaces:
2.0 l/m2
n.a.
n.a.
0.09 kg
(1 % solution)
n.a.
n.a.
n.a.
soaking (16 h)
after the
last use
n.a.
n.a.
0.36 kg
(4 % solution)
n.a.
n.a.
n.a.
soaking (16 h)
dipping
before
the use
n.a.
n.a.
0.18 kg
(2 % solution)
n.a.
n.a.
n.a.
dipping
(3 minutes)
dipping
before
the use
n.a.
n.a.
0.27 kg
(3 % solution)
n.a.
n.a.
n.a.
dipping
(3 minutes)
Crop and/
or situation
(a)
Member
State
or
Country
Product
name
F
G
or
I
(b)
Pests or
Group of pests
controlled
(c)
22 November 2000
Formulation
Type
Application
(d-f)
Conc
of as
(i)
method
kind
(f-h)
growth
stage &
season
(j)
after the
last use
number
min max
(k)
1
interval
between
applications
(min)
n.a.
Surfaces
Germany
Menno
Florades
G
+
I
Bacteria and fungi
SL
90 g/l
watering
Culture vessels
Germany
Menno
Florades
G
+
I
Bacteria and fungi
SL
90 g/l
soaking
after the
last use
n.a.
Equipment (eg
knives)
Germany
Menno
Florades
G
+
I
Bacteria and fungi
SL
90 g/l
dipping
before
the use
Equipment (eg
knives)
Germany
Menno
Florades
G
+
I
Viroids
SL
90 g/l
dipping
before
the use
kg as/hl
min max
water
l/ha
min max
PHI
(days)
(l)
Remarks
(m)
kg as/ha
min max
0.09 kg
(1 % solution)
2000 20000
1.8 - 18 kg n.a.
watering (16 h)
ebb/flood benches:
0.2 l/m2
other surfaces:
2.0 l/m2
n.a.
0.09 kg
(1 % solution)
n.a.
n.a.
n.a.
soaking (16 h)
n.a.
n.a.
0.09 kg
(1 % solution)
n.a.
n.a.
n.a.
dipping
(3 minutes)
n.a.
n.a.
0.09 kg
(1 % solution)
n.a.
n.a.
n.a.
dipping
(3 minutes)
(i) g/kg or g/l
Classification and proposed labelling (Annex IIA, point 10)
with regard to physical/chemical data
with regard to toxicological data
Xi, R 41
with regard to fate and behaviour data
-
with regard to ecotoxicological data
22 November 2000
22 November 2000
Appendix III.2: Chapter 2 (methods of analysis)
Analytical methods for the active substance (Annex IIA, point 4.1)
Technical as (principle of method)
RP HPLC (isocratic, Sperisorb 5 ODS, UV: 254 nm)
Impurities in technical as (principle of method)
Plant protection product (principle of method)
Analytical methods for residues (Annex IIA, point 4.2)
Food/feed of plant origin (principle of method and
Not relevant
LOQ for methods for monitoring purposes)
Food/feed of animal origin (principle of method and
Not relevant
LOQ for methods for monitoring purposes)
Soil (principle of method and LOQ)
Not relevant
Water (principle of method and LOQ)
Not relevant
Air (principle of method and LOQ)
Not relevant
Body fluids and tissues (principle of method and
Not relevant
LOQ)
22 November 2000
Appendix III.3: Chapter 3 (impact on human and animal health)
Bridging concept
BA and SB are widely spread natural compounds, a
constituent in many foodstuffs and used as preservative
in food, cosmetics and pharmaceuticals. Any additional
exposure of the general population from the intended
uses can be excluded.
Absorption, distribution, excretion and metabolism in mammals (Annex IIA, point 5.1)
Rate and extent of absorption
Rapid (peak plasma concentration within 1-2 h), nearly
complete (excretion up to 100%), human data
Distribution
Widely distributed
Potential for accumulation
No potential
Rate and extent of excretion
Depending on species (in man and rat 80-100% within 24
h)
Metabolism in animals
Completely metabolized in humans; conjugation with
glycine to hippuric acid (up to 100%) and glucuronic
acid to benzoyl-glucuronic acid (0-20%)
Toxicologically significant compounds (animals,
Parent material
plants and environment)
Acute toxicity (Annex IIA, point 5.2)
Rat LD50 oral
BA: ≥ 1700 mg/kg bw
SB: ≥ 2100 mg/kg bw
Rabbit LD50 dermal
BA: > 5000 mg/kg bw
Rat LC50 inhalation
BA: > 0.026 mg/l (1 h exposure to vapor)
Skin irritation
BA: Not irritating
SB: Not irritating
Eye irritation
BA: Severely irritating (R 41)
SB: Not irritating
Skin sensitization (test method used and result)
BA: Not sensitizing (M & K)
Short term toxicity (Annex IIA, point 5.3)
Target / critical effect
Liver, kidney, brain
Lowest relevant oral NOAEL / NOEL
Rat, all relevant studies: ca 500 mg/kg bw/d
Lowest relevant dermal NOAEL / NOEL
No data, not required
Lowest relevant inhalation NOAEL / NOEL
Genotoxicity (Annex IIA, point 5.4)
No genotoxic potential
22 November 2000
Long term toxicity and carcinogenicity (Annex IIA, point 5.5)
Target / critical effect
No target identified
Lowest relevant NOAEL / NOEL
Rat, all relevant studies: ca 500 mg/kg bw/d
Carcinogenicity
No carcinogenic potential
Reproductive toxicity (Annex IIA, point 5.6)
Reproduction target / critical effect
No reproductive effect at highest dose level tested (combined chronic/reproduction study, 4 generations)
Lowest relevant reproductive NOAEL / NOEL
Ca 750 mg/kg bw/d
Developmental target / critical effect
Abnormalities/malformations in eye, kidney and brain at
severe maternaltoxic doses
Lowest relevant developmental NOAEL / NOEL
Rat: ca 500 mg/kg bw/d
Neurotoxicity / Delayed neurotoxicity (Annex IIA, point 5.7)
Effect on brain only in one short-term study at one high
dose (1967, without guideline)
Other toxicological studies (Annex IIA, point 5.8)
Glycine, ATP and coenzyme A can be reduced by BA
and SB.
Medical data (Annex IIA, point 5.9)
Tolerance for BA, SB varies in a wide range (ca 3 to 42
g at single administration)
SB is therapeutically used, e.g. treatment of
hyperammonemia
0.003 to 0.15% of the general population react
sensitively to pseudoallergic substances in food (nonimmune immediate contact reactions, NIICRs)
No sensitization potential of BA and benzoates in a
maximization test developed for humans
Summary (Annex IIA, point 5.10)
Value
ADI
5 mg/kg bw
AOEL systemic
5 mg/kg bw
Study
Overall evaluation of short-term
Safety factor
100
and long-term studies, rat
Overall evaluation of short-term
and long-term studies, rat
Drinking water limit
Not allocated
not necessary
ARfD (acute reference dose)
Not allocated
not necessary
100
22 November 2000
Dermal absorption (Annex IIIA, point 7.3)
Default value: 100%
Acceptable exposure scenarios (including method of calculation)
Operator
Acceptable for proposed uses
Workers
Bystanders
2.8.3.2 Appendix III.4: Chapter 4 (residues)
Metabolism in plants (Annex IIA, point 6.1 and 6.7, Annex IIIA, point 8.1 and 8.6)
Plant groups covered
not applicable
Rotational crops
not applicable
Plant residue definition for monitoring
not applicable
Plant residue definition for risk assessment
not applicable
Conversion factor (monitoring to risk assessment)
not applicable
Metabolism in livestock (Annex IIA, point 6.2 and 6.7, Annex IIIA, point 8.1 and 8.6)
Animals covered
not applicable
Animal residue definition for monitoring
not applicable
Animal residue definition for risk assessment
not applicable
Conversion factor (monitoring to risk assessment)
not applicable
Metabolism in rat and ruminant similar (yes/no)
not applicable
Fat soluble residue: (yes/no)
not applicable
Residues in succeeding crops (Annex IIA, point 6.6, Annex IIIA, point 8.5)
...............................................................................
not applicable
Stability of residues (Annex IIA, point 6 introduction, Annex IIIA, point 8 introduction)
...............................................................................
not applicable
Residues from livestock feeding studies (Annex IIA, point 6.4, Annex IIIA, point 8.3)
Intakes by livestock ≥ 0.1 mg/kg diet/day:
Ruminant:
Poultry:
Pig:
yes/no
yes/no
yes/no
Muscle
not applicable
not applicable
not applicable
Liver
not applicable
not applicable
not applicable
Kidney
not applicable
not applicable
not applicable
Fat
not applicable
not applicable
not applicable
Milk
not applicable
not applicable
not applicable
Eggs
not applicable
not applicable
not applicable
22 November 2000
Summary of critical residues data (Annex IIA, point 6.3, Annex IIIA, point 8.2)
Crop
Northern or
Trials results relevant to the critical GAP
Recommendation/comments
MRL
STMR
Mediterranean
Region
not applicable
not applicable
(a)
not applicable
(b)
not applicable
(use in flori- and
horticulture constitutes no Critical
GAP in relation to
residues in plants
and crops)
(a) Numbers of trials in which particular residue levels were reported e.g. 3 x <0.01, 1 x 0.01, 6 x 0.02, 1 x 0.04, 1 x 0.08, 2 x 0.1, 2 x 0.15, 1 x 0.17
(b) Supervised Trials Median Residue i.e. the median residue level estimated on the basis of supervised trials relating to the critical GAP
not applicable
not applicable
22 November 2000
Consumer risk assessment (Annex IIA, point 6.9, Annex IIIA, point 8.8)
ADI
0-5 mg/kg bw
TMDI (European Diet) (% ADI)
not applicable
NEDI (% ADI)
not applicable
Factors included in NEDI
not applicable
ARfD
not applicable
Acute exposure (% ARfD)
not applicable
Processing factors (Annex IIA, point 6.5, Annex IIIA, point 8.4)
Crop/processed crop
Number of studies
Transfer factor
% Transference *
not applicable
not applicable
not applicable
not applicable
* Calculated on the basis of distribution in the different portions, parts or products as determined through balance studies
Proposed MRLs (Annex IIA, point 6.7, Annex IIIA, point 8.6)
...............................................................................
not applicable
2.8.3.3 Appendix III.5: Chapter 5 (fate and behaviour in the environment)
Route of degradation (aerobic) in soil (Annex IIA, point 7.1.1.1.1)
Mineralization after 100 days
The active substance is a compound naturally occurring
in soil where it can be readily biodegraded. Contamination of soil following use as a disinfectant according to
the GAP is not expected.
Non-extractable residues after 100 days
Not relevant
Relevant metabolites - name and/or code, % of
Not relevant
applied (range and maximum)
Route of degradation in soil - Supplemental studies (Annex IIA, point 7.1.1.1.2)
Anaerobic degradation
Not relevant
Soil photolysis
Not relevant
22 November 2000
Rate of degradation in soil (Annex IIA, point 7.1.1.2, Annex IIIA, point 9.1.1)
Method of calculation
No data
Laboratory studies (range or median, with n value,
DT50lab (20°C, aerobic):
with r2 value)
DT50lab (20°C, anaerobic):
degradation in the saturated zone: no data
Field studies (state location, range or median with n
DT50f: no data
value)
DT90f:
Soil accumulation and plateau concentration
Not relevant
Soil adsorption/desorption (Annex IIA, point 7.1.2)
Kf /Koc
Benzoic acid is not or only slightly adsorbed.
Kd
pH dependence (yes / no) (if yes type of dependence)
Mobility in soil (Annex IIA, point 7.1.3, Annex IIIA, point 9.1.2)
Column leaching
No data
Aged residues leaching
No data
Lysimeter/ field leaching studies
No data
PEC (soil) (Annex IIIA, point 9.1.3)
Contamination of soil following use as a disinfectant
according to the GAP is not expected.
Application rate
Application (watering of surfaces, soaking of culture
vessels, dipping of tools) is made using solutions containing 0.9 – 3.6 g a.s./l.
22 November 2000
Single
Single
Multiple
Multiple
application
application
application
application
Actual
Time weighted aver-
Actual
Time weighted
PEC(s)
average
age
Initial
Not relevant
Not relevant
Short term
Not relevant
Not relevant
Not relevant
Not relevant
Not relevant
Not relevant
Not relevant
Not relevant
24 h
2d
4d
Long term
7d
28 d
50 d
100 d
Route and rate of degradation in water (Annex IIA, point 7.2.1)
Hydrolysis of active substance and relevant me-
Stable
tabolites (DT50) (state pH and temperature)
Photolytic degradation of active substance and
Not relevant
relevant metabolites
Readily biodegradable (yes/no)
Yes
Degradation in wa-
- DT50 water
Not relevant
ter/sediment
- DT90 water
- DT50 whole system
-
DT90 whole system
-
Mineralization
Non-extractable residues
Distribution in water / sediment systems (active
substance)
Distribution in water / sediment systems (metabolites)
22 November 2000
PEC (surface water) (Annex IIIA, point 9.2.3)
1/1000 dilution in waste water, 95 % degradation during
waste water treatment, 1/10 dilution in waste water
treatment effluent, no adsorption on sediment
Application rate
Application (watering of surfaces, soaking of culture
vessels, dipping of tools) is made using solutions containing 0.9 – 3.6 g a.s./l.
Main routes of entry
PEC(sw)
Disposal of waste water
Single
Single
Multiple
Multiple
application
application
application
application
Actual
Time weighted
Actual
Time weighted average
average
Initial
18 µg/l
Short term
Not relevant
Not relevant
Not relevant
Not relevant
Not relevant
Not relevant
Not relevant
Not relevant
Not relevant
24 h
2d
4d
Long term
7d
14 d
21 d
28 d
42 d
PEC (sediment)
Not relevant
Application rate
PEC(sed)
Single
Single
Multiple
Multiple
application
application
application
application
Actual
Time weighted
Actual
Time weighted aver-
average
Initial
Short term
Long term
age
22 November 2000
PEC (ground water) (Annex IIIA, point 9.2.1)
Method of calculation and type of study (e.g. mod-
Since contamination of soil is not expected and the active
elling, monitoring, lysimeter )
substance is a natural component of soils which is readily
degraded a risk of ground water contamination resulting
from application of benzoic acid according to the GAP is
not expected.
Application rate
Not relevant
PEC(gw)
Maximum concentration
Not relevant
Average annual concentration
Not relevant
Fate and behaviour in air (Annex IIA, point 7.2.2, Annex III, point 9.3)
Direct photolysis in air
Not relevant
Quantum yield of direct phototransformation
Not relevant
Photochemical oxidative degradation in air
Not relevant
Volatilization
from plant surfaces: Not relevant
from soil: Not relevant
PEC (air)
Not relevant due to kind of application
PEC(a)
Maximum concentration
Negligible
Definition of the Residue (Annex IIA, point 7.3)
Relevant to the environment
A relevant residue of concern in the environmental
compartments needs not to be defined.
Monitoring data, if available (Annex IIA, point 7.4)
Soil (indicate location and type of study)
Not relevant
Surface water (indicate location and type of study)
Not relevant
Ground water (indicate location and type of study)
Not relevant
Air (indicate location and type of study)
Not relevant
22 November 2000
2.8.3.4 Appendix III.6: Chapter 6 (effects on non-target species)
Effects on terrestrial vertebrates (Annex IIA, point 8.1, Annex IIIA, points 10.1 and 10.3)
Acute toxicity to mammals
LD 50 > 2000 mg/kg bw (rat)
Acute toxicity to birds
No data submitted.
Dietary toxicity to birds
No data submitted.
Reproductive toxicity to birds
No data submitted.
Toxicity/exposure ratios for terrestrial vertebrates (Annex IIIA, points 10.1 and 10.3)
Crop
Application
Time-scale
Category
rate
(e.g. insectivorous
(kg as/ha)
bird)
TER
Annex VI
Trigger
Not applicable.
Toxicity data for aquatic species (most sensitive species of each group)
(Annex IIA, point 8.2, Annex IIIA, point 10.2)
Group
Test sub-
Time-scale
Endpoint
Toxicity
stance
(mg/l)
Laboratory tests
Oncorhynchus mykiss
benzoic acid
96 h
NOEC
120 mg/l
Daphnia magna
benzoic acid
48 h
NOEC
55 mg/l
Pseudokirchneriella subcapitata
benzoic acid
72 h
NOEC
7.5 mg/l
EbC50
33 mg/l
Microcosm or mesocosm tests
Not required.
Toxicity/exposure ratios for the most sensitive aquatic organisms (Annex IIIA, point 10.2)
Application
Crop
Organism
Time-scale
rate
(m)
(kg as/ha)
Not applicable.
Bioconcentration
Bioconcentration factor (BCF)
Annex VI Trigger for the bioconcentration factor
Clearance time
(CT50)
(CT90)
Level of residues (%) in organisms after the 14 day
depuration phase
Distance
Not required.
TER
Annex VI
Trigger
22 November 2000
Effects on honeybees (Annex IIA, point 8.3.1, Annex IIIA, point 10.4)
Acute oral toxicity
Not required.
Acute contact toxicity
Not required.
Hazard quotients for honey bees (Annex IIIA, point 10.4)
Application rate
Crop
Route
Hazard quotient
Annex VI
(kg as/ha)
Trigger
Laboratory tests
Not applicable
Field or semi-field tests
Not required.
Effects on other arthropod species (Annex IIA, point 8.3.2, Annex IIIA, point 10.5)
Species
Stage
Test
Dose
Endpoint
Substance
(kg as/ha)
Effect
Annex VI
Trigger
Laboratory tests
Not required.
Field or semi-field tests
Not required.
Note: The intended uses for formulated benzoic acid cover disinfection of culture vessels and equipment on
deposit areas, only. Therefore the exposure of non-target arthropods to the active substance is not likely and
consequently unacceptable risks to non-target arthropods are most unlikely to occur. No data are required.
Effects on earthworms (Annex IIA, point 8.4, Annex IIIA, point 10.6)
Acute toxicity
Not required.
Reproductive toxicity
Not required.
Toxicity/exposure ratios for earthworms (Annex IIIA, point 10.6)
Application rate
Crop
Time-scale
TER
(kg as/ha)
Annex VI
Trigger
Not applicable.
Effects on soil micro-organisms (Annex IIA, point 8.5, Annex IIIA, point 10.7)
Nitrogen mineralization
Not required.
Carbon mineralization
Not required.
Level 3
Benzoic acid
Proposal for the Decision
- 65 Benzoic acid – Level 3: Propopsed decision
3
22 November 2000
Proposed decision with respect to the application for inclusion of the
active substance in Annex I
3.1 Background to the proposed decision
Benzoic acid is an active substance with fungicidal, bactericidal, virucidal and viroicidal
properties and thus serves for disinfection. It is proposed to be used in horticulture
(floriculture) for disinfection of surfaces (i.e. the surfaces on which plants in culture vessels
stand inculuding culture- and storerooms), equipment and culture vessels in glasshouses and
other similarly protected cultivation areas.
Validated methods for the determination of bencoic acid in the technical active substance and
in SL formulations are available.
Due to its use as a disinfectant, relevant residues in food and the environmental compartments
arising from the application of benzoic acid according to the GAP are not expected to occur.
Therefore, residue analytical methods for the determination of the active substance in food of
plant and animal origin for enforcement purposes as well as for soil, water and air are not
required.
With regard to fate and behaviour in the environment and because the active substance is
naturally occurring in the environment, contamination of soil following application according
to the GAP is not expectecd.
Benzoic acid and its salts are widely spread natural compounds in the environment. They are
generated in plant and animal metabolism and therefore a constituent in many foodstuffs.
Because of its antimicrobial activity, benzoic acid is commonly used as preservative in food,
cosmetics and pharmaceuticals. From the use of benzoic acid as disinfectant in horticulture
any additional exposure of the general population can be excluded. Likewise an environmental
exposure can be excluded.
The human health risk assessment for the active substance benzoic acid is based almost
exclusively on original literature, cited to some extent in other reviews (e.g. JECFA, 1974,
1983, 1996). The available data do not support any evidence of genotoxic, carcinogenic and
the fertility or development damaging properties.
3.2 Proposed decision concerning inclusion in Annex I
It is proposed to include benzoic acid in Annex I of Directive 91/414/EEC.
- 66 Benzoic acid – Level 3: Propopsed decision
22 November 2000
3.3 Rational for the postponement of the decision to include the active
substance in Annex I, or for the conditions and restrictions to be
associated with a proposed inclusion in Annex I, as appropriate
Level 4
Benzoic acid
Demand for Further Information
- 69 Benzoic acid – Level 4: Further information
4
22 November 2000
Further information to permit a decision to be made, or to support a
review of the conditions and restrictions associated with the proposed
inclusion in Annex I
4.1 Identity of the active substance
None
4.2 Physical and chemical properties of the active substance
None
4.3 Data on application and further information
4.3.1 Data on application
None.
4.3.2 Further information
None
4.4 Classification, packaging and labelling
4.5 Methods of analysis
4.5.1 Analytical methods for formulation analysis
None
4.5.2 Analytical methods for residue analysis
None
4.6 Toxicology and metabolism
No additional studies or information are required for the active ingredient and the preparation.
- 70 Benzoic acid – Level 4: Further information
4.7 Residue data
None
4.8 Environmental fate and behaviour
None
4.9 Ecotoxicology
None.
22 November 2000
Monograph
22 November 2000
Benzoic acid
Volume 2
Annex A
List of Tests and Studies
-iBenzoic acid – Annex A: List of tests and studies
22 November 2000
Contents
A.1
Identity (Annex IIA 1, 3.1 to 3.4; Annex IIIA 1, 3.1 to 3.7, 3.9 and 12.1)......... 1
A.2
Physical and chemical properties (Annex IIA 2; Annex IIIA 2) ....................... 6
A.3
Further information (Annex IIA 3; Annex IIIA 3 and 4)................................ 11
A.4
Classification, packaging and labelling (Annex IIA 10; Annex IIIA 12.3
and 12.4) ............................................................................................................... 12
A.5
Methods of analysis (Annex IIA 4; Annex IIIA 5) ........................................... 13
A.6
Toxicology and metabolism (Annex IIA 5; Annex IIIA 7) .............................. 14
A.7
Residue data (Annex IIA 6; Annex IIIA 8 and 12.2)........................................ 58
A.8
Environmental fate and behaviour (Annex IIA 7; Annex IIIA 9) .................. 59
A.9
Ecotoxicology (Annex IIA 8; Annex IIIA 10) ................................................... 61
-1Benzoic acid – Annex A: List of tests and studies
A.1 Identity
22 November 2000
A.1 Identity (Annex IIA 1, 3.1 to 3.4; Annex IIIA 1, 3.1 to 3.7, 3.9 and 12.1)
Author(s)
Anonym
Annex
point/
reference
number
AIIA-1.3;
AIIA-1.4;
AIIA-1.7
Year Title
source (where different from company)
report no.
GLP or GEP status (where relevant),
published or not
BBA registration number
1993 Benzoesäure - Acidum benzoicum Kommentar
zum DAB 10 - Grundlfg. 1991.
not GLP, published
Data
Owner
protection
claimed
Y/N
N
-
N
-
N
-
N
-
CHE98-00890
Anonym
AIIA-1.3;
AIIA-1.4;
AIIA-1.7
not GLP, published
CHE98-00890
Anonym
AIIA-1.3;
AIIA-1.4;
AIIA-1.7
not GLP, published
CHE98-00890
Anonym
AIIA-1.3;
AIIA-1.4;
AIIA-1.6;
AIIA-1.7;
AIIA-1.8;
AIIA-1.10;
AIIA-2.1;
AIIA-2.2;
AIIA-2.3;
AIIA-2.4;
AIIA-2.6;
AIIA-4.1
1993 Benzoic acid / sodium benzoate.
not GLP, published
BUA report 145. Ed.: GDCh-Advisory Committee on Existing Chemicals of Environmental
Relevance., 1993
CHE98-00891
A.1 Identity
Author(s)
Anonym
Anonym
Anonym
Annex
point/
reference
number
AIIA-1.3;
AIIA-1.4;
AIIA-1.6;
AIIA-1.7;
AIIA-1.8;
AIIA-1.10;
AIIA-2.1;
AIIA-2.2;
AIIA-2.3;
AIIA-2.4;
AIIA-2.6;
AIIA-4.1
Year Title
report no.
published or not
not GLP, published
Relevance., 1993
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
N
-
N
-
CHE98-00891
AIIA-1.3;
AIIA-1.4;
AIIA-1.6;
AIIA-1.7;
AIIA-1.8;
AIIA-1.10;
AIIA-2.1;
AIIA-2.2;
AIIA-2.3;
AIIA-2.4;
AIIA-2.6;
AIIA-4.1
not GLP, published
Relevance., 1993
AIIA-1.3;
AIIA-1.4;
AIIA-1.6;
AIIA-1.7;
AIIA-1.8;
AIIA-1.10;
AIIA-2.1;
AIIA-2.2;
AIIA-2.3;
AIIA-2.4;
AIIA-2.6;
AIIA-4.1
not GLP, published
Relevance., 1993
CHE98-00891
CHE98-00891
A.1 Identity
Author(s)
Anonym
Anonym
Anonym
Annex
point/
reference
number
AIIA-1.3;
AIIA-1.4;
AIIA-1.6;
AIIA-1.7;
AIIA-1.8;
AIIA-1.10;
AIIA-2.1;
AIIA-2.2;
AIIA-2.3;
AIIA-2.4;
AIIA-2.6;
AIIA-4.1
Year Title
report no.
published or not
not GLP, published
Relevance., 1993
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
N
-
N
-
N
-
N
-
CHE98-00891
AIIA-1.3;
AIIA-1.4;
AIIA-1.6;
AIIA-1.7;
AIIA-1.8;
AIIA-1.10;
AIIA-2.1;
AIIA-2.2;
AIIA-2.3;
AIIA-2.4;
AIIA-2.6;
AIIA-4.1
not GLP, published
Relevance., 1993
AIIA-1.7;
AIIA-2.1;
AIIA-2.4
1991 Benzoesäure - Acidum benzoicum Aus: DAB 10
- Grundlfg. 1991.
not GLP, published
CHE98-00891
CHE98-00889
Anonym
AIIIA-1.4
1996 Angaben zum Beistoff Mersolat W 93.
not GLP, published
BEI96-00490
Anonym
AIIIA-1.4
1993 Sicherheitsdatenblatt für Mersolat W 93.
not GLP, published
BEI96-00492
A.1 Identity
Author(s)
Anonym
Annex
point/
reference
number
AIIIA-1.4
Year Title
report no.
published or not
1995 Produktinformation für KNA-Cumolsulfonat 40.
not GLP, published
Hüls AG
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
N
-
N
-
N
-
N
-
N
-
N
-
BEI96-00493
Anonym
AIIIA-1.4
1994 EG-Sicherheitsdatenblatt für KNACumolsulfonat 40.
not GLP, published
BEI96-00494
Anonym
AIIIA-1.4
1995 Sicherheitsdatenblatt für N-Propanol.
not GLP, published
BASF
BEI96-00496
Anonym
AIIIA-1.4
1986 Isopropylalkohol.
not GLP, published
DAC, 2. Ergänzung 90, 1986, 1-5
BEI96-00497
Anonym
AIIIA-1.4
1995 Sicherheitsdatenblatt für IsopropylalkoholCosmetic.
not GLP, published
Shell Chemicals
BEI96-00498
Anonym
AIIIA-1.4
1996 Lieferspezifikation für Ameisensäure 99%.
not GLP, published
BEI96-00499
Anonym
AIIIA-1.4
1993 Sicherheitsdatenblatt für Ameisensäure techn. ca.
98%.
not GLP, published
BEI96-00500
A.1 Identity
Author(s)
Anonym
Annex
point/
reference
number
AIIIA-1.4
Year Title
report no.
published or not
1994 Spezifikation und Kenndaten für Monoethylenglykol.
not GLP, published
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
N
-
N
-
N
-
BEI96-00501
Anonym
AIIIA-1.4
1994 EG - Sicherheitsdatenblatt für Monoethylenglykol.
not GLP, published
BEI96-00502
Freitag, D.,
Ballhorn, L.,
Geyer, H.,
Korte, F.
AIIA-1
1985 Environmental hazard profile of organic chemicals.
not GLP, published
Chemosphere, 14, 10, 1985, 1589-1616
CHE98-00884
Klokkers
AIIIA-1.4
1996 Information zum Beistoff N-Propanol.
not GLP, published
BASF AG
BEI96-00495
Codes of owner
All references published
A.2 Physical and chemical properties
22 November 2000
A.2 Physical and chemical properties (Annex IIA 2; Annex IIIA 2)
Author(s)
Annex
point/
reference
number
Year Title
report no.
published or not
1996 Menno Florades Batch No. 9507.
not GLP, unpublished
CHE98-00855
Data
Owner
protection
claimed
Y/N
Y
MEN
AFP GmbH
AIIIA-2.4
AFP GmbH
AIIIA-2.5
1996 Menno Florades Batch No. 9507 Prüfung der
Lagerstabilität bei 54 °C (+/-2) für 14 Tage.
CHE98-00856
Y
MEN
AFP GmbH
AIIIA-2.6
1996 Menno Florades Batch No. 9507 Test on Storage
Stability at 0 °C (+/-1) over 7 days.
CHE98-00857
Y
MEN
Angly, H.
AIIIA-2.3
2000 Determination of the Auto-Ignition Temperature
(Liquids and Gases) of MENNO Florades according to EC Council Directive 92/69/EEC, Part.
A. 15.
2000.4048.AFG
GLP, unpublished
PHY2000-664
Y
MEN
Anonym
AIIA-1.3;
AIIA-1.4;
AIIA-1.6;
AIIA-1.7;
AIIA-1.8;
AIIA-1.10;
AIIA-2.1;
AIIA-2.2;
AIIA-2.3;
AIIA-2.4;
AIIA-2.6;
AIIA-4.1
not GLP, published
Relevance., 1993
CHE98-00891
N
-
Author(s)
Annex
point/
reference
number
Year Title
report no.
published or not
not GLP, published
Relevance., 1993
CHE98-00891
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
Anonym
AIIA-1.3;
AIIA-1.4;
AIIA-1.6;
AIIA-1.7;
AIIA-1.8;
AIIA-1.10;
AIIA-2.1;
AIIA-2.2;
AIIA-2.3;
AIIA-2.4;
AIIA-2.6;
AIIA-4.1
Anonym
AIIA-1.3;
AIIA-1.4;
AIIA-1.6;
AIIA-1.7;
AIIA-1.8;
AIIA-1.10;
AIIA-2.1;
AIIA-2.2;
AIIA-2.3;
AIIA-2.4;
AIIA-2.6;
AIIA-4.1
not GLP, published
Relevance., 1993
CHE98-00891
N
-
Anonym
AIIA-1.3;
AIIA-1.4;
AIIA-1.6;
AIIA-1.7;
AIIA-1.8;
AIIA-1.10;
AIIA-2.1;
AIIA-2.2;
AIIA-2.3;
AIIA-2.4;
AIIA-2.6;
AIIA-4.1
not GLP, published
Relevance., 1993
CHE98-00891
N
-
Author(s)
Annex
point/
reference
number
Year Title
report no.
published or not
not GLP, published
Relevance., 1993
CHE98-00891
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
Anonym
AIIA-1.3;
AIIA-1.4;
AIIA-1.6;
AIIA-1.7;
AIIA-1.8;
AIIA-1.10;
AIIA-2.1;
AIIA-2.2;
AIIA-2.3;
AIIA-2.4;
AIIA-2.6;
AIIA-4.1
Anonym
AIIA-2.5
1966 Benzoic Acid - UV Spectrum.
CHE98-00885
Y
MEN
Anonym
AIIA-2.5
1998 Benzoic Acid - IR Spectrum.
CHE98-00886
Y
MEN
Anonym
AIIA-2.5
1998 Benzoic Acid -NMR Spectrum.
CHE98-00887
Y
MEN
Anonym
AIIA-2.5
1998 Benzoic Acid - MS Spectrum.
CHE98-00888
Y
MEN
Anonym
AIIA-1.7;
AIIA-2.1;
AIIA-2.4
- Grundlfg. 1991.
not GLP, published
N
-
N
-
Y
MEN
CHE98-00889
Anonym
AIIA-1.7;
AIIA-2.1;
AIIA-2.4
- Grundlfg. 1991.
not GLP, published
CHE98-00889
Gericke, K. and
Schlorff, S.
AIIIA-2.3
1996 Analysenbericht: HH-0245a.
CHE98-00854
22 November 2000
Author(s)
Annex
point/
reference
number
Year Title
Data
Owner
protection
report no.
claimed
published or not
Y/N
1994 Untersuchungsbericht Flammpunktbestimmung
Y
MEN
nach DIN 51755 Produkt Menno Florades - AFP
GmbH.
CHE98-00852
Hahn
AIIIA-2.1
Hahn
AIIIA-2.2
1994 Report - Determination of the Flash Point - Method: DIN 51755.
CHE98-00853
Y
MEN
Hahn
AIIA-2.5;
AIIIA-5.1
1996 Menno-Florades - Analysenmethode C 17.2 mit
Validierung, Linearitätsnachweis und Musterchromatogramme Benzoesäure und Menno- Florades.
CHE98-00862
Y
MEN
Hahn
AIIIA-2.7
1998 Stability Test over 29 months Menno Florades
Batch No. 9601, manufactured 18.1.1996.
CHE98-00858
Y
MEN
Informatics Inc.
AIIA-2.1;
AIIA-2.3
1972 GRAS (Generally Recognize As Safe) Food
Ingredients: Benzoic Acid and Sodium Benzoate.
PB-221 208
not GLP, published
National Technical Information Service (NTIS),
PB-221 20, 1972
CHE98-00848
N
-
Informatics Inc.
AIIA-2.1;
AIIA-2.3
PB-221 208
not GLP, published
PB-221 20, 1972
CHE98-00848
N
-
Keller, G.
AIIIA-2.8.4
2000 Determination of the Dilution Stability of
MENNO Florades.
ChemCon Project No. CC00C07
PHY2000-665
Y
MEN
- 10 Benzoic acid – Annex A: List of tests and studies
Author(s)
Annex
point/
reference
number
Year Title
report no.
published or not
1998 Determination of the Water Solubility of Benzoic Acid at pH 5.2 and pH 9.0.
CHEMCON PROJECT NO.CC98B05
CHE98-00892
22 November 2000
Data
Owner
protection
claimed
Y/N
Y
MEN
2000 Determination of the Surface Tension of MENNO florades in Aqueous Solution.
IF-100/22588-00
GLP, unpublished
PHY2000-663
Y
MEN
Ware, G. W.,
AIIA-2.9
Crosby, D. G.
and Giles, J. W.
1980 Photodecomposition of DDA.
not GLP, published
Arch. Environm. Contam. Toxicol., 9, 1980,
135-146
LUF2000-207
N
-
Williams, A.E.
1978 Benzoic Acid.
not GLP, published
Kirk-Othmer, Enzcyclopedia of Chemical Technology, 3rd Ed, 1978, 778-792
CHE98-00847
N
-
Kellner, G.
AIIA-2.6
Schulz, H.
AIIIA-2.5
AIIA-2.1
Codes of owner
MEN:
Menno-Chemie-Vertrieb GmbH
A.3 Further information
22 November 2000
A.3 Further information (Annex IIA 3; Annex IIIA 3 and 4)
Author(s)
Annex
point/
reference
number
Year Title
report no.
published or not
1993 1. Nachtrag zur 1. Neufassung zum Zulassungsschein Zulassungs-Nr. 8018/3H1 - Deutsche
Bundesbahn Bundesbahn-Zentralamt Minden
(Westf).
CHE98-00859
Data
Owner
protection
claimed
Y/N
N
MEN
Anonym
AIIIA-4.1
Anonym
AIIIA-4.2
1989 1. Neufassung zum Zulassungsschein Zulassungs-Nr. 8249/3H1 - Deutsche Bundesbahn
Bundesbahn-Zentralamt Minden (Westf).
CHE98-00860
N
MEN
Freese, E.,
Sheu, C.W.,
Galliers, E.
AIIA-3
1973 Function of Lipophilic Acids as Antimicrobial
Food Additives.
not GLP, published
Nature 241, 321-325, 1973
BIO1999-473
N
-
Verschueren, K. AIIA-3
1977 Handbook of environmental data on organic
chemicals.
not GLP, published
Van Nostrand Reinhold Company, 1977
BIO1999-472
N
-
1977 Handbook of Environmental Data on Organic
Chemicals.
not GLP, published
N
-
N
MEN
CHE98-00849
Wieser, K.E.
AIIIA-4.3
1995 3. Neufassung zum Zulassungsschein - Nr.
9640/1H1 Bundesanstalt für Materialforschung
und -Prüfung (BAM).
CHE98-00861
Codes of owner
MEN:
A.4 Classification, packaging and labelling
22 November 2000
A.4 Classification, packaging and labelling (Annex IIA 10; Annex IIIA
12.3 and 12.4)
No references submitted
A.5 Methods of analysis
22 November 2000
A.5 Methods of analysis (Annex IIA 4; Annex IIIA 5)
Author(s)
Annex
point/
reference
number
Anonym
AIIA-1.3;
AIIA-1.4;
AIIA-1.6;
AIIA-1.7;
AIIA-1.8;
AIIA-1.10;
AIIA-2.1;
AIIA-2.2;
AIIA-2.3;
AIIA-2.4;
AIIA-2.6;
AIIA-4.1
Baziramakenga, AIIA-4.2
R.; Simrad, R.R.
and Leroux,
G.D.
Hahn
AIIA-2.5;
AIIIA-5.1
Jalal, M.A.F.
and Read, D.J.
AIIA-4.2
Year Title
report no.
published or not
not GLP, published
Relevance., 1993
CHE98-00891
Y/N
N
-
1995 Determination of organic acids in soil extracts by
ion chromatography.
not GLP, published
Soil Biol. Biochem., 27, 1995, 349 - 356
MET1999-141
CHE98-00862
N
-
Y
MEN
1983 The organic acid composition of Calluna heathland soil with special reference to phyto- and
fungitoxicity.
not GLP, published
Plant and Soil, 70, 1983, 273 - 286
MET1999-140
N
-
Codes of owner
MEN:
Data
Owner
protection
claimed
A.6 Toxicology and metabolism
22 November 2000
A.6 Toxicology and metabolism (Annex IIA 5; Annex IIIA 7)
Author(s)
Abe, S. and
Sasaki, M.
Annex
point/
reference
number
AIIA-5.4
Year Title
report no.
published or not
1977 Chromosome aberrations and sister chromatid
exchanges in chinese hamster cells exposed to
various chemicals.
not GLP, published
J. Natl. Cancer Inst., 58, 6, 1635-1641
TOX2000-399
Data
Owner
protection
claimed
Y/N
N
-
Abe, S., Tsutsui, AIIA-5.2
Y., Tarumoto,
Y. and Nakane,
S.
1984 Studies on the toxicity of oxaprozin (1) - Acute
toxicity of oxaprozin, its metabolites and contaminants.
not GLP, published
Iyakuhin Kenkyu, 15, 3, 359-370
TOX2000-356
N
-
Akira, K., TaAIIA-5.1
kagi, N., Takeo,
S. and Shindo,
H. Baba, S.
1993 Application of 13C-labeling and nuclear magnetic resonance spectroscopy to pharmacokinetic
research: measurement of metabolic rate of benzoic acid to hippuric acid in the rat.
not GLP, published
Analytical Biochemistry, 210, 86-90
TOX2000-279
N
-
Altman, K.I.,
AIIA-5.1
Haberland, G.L.
and Bruns, F.
1954 Cited in JECFA, 1974.
not GLP, published
Biochem. Z., 326, 107
TOX2000-280
N
-
Amsel, L.P.;
Levy, G.
AIIA-5.1
1969 Drug biotransformation interactions in man. II: A
pharmacokinetic study of the simultaneous conjugation of benzoic and salicylic acids with glycine.
not GLP, published
J. Pharm. Sci., 58, 3, 321-326
TOX2000-281
N
-
Andersen, K.E., AIIA-5.1
Maibach, H.I.
and Anjo, M.D.
1980 The guinea-pig: an animal model for human skin
absorption of hydrocortisone, testosterone and
benzoic acid?.
not GLP, published
British Journal of Dermatology, 102, 447-453
TOX2000-282
N
-
Author(s)
Annex
point/
reference
number
Year Title
report no.
published or not
1978 The bacterial mutation test.
not GLP, published
Br. J. Cancer, 37, 1978, 924-930
TOX1999-1421
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
Anderson, D.
and Styles, J.A.
AIIA-5.4
Anderson, D.
and Styles, J.A.
AIIA-5.4
1978 The bacterial mutation test; Appendix II to article of Purchase et al.
not GLP, published
Br. J. Cancer, 37, 924-930
TOX2000-400
N
-
Anonym
AIIA-5.1;
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.5;
AIIA-5.6
not GLP, published
Relevance., 1993
TOX1999-1413
N
-
Anonym
AIIA-5.1;
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.5;
AIIA-5.6
not GLP, published
Relevance., 1993
TOX1999-1413
N
-
Anonym
AIIA-5.1;
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.5;
AIIA-5.6
not GLP, published
Relevance., 1993
TOX1999-1413
N
-
Anonym
AIIA-5.1;
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.5;
AIIA-5.6
not GLP, published
Relevance., 1993
TOX1999-1413
N
-
Anonym
AIIA-5.1;
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.5;
AIIA-5.6
not GLP, published
Relevance., 1993
TOX1999-1413
N
-
Author(s)
Annex
point/
reference
number
Year Title
report no.
published or not
not GLP, published
Relevance., 1993
TOX1999-1413
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
Anonym
AIIA-5.1;
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.5;
AIIA-5.6
Anonym
AIIA-5.1;
AIIA-5.2;
AIIA-5.3;
AIIA-5.5;
AIIA-5.6
1974 Benzoic acid and its potassium and sodium salts.
not GLP, published
WHO, 1974
TOX1999-1420
N
-
Anonym
AIIA-5.1;
AIIA-5.2;
AIIA-5.3;
AIIA-5.5;
AIIA-5.6
not GLP, published
WHO, 1974
TOX1999-1420
N
-
Anonym
AIIA-5.1;
AIIA-5.2;
AIIA-5.3;
AIIA-5.5;
AIIA-5.6
not GLP, published
WHO, 1974
TOX1999-1420
N
-
Anonym
AIIA-5.1;
AIIA-5.2;
AIIA-5.3;
AIIA-5.5;
AIIA-5.6
not GLP, published
WHO, 1974
TOX1999-1420
N
-
Anonym
AIIA-5.1;
AIIA-5.2;
AIIA-5.3;
AIIA-5.5;
AIIA-5.6
not GLP, published
WHO, 1974
TOX1999-1420
N
-
Anonym
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.6
1985 Benzoesäure.
not GLP, published
Henschler, D. (Ed.)
TOX1999-1415
N
-
Anonym
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.6
1985 Benzoesäure.
not GLP, published
Henschler, D. (Ed.)
TOX1999-1415
N
-
Author(s)
Annex
point/
reference
number
22 November 2000
Anonym
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.6
Year Title
report no.
published or not
1985 Benzoesäure.
not GLP, published
Henschler, D. (Ed.)
TOX1999-1415
Anonym
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.6
1985 Benzoesäure.
not GLP, published
Henschler, D. (Ed.)
TOX1999-1415
N
-
Anonym
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.5;
AIIA-5.6
1989 Benzoic acid and its common salts.
not GLP, published
The British Industrial Biological Research Association., 1989
TOX1999-1416
N
-
Anonym
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.5;
AIIA-5.6
not GLP, published
TOX1999-1416
N
-
Anonym
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.5;
AIIA-5.6
not GLP, published
TOX1999-1416
N
-
Anonym
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.5;
AIIA-5.6
not GLP, published
TOX1999-1416
N
-
Anonym
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.5;
AIIA-5.6
not GLP, published
TOX1999-1416
N
-
Anonym
AIIIA-7.4
1996 Safety Data Sheet Menno Florades.
not GLP, published
N
-
TOX2000-543
Data
Owner
protection
claimed
Y/N
N
-
Author(s)
Annex
point/
reference
number
Year Title
report no.
published or not
1955 Endogenous formation of hippuric acid.
not GLP, published
Proc. Soc. Exp. Biol. Med., 90, 675-679
TOX2000-283
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
Armstrong,M.D.,Ch
ao, F.-C., Parker, V.J. and
Wall, P.E.
AIIA-5.1
Avigan, J.,
Quastel, J.H.
and Scholefield
P.G.
AIIA-5.8
1955 Study of fatty acid oxidation. 3. The effect of
acetyl-CoA complexes on fatty acid oxidation.
not GLP, published
Biochem. J., 60, 329-334
TOX2000-454
N
-
Baer, R.L.,
Serri, F. and
WeissenbachVial, C.
AIIA-5.9
1955 Studies on allergic sensitization to certain topical
therapeutic agents.
not GLP, published
AMA Arch. Dermatol. Syphil., 71, 19-23
TOX2000-483
N
-
Baines, P.J.,
Bray, H.G.,
Hall, B.E. and
James, S.P.
AIIA-5.1
1978 Metabolism of 14C-benzoic acid in the developing rat.
not GLP, published
IRCS Medical Science, 6, 221
TOX2000-284
N
-
Baird, K.A.
AIIA-5.9
1945 Allergy to chemicals in flour; a case of dermatitis
due to benzoic acid.
not GLP, published
J. Allergy, 16, 195-198
TOX2000-484
N
-
Baltes, W.
AIIA-5.9
1989 Lebensmittelchemie; Springer Verlag Berlin,
Heidelberg; cited in Götz etal., 1994.
not GLP, published
N
-
N
-
TOX2000-485
Barnes, J.M.
AIIA-5.1;
AIIA-5.9
1959 Food preservatives: Toxicological considerations.
not GLP, published
Chemistry and Industry, May 2, 1, 557-561
TOX2000-285
Author(s)
Annex
point/
reference
number
Year Title
report no.
published or not
not GLP, published
TOX2000-285
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
Barnes, J.M.
AIIA-5.1;
AIIA-5.9
Basketter, D.A.
and Wilhelm,
K.-P.
AIIA-5.9
1996 Studies on non-immune immediate contact reactions in an unselected population.
not GLP, published
Contact Dermatitis, 35, 1996, 237-240
TOX1999-1445
N
-
Batshaw, M.L., AIIA-5.9
Painter, M.J.,
Sproul, G.T.,
Schafer, I.A.,
Thomas, G.H.
and Brusilow, S.
1981 Therapy of urea cycle enzymopathies: Three
case studies.
not GLP, published
The Johns Hopkins Medical Journal, 148, 34-40
TOX2000-487
N
-
Bayer AG
1978 Untersuchungen zur Haut- und Schleimhautverträglichkeit unpublished report.
not GLP, published
Bayer AG Wuppertal, cited in BUA, 1995
TOX2000-357
N
-
Bedford, B. and AIIA-5.2;
Clarke, M.A.
AIIA-5.3
1971 Suspected benzoic acid poisoning in the cat.
not GLP, published
The Veterinary Record, 88, 599-601
TOX2000-358
N
-
Clarke, M.A.
AIIA-5.3
1971 Suspected benzoic acid poisoning in the cat.
not GLP, published
TOX2000-358
N
-
Clarke, M.A.
AIIA-5.3
1972 Experimental benzoic acid poisoning in the cat.
not GLP, published
The Veterinary Record, 90, 3, 53-58
TOX2000-359
N
-
Clarke, M.A.
AIIA-5.3
1972 Experimental benzoic acid poisoning in the cat.
not GLP, published
TOX2000-359
N
-
AIIA-5.2
Author(s)
Annex
point/
reference
number
Year Title
report no.
published or not
1955 Zur Frage der Entstehung der Benzoesäure im
Tierkörper.
not GLP, published
Helvetica Chimica Acta, 38, 173, 1438-1444
TOX2000-286
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
Bernhard, K.,
Vuilleumier, J.
P. and Brubacher, G.
AIIA-5.1
Bien, E.
AIIIA-7.1.1
1994 Acute oral toxicity test of "Menno Florades" in
rats.
PROJECT NO.: 10-04-0859/00-94
GLP, unpublished
TOX98-51130
Y
MEN
Bien, E.
AIIIA-7.1.2
1994 Acute dermal toxicity test of "Menno Florades"
in rats.
PROJECT NO.: 10-04-0860/00-94
GLP, unpublished
TOX98-51131
Y
MEN
Bien, E.
AIIIA-7.1.4
1994 Acute dermal irritation / corrosion test of "Menno Florades" in rabbits.
PROJECT NO.: 10-03-0862/00-94
GLP, unpublished
TOX98-51132
Y
MEN
Bien, E.
AIIIA-7.1.5
1994 Acute eye irritation / corrosion test of "Menno
Florades" in rabbits.
PROJECT NO.: 10-03-0861/00-94
GLP, unpublished
TOX98-51133
Y
MEN
Bignani, G.
AIIA-5.1;
AIIA-5.9
1924 Ricerche sulla sintesi ippurica nell organismo
umano.
not GLP, published
Biochim. Ter. Sper., 11, 383-393
TOX2000-287
N
-
Bignani, G.
AIIA-5.1;
AIIA-5.9
umano.
not GLP, published
TOX2000-287
N
-
Author(s)
Annex
point/
reference
number
Bio-Fax
AIIA-5.2;
AIIA-5.3
22 November 2000
Year Title
Data
Owner
protection
report no.
claimed
published or not
Y/N
1973 Benzoic acid. Industrial Bio-Test Laboratories,
N
Inc.; Northbrook Ill., Data sheet no. 28-4/7; cited
in BUA, 1995.
not GLP, published
TOX2000-360
Bio-Fax
AIIA-5.2;
AIIA-5.3
in BUA, 1995.
not GLP, published
N
-
TOX2000-360
Bordas, Francois-Dainville,
Roussel
AIIA-5.1
1925 L'elimination de l'acide benzoique et des benzoates dans l economie.
not GLP, published
compt. Rend., 181, 304-306
TOX2000-288
N
-
Bosund, I.
AIIA-5.8
1957 The effect of salicylic acid, benzoic acid and
some of their derivatives on oxidative phosphorylation.
not GLP, published
Acta Chem. Scand., 11, 3, 541-544
TOX2000-455
N
-
Brand, E. and
Harris, M.M.
AIIA-5.8
1933 Some aspects of intermediary protein metabolism; cited in FDA, 1972.
not GLP, published
Science, 77, 2007, 589-590
TOX2000-467
N
-
Brasch, J., Hen- AIIA-5.9
seler, T. and
Frosch, P.
1993 Patch test reaction to a preliminary preservative
series.
not GLP, published
Dermatosen, 41, 2, 71-76
TOX2000-488
N
-
Bridges, J.W.,
French, M.R.,
Smith, R.L. and
Williams, R.T.
1970 The fate of benzoic acid in various species.
not GLP, published
Biochem. J., 118, 1970, 45-51
TOX1999-1414
N
-
AIIA-5.1
Author(s)
Annex
point/
reference
number
Year Title
report no.
published or not
1987 Cosmetic intolerance.
not GLP, published
Contact Dermatitis, 16, 189-194
TOX2000-489
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
Broeckx, W.,
Blondeel, A.,
DoomsGoossens, A.
and Achten, G.
AIIA-5.9
Bronaugh, R.L.
and Stewart,
R.F.
AIIA-5.1
1985 Methods for in vitro percutaneous absorption
studies. V: Permeation through damaged skin.
not GLP, published
Journal of Pharmaceutical Sciences, 74, 10,
1062-1066
TOX2000-290
N
-
Brusilow, S.W.
and Maestri,
N.E.
AIIA-5.9
1996 Urea cycle disorders: Diagnosis, pathophysiology and therapy.
not GLP, published
Adv Pediatr, 43, 127-170
TOX2000-490
N
-
Bucks, D.A.W.,
Hinz, R.S.,
Sarason, R.,
Maibach, H.I.
and Guy, R.H.
AIIA-5.8
1990 In vivo percutaneous absorption of chemicals: A
multiple dose study in rhesus monkeys.
not GLP, published
Fd. Chem. Toxic., 28, 2, 1990, 129-132
TOX1999-1440
N
-
Carver, M.P.and AIIA-5.1
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Cotruvo, J.A.,
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Doeglas,
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Ellinger, A.
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Fassett, D.W.
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FDA
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Feillet, F. and
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Feldmann,
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AIIA-5.1
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Freedman, B.J.
AIIA-5.9
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Frosch, P.J. and
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AIIA-5.9
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Fujii, T., Omori, AIIA-5.1
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Fujitani, T.
AIIA-5.2
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Gad, S.C.,
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Gerberick, G.F., AIIA-5.2
House, R.V.,
Fletcher, E.R.
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MEN
Gerlach, V.
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Green, T.P.,
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Griffith, W.H.
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Griffith, W.H.
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AIIA-5.9
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AIIA-5.9
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Annex
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W.H.and Lewis,
H.B.
Gupta, M.M.
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22 November 2000
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protection
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claimed
published or not
Y/N
1923 Studies in the synthesis of hippuric acid in the
N
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AIIA-5.5
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Hager, G.P.,
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1942 The toxicity of benzoic acid for white rats.
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Hall, B.E.and
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AIIA-5.1
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Harris,
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AIIA-5.8
1949 Effect of administration of sodium benzoate on
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Harshbarger,
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AIIA-5.3
1942 Report of a study on the toxicity of several food
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AIIA-5.5
22 November 2000
Year Title
Data
Owner
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claimed
published or not
Y/N
1951 Survey of compounds which have been tested for
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Hatanaka, J.,
AIIA-5.5
Doke, N., Harada, T., Aikawa,
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Häussinger D.,
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Hirom, P.C.,
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AIIA-5.1
1976 Bile and urine as complementary pathways for
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Hjorth, N.
AIIA-5.9
1961 Reactions to single components in balsam of
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-
1983 Drug absorption by the rat jejunum perfused in
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Högerle,
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M.L.and Winne,
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Annex
point/
reference
number
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report no.
claimed
published or not
Y/N
1985 Mechanism of nasal absorption of drugs. I: PhyN
siochemical parameters influencing the rate of in
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Huang, C.H.,
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Nassar, R.
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AIIA-5.1
Huckle, K.R.,
Hutson,
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AIIA-5.1
1981 Species differences in the metabolism of 3phenoxybenzoic acid.
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Hunziker, N.,
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AIIA-5.1
1978 Animal models of percutaneous penetration:
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Ignatev, A.D.
AIIA-5.2;
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1965 Experimental materials contributive to hygienic
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Ignatev, A.D.
AIIA-5.2;
AIIA-5.3;
AIIA-5.9
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TOX2000-369
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Ignatev, A.D.
AIIA-5.2;
AIIA-5.3;
AIIA-5.9
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TOX2000-369
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-
Author(s)
Annex
point/
reference
number
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1999 Concise international chemical assessment document benzoic acid and sodium benzoate,
IPCS (International Programme on chemical
safety), 1. Draft, prepared by Wibbertmann, A.
November 1999.
TOX2000-272
22 November 2000
Data
Owner
protection
claimed
Y/N
N
MEN
N
-
1977 Chromosome tests with 134 compounds on Chinese hamster cells in vitro - A screening for
chemical carcinogens.
not GLP, published
Mutation Research, 48, 1977, 337-354
TOX1999-1423
N
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Ishidate, Jr., M., AIIA-5.4
Sofuni, T., Yoshikawa, K.,
Hayashi, M.,
Nohmi, T.,
Sawada, M. and
Matsuoka, A.
1984 Primary mutagenicity screening of food additives
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Fd. Chem. Toxic., 22, 8, 1984, 623-636
TOX1999-1422
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Ishidate, M.
1988 Chromosomal aberration test in vitro.
not GLP, published
Mutat. Res., 195, 151-213
TOX2000-410
N
-
1977 Chromosome tests with 134 compounds on chinese hamster cells in vitro - a screening for chemical carcinogens.
not GLP, published
Mutation Research, 48, 337-354
TOX2000-407
N
-
IPCS
AIIA-5
IRDC
AIIA-5.3
1981 Four-week subacute inhalation toxicity study of
benzoic acid in rats with amendment; Intl. Res.
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1995.
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AIIA-5.4
AIIA-5.4
Ishidate, M. and AIIA-5.4
Odashima,S.
Author(s)
Annex
point/
reference
number
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Sofuni, T. and
Yoshikawa K.
AIIA-5.4
22 November 2000
Year Title
Data
Owner
protection
report no.
claimed
published or not
Y/N
1980 Chromosome aberration tests with chinese
N
hamster cells in vitro with and without metabolic
activation a comparative study on mutagens
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not GLP, published
Arch. Toxicol. suppl., 4, 41-44
TOX2000-408
Ishidate, M.,
AIIA-5.4
Sofuni, T., Yoshikawa K.,
Hayashi, M. and
Nohmi, T.
currently used in Japan.
not GLP, published
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Ishizaki, M. and AIIA-5.4
Ueno, S.
1989 The DNA-damaging activity of natural and synthetic food additives (V).
not GLP, published
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Ito, N., Imaida,
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1989 Rapid bioassay methods for carcinogens and
modifiers of hepatocarcinogenesis.
TOX2000-440
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MEN
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Dani, H.M.
1985 Improved detection of carcinogens by degranulation of microsomes prepared at low g force by
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Jansson, T.,
Curvall, M.,
Hedin, A. and
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1988 In vitro studies of the biological effects of cigarette smoke condensate. III. Induction of SCE by
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N
-
AIIA-5.5
AIIA-5.4
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JECFA
Annex
point/
reference
number
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Year Title
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published or not
1974 17th report of the joint FAO/WHO expert committee on food additives WHO Food additives
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Data
Owner
protection
claimed
Y/N
N
-
N
-
N
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TOX2000-273
JECFA
AIIA-5
1983 27th report of the joint FAO/WHO expert committee on food additives WHO technical report
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JECFA
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Jelinek, R.,
Peterka, M. and
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AIIA-5.6
1985 Chick embryotoxicity sreening test - 130 substances tested.
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Indian Journal of Experimental Biology, 23,
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TOX2000-447
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Jones, A.R.
AIIA-5.1
1982 Some observations on the urinary excretion of
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N
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Juhlin, L., Michaelsson, G.
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AIIA-5.9
1972 Urticaria and asthma induced by food-and-drug
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Annex
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reference
number
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Year Title
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published or not
1988 Sodium benzoate inhibits fatty acid oxidation in
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not GLP, published
Biochemical Medicine and Metabolic Biology,
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TOX2000-470
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
Kao, J., Jones,
AIIA-5.1
C.A., Fry,
J.R.and Bridges,
J.W.
1978 Species differences in the metabolism of benzoic
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TOX2000-307
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Kaplan, E.H.,
AIIA-5.8
Kennedy, J. and
Davis, J.
1954 Effects of salicylate and other benzoates on oxidative enzymes of the tricarboxylic acid cycle in
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Kawachi, T.,
AIIA-5.4
Komatsu, T.,
Kada, T., Ishidate, M., Sasaki,
M., Sugiyama,
T. and Tazima,
Y.
1980 Results of recent studies on the relevance of
various short-term screening tests in Japan; In:
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Kemp, A.S. and AIIA-5.9
Schembri, G.
1985 An elimination diet for chronic urticaria of
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Khoudokormoff, B. and
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1978 Potential carcinogenicity of some food preservatives in the presence of traces of nitrite.
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1960 Die Verträglichkeit der Benzoesäure im chronischen Fütterungsversuch.
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Owner
protection
claimed
Y/N
N
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Kieckebusch,
W. und Lang,
K.
AIIA-5.3;
AIIA-5.5;
AIIA-5.6
Kieckebusch,
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K.
AIIA-5.3;
AIIA-5.5;
AIIA-5.6
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Kieckebusch,
W. und Lang,
K.
AIIA-5.3;
AIIA-5.5;
AIIA-5.6
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Kimmel, C.A.,
Wilson, J.G.
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AIIA-5.6
1971 Studies on metabolism and identification of the
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Kingsbury, F.B. AIIA-5.1
1923 The synthesis and excretion of hippuric acid: the
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Kinsey, R.E.
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1944 Reaction following ingestion of sodium benzoate
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Klein, J.R. and
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1966 The identification of contact allergens by human
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Kluge, H.
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Knoefel,
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Kowalewski, K. AIIA-5.3
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Kramer, M. und AIIA-5.3
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Kreis, H., Frese, AIIA-5.3
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claimed
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Kubota, K.,
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Kubota, K.and
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Lahti, A.
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Lahti, A.
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AIIA-5.9
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Lang, H.und
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A. and Hannuksela, M.
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Litton Bionetics AIIA-5.4
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Loncin, M.
AIIA-5.3
Lucas, D.R.
AIIA-5.2;
AIIA-5.9
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Lucas, D.R.
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Marquardt, P.
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Martin, A.K.
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McCann, J.,
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McCormick
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Michaelsson, G. AIIA-5.9
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Michils, A.,
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Milvy, P. and
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Minor, J.L. and
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AIIA-5.4
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Njagi, G.D.E.
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Nonaka, M.
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AIIA-5.5
Odashima, S.
AIIA-5.5
22 November 2000
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1980 Cooperative programme on long-term assays for
N
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Oikawa, A.,
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AIIA-5.4
1980 Inhibitors of poly(adeosine diphosphate ribose)
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-
Onodera, H.,
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1978 Studies on effects of sodium benzoate on fetuses
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1979 Benzoic acid.
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N
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Opdyke, D.L.
AIIA-5.2
Ortolani, C.,
Pastorello, E.,
Fontana, A.,
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AIIA-5.9
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Palekar, A.G.,
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Kalberg, S.S.,
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Annex
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number
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AIIA-5.8;
Canas, J.A.,
AIIA-5.9
Kalberg, S.S.,
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Parke, D.V. and AIIA-5.8
Lewis, D.F.V.
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Pevny, I., Rauscher, E., Lechner, W. and
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Polonovski M.
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Prival, M.J.,
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AIIA-5.4
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Owner
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claimed
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N
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Pujara, C.P.,
Shao, Z., Duncan, M.R.and
Mitra, A.K.
AIIA-5.1
Purchase,
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Quick, A.J.
AIIA-5.1
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Quick, A.J.
AIIA-5.1;
AIIA-5.9
1932 Conjugation of benzoic acid with glycine, a test
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N
-
Quick, A.J.
AIIA-5.1;
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Rademaker M.
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Rapson, W.H.,
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RCC Notox
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22 November 2000
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claimed
published or not
Y/N
1988 Primary skin irritation/corrosion study of benzoic
N
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RCC Notox
AIIA-5.2
1988 Eye irritation/corrosion study of benzoic acid in
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N
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N
-
N
-
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RCC Notox
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RCC Notox
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AIIA-5.4
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Riihimäki, V.
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Owner
protection
claimed
Y/N
N
-
Ros, A., Juhlin,
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Rosenhall, L.
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1975 Asthmatic patients with hypersensitivity to aspirin, benzoic acid and tartrazine.
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Roskos, K.V.,
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MEN
Rossman, T.G., AIIA-5.4
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Rost, E., Franz,
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Rost, E., Franz,
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A.
AIIA-5.2;
AIIA-5.3
not GLP, published
, U5, 425-479
TOX2000-379
N
-
22 November 2000
Author(s)
Annex
point/
reference
number
Year Title
Data
Owner
protection
report no.
claimed
published or not
Y/N
1983 In vivo correlation between stratum corneum
N
reservoir function and percutaneous absorption.
not GLP, published
275-278
TOX2000-325
Rougier, A.,
Dupuis, D.,
Lotte, C., Roguet, R. and
Schaefer, H.
AIIA-5.1
Schachter, D.
AIIA-5.1
1957 The chemical estimation of acyl glucuronides
and its application to studies on the metabolism
of benzoate and salicylate in man.
not GLP, published
Journal Clinical Investigation, 36, 297-302
TOX2000-326
N
-
Schafer, E.W.
and Bowles,
W.A.
AIIA-5.3
1985 Acute oral toxicity and repellency of 933 chemicals to house and deer mice.
not GLP, published
Arch. Environ. Contam. Toxicol., 14, 111-129
TOX2000-394
N
-
Schanker, L.S.
AIIA-5.1
1959 Absorption of drugs from the rat colon.
not GLP, published
Journal of Pharmacology and Experimental Therapeutics, 126, 283-290
TOX2000-329
N
-
Schanker, L.S., AIIA-5.1
Shore, A.P.,
Brodie, B.B.and
Hogben, C.A.M.
1957 Absorption of drugs from the stomach I. The rat.
not GLP, published
TOX2000-327
N
-
Schanker, L.S., AIIA-5.1
Tocco, D.J.,
Brodie, B.B.and
Hogben, C.A.M.
1958 Absorption of drugs from the rat small intestine.
not GLP, published
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N
-
Schaubschläger, AIIA-5.9
W.W., Becker,
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and Schlaak, M.
1991 Release of mediators from human gastric mucosa
and blood in adverse reactions to benzoate.
not GLP, published
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Annex
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reference
number
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published or not
1999 Without given reference, cited in Ellinger, A.:
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not GLP, published
TOX2000-380
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
Schulte, E.
AIIA-5.2
Senator, H.
AIIA-5.9
1879 Über die Wirkung der Benzoesäure bei der
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Zeitschr. f. klin. Medicin, 1, 2, 243-264
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-
Shtenberg, A.J.
and Ignat ev,
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AIIA-5.3
1970 Toxicological evaluation of some combinations
of food preservatives.
not GLP, published
TOX2000-395
N
-
Simkin, J.L. and AIIA-5.8
White, K.
1957 The formation of hippuric acid.
not GLP, published
Biochem. J., 65, 574-581
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-
Simkin, J.L. and AIIA-5.8
White, K.
1957 The formation of glycine and serine.
not GLP, published
Biochem. J., 67, 287-291
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-
Smyth, H.F. and AIIA-5.2;
Carpenter, C.P. AIIA-5.3
1948 Further experience with the range finding test in
the industrial toxicology laboratory.
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J. Ind. Hyg., 30, 63-68
TOX2000-381
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Smyth, H.F. and AIIA-5.2;
Carpenter, C.P. AIIA-5.3
1948 Further experience with the range finding test in
not GLP, published
J. Ind. Hyg., 30, 63-68
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Author(s)
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reference
number
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report no.
published or not
1924 Über die Hippursäuresynthese in der überlebenden Niere von verschiedenen Tiergattungen,
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Biochemische Zeitschrift, 145, 40-46
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Data
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Y/N
N
-
Snapper, I.,
Grünbaum, A.
und Neuberg, J
AIIA-5.1
Sodemoto, Y.
and Enomoto,
M.
AIIA-5.3;
AIIA-5.5
1980 Report of carcinogenesis bioassay of sodium
benzoate in rats: Absence of carcinogenicity of
sodium benzoate in rats.
not GLP, published
Journal of Environmental Pathology and Toxicology, 4, 87-95
TOX2000-396
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Sodemoto, Y.
and Enomoto,
M.
AIIA-5.3;
AIIA-5.5
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Spustová, V.
and Oravec, C.
AIIA-5.5
1989 Antitumor effect of hippurate. An experimental
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Stein, W.H.,
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AIIA-5.1
1954 Phenylacetylglutamine as a constituent of normal
human urine.
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Journal Amer. Chem. Society, 76, 2848
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Stol, M., Cifkova, I. and Brynda, E.
AIIA-5.2
1988 Irritation effects of residual products derived
from poly (2-hydroxyethyl methacrylate) gels.
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point/
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number
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AIIA-5.9
22 November 2000
Year Title
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protection
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claimed
published or not
Y/N
1925 The effect of sodium benzoate ingestion upon the
N
composition of the blood and urine with especial
reference to the possible synthesis of glycine in
the body.
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Szydlowska, H., AIIA-5.6
Dluzniewski, A.
and Buczynska,
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1980 Inhibition of histochemical reaction to SH
groups by pharmacological agents as a preliminiary test for the teratogenic activity.
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Pol. J. Pharmacol. Pharm., 32, 557-565
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Takeda, E.,
Kuroda, Y.,
Toshima, K.,
Watanabe, T.,
Naito, E. and
Miyao, M.
AIIA-5.9
1983 Effect of long-term administration of sodium
benzoate to a patient with partial ornithine carbamoyl transferase deficiency.
not GLP, published
Clinical Pediatrics, 22, 3, 1983, 206-208
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Tarlo, S.M. and
Broder, I.
AIIA-5.9
1980 Tartrazine/benzoate challenge and dietary avoidance in troublesome asthma.
not GLP, published
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-
Temellini, A.,
Mogavero, S.,
Giulianotti,
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F. and Pacifici,
G. M.
AIIA-5.1
1993 Conjugation of benzoic acid with glycine in
human liver and kidney: A study on the interindividual variability.
not GLP, published
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Thabrew, M.I.,
Bababunmi E.
A. and French,
M.R.
AIIA-5.1
1980 The metabolic fate of (14C) benzoic acid in
protein-energy deficient rats.
not GLP, published
Toxicology Letters, 5, 363-367
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Author(s)
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number
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report no.
published or not
1975 Provocation tests with antiphlogistica and food
additives in recurrent urticaria.
not GLP, published
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Data
Owner
protection
claimed
Y/N
N
-
Thune, P. and
Granholt, A.
AIIA-5.9
Tohda, H.,
Horaguchi, K.,
Takahashi, K.,
Oikawa, A. and
Matsushima, T.
AIIA-5.4
1980 Epstein-barr virus-transformed human
lymphoblastoid cells for study of sister chromatid exchange and their evaluation as a test system.
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Cancer Research, 40, 4775-4780
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Toth, B.
AIIA-5.3;
AIIA-5.5
1984 Short communications; Lack of tumorigenicity of
sodium benzoate in mice.
not GLP, published
Fundamental and Applied Toxicology, 4, 494496
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N
-
Toth, B.
AIIA-5.3;
AIIA-5.5
not GLP, published
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N
-
Tsushima, K.
AIIA-5.8
1954 Interrelation between the function of hemeproteins and the structural modifications of their
protein parts.
not GLP, published
The Journal of Biochemistry, 41, 3, 359-366
TOX2000-481
N
-
Van Bever,
H.P., Docx, M.
and Stevens,
W.J.
AIIA-5.9
1989 Food and food additives in severe atopic dermatitis.
not GLP, published
Allergy, 44, 588-594
TOX2000-534
N
-
22 November 2000
Author(s)
Annex
point/
reference
number
Verrett, M.J.,
Scott, W.F.,
Reynaldo, E.F.,
Alterman, E.K.
and Thomas,
C.A.
AIIA-5.6
Vieluf, D.,
Przybilla, B.,
Tränker, I. and
Ring, J.
AIIA-5.9
1990 Provocation of atopic eczema by oral challenge
tests with food additives.
not GLP, published
Arch Dermatol Res, 281, 544
TOX2000-535
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Vogt; T.
AIIA-5.9
1999 Sodium benzoate-induced acute leucocytoplastic
vasculitis with unusual clinical appearance.
not GLP, published
Arch Dermatol, 135, 726-727
TOX2000-536
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Vries, de A. and AIIA-5.1
Alexander, B.
1948 Studies on amino acid metabolism. III. Plasma
glycine concentration and hippuric acid formation following the ingestion of benzoate.
not GLP, published
Journal Clin. Invest, 27, 665-668
TOX2000-352
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-
Waldo, J.F.,
Masson, J.M.,
Lu, W. and
Tollstrup, J.
AIIA-5.9
1948 The effect of benzoic acid and caronamide on
blood penicillin levels and on renal function.
not GLP, published
Amer. J. Med. Sci., 117, 563-568
TOX2000-537
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-
Wan, S.H. and
Riegelman, S.
AIIA-5.1
1972 Renal contribution to overall metabolism of
drugs I: Conversion of benzoic acid to hippuric
acid.
not GLP, published
Journal of Pharmaceutical Sciences, 61, 12781284
TOX2000-353
N
-
1976 Challenge test battery in chronic urticaria.
not GLP, published
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-
Warin, R.P. and AIIA-5.9
Smith, R.J.
Year Title
Data
Owner
protection
report no.
claimed
published or not
Y/N
1980 Toxicity and teratogenicity of food additive
N
chemicals in the developing chicken embryo.
not GLP, published
TOX2000-452
Author(s)
Annex
point/
reference
number
Year Title
report no.
published or not
1982 Chronic urticaria investigations with patch and
challenge tests.
not GLP, published
TOX2000-539
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
1982 Effects of oxygen radical scavengers and antioxidants on phagocyte-induced mutagenesis.
not GLP, published
The Journal of Immunology, 128, 6, 1982, 27702772
TOX1999-1427
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Wester, R.C.
AIIA-5.1
and Maibach, H.
I.
1976 Relationship of topical dose and percutaneous
absorption in rhesus monkey and man.
not GLP, published
The Journal of Investigative Dermatology, 67,
518-520
TOX2000-354
N
-
White, A.
1941 Growth-inhibition produced in rats by the oral
administration of sodium benzoate.
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Yale J. Biol. Med., 13, 759-768
TOX2000-398
N
-
White, F.D. and AIIA-5.8
Kerr, A.
1957 The effect of various denaturants on the hemoglobins of adult and cord blood.
not GLP, published
Can. J. of Biochem. and Physiol., 35, 5, 273-279
TOX2000-482
N
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Wiessler, M.,
Romruen, K.
and Pool, B.L.
1983 Biological activity of benzylating N-nitroso
compounds. Models of activated Nnitrosomethyl benzylamine; cited in JECFA
1997.
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Carcinogenesis, 4, 867-871
TOX2000-432
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-
Warin, R.P. and AIIA-5.9
Smith, R.J.
Weitzman, S.A.
and Stossel,
Th.P.
AIIA-5.4
AIIA-5.3
AIIA-5.4
Author(s)
Annex
point/
reference
number
Wiley, H.M.
and Bigelow,
W.D.
AIIA-5.9
22 November 2000
Year Title
Data
Owner
protection
report no.
claimed
published or not
Y/N
1908 Influence of benzoic acid and benzoates on diN
gestion and health. Bulletin 84, Pt. IV, Bureau of
Chemistry, U. S. Department of Agriculture,
cited in FDA, 1972.
not GLP, published
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Williams, A.E.
AIIA-5.8
1978 Benzoic acid.
not GLP, published
Encyclopaedia of Chemical Technology. 3. Ed.,
1978
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Williams, R.T.
AIIA-5.1
1959 Detoxication mechanisms, chapter 11 (The metabolism of aromatic acids), 348.
not GLP, published
Chapman and Hall, Ltd., London, 1959
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Xing, W. and
Zhang, Z.
AIIA-5.4
1990 A comparison of SCE test in human lymphocytes
and Vicia faba: A hopefull technique using
plants to detect mutagens and carcinogens.
not GLP, published
Mut. Res., 241, 109-113
TOX2000-433
N
-
Ylipieti, S. and
Lahti, A.
AIIA-5.9
1989 Effect of the vehicle on non-immunologic immediate contact reactions.
not GLP, published
TOX2000-541
N
-
Young, E.,
AIIA-5.9
Patel, S., Stoneham, M., Rona,
R. and Wilkinson, J.D.
1987 The prevalence of reaction to food additives in a
survey population.
not GLP, published
Journal of the Royal College of Physicians of
London, 21, 4, 241-247
TOX2000-542
N
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Zeiger, E., Anderson, B.,
Haworth, S.,
Lawelor, T. and
Mortelmans, K.
1988 Salmonella mutagenicity tests: IV. Results from
the testing of 300 chemicals.
not GLP, published
Environmental and Molecular Mutagenesis, 11,
12, 1-158
TOX2000-434
N
-
AIIA-5.4
Author(s)
Annex
point/
reference
number
Zhurkov, V.S.
AIIA-5.4
Year Title
report no.
published or not
1975 Investigation of the mutagenic activity of drug
preparations and food additives in a culture of
human lymphocytes.
not GLP, published
Sov. Genetika, 11, 4, 1975, 146-149
TOX1999-1428
Codes of owner
MEN:
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
A.7 Residue data
A.7 Residue data (Annex IIA 6; Annex IIIA 8 and 12.2)
No references submitted.
22 November 2000
A.8 Environmental fate and behaviour
22 November 2000
A.8 Environmental fate and behaviour (Annex IIA 7; Annex IIIA 9)
Author(s)
Annex
point/
reference
number
Year Title
report no.
published or not
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BUA Report 145. Ed.: GDCh Advisory Committee on Existing Chemicals of Environmental
Relevance, 1993
BOD2000-562
Data
Owner
protection
claimed
Y/N
N
-
not GLP, published
Relevance, 1993
BOD2000-562
N
-
Baziramakenga, AIIA-7.1
R.; Simrad, R.R.
and Leroux,
G.D.
1995 Determination of organic acids in soil extracts by
ion chromatography.
not GLP, published
BOD2000-559
N
-
Dao, T.H. and
Lavy, T.L.
AIIA-7.1
1987 A Kinetic Study of Adsorption and Degradation
of Aniline, Benzoic Acid, Phenol, and Diuron in
Soil Suspensions.
not GLP, published
Soil Science , 143, 1, 1987, 66-72
BOD97-00592
N
-
Jalal, M.A.F.
and Read, D.J.
AIIA-7.1
fungitoxicity.
not GLP, published
Plant and Soil, 70, 1983, 273 - 286
BOD2000-558
N
-
Lokke, H.
AIIA-7.1.2
1984 Leaching of Ethylene Glycol and Ethanol in
Subsoils.
not GLP, published
Water, Air, and Soil Pollution , 2, 1984, 373-387
BOD97-00593
N
-
Anonym
AIIA-7.1;
AIIA-7.2
Anonym
AIIA-7.1;
AIIA-7.2
A.8 Environmental fate and behaviour
Author(s)
Annex
point/
reference
number
Year Title
report no.
published or not
1982 Rates of Mineralization of Trace Concentrations
of Aromatic Compounds in Lake Water and
Sewage Samples.
not GLP, published
Applied and Environmental Microbiology , 43,
5, 1982, 1133-1138
WAS97-00186
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
1992 Allgemeine Mikrobiologie
7. Auflage.
not GLP, published
, 1992
BOD2000-543
N
-
1977 Handbook of environmental data on organic
chemicals.
not GLP, published
, 1977, 120-121
BOD2000-542
N
-
Zahn, R. und
Wellens, H.
1980 Prüfung der biologischen Abbaubarkeit im
Standversuch - weitere Erfahrungen und neue
Einsatzmöglichkeiten.
not GLP, published
Z. Wasser Abwasser Forsch. , 13, 1, 1980, 1-7
WAS97-00187
N
-
Rubin, H.E.,
Subba-Rao,
R.V. and Alexander, M.
AIIA-7.2.1.3
Schlegel, H. G.
AIIA-7
AIIA-7.2.1.3
Codes of owner
A.9 Ecotoxicology
22 November 2000
A.9 Ecotoxicology (Annex IIA 8; Annex IIIA 10)
Author(s)
Annex
point/
reference
number
Year Title
report no.
published or not
1998 Acute toxicity test on the rainbow trout (Oncorhynchus mykiss) Semistatic test procedure
Testsubstance: Benzoic Acid.
NA 98 9408/3
GLP, unpublished
WAT98-50279
Data
Owner
protection
claimed
Y/N
Y
MEN
Jonas, W.
AIIA-8.2.1
Jonas, W.
AIIA-8.2.4
1998 Acute immobilisation test on Daphnia magna
(semistatic test procedure) Testsubstance: Benzoic Acid.
NA 98 9408/2
GLP, unpublished
WAT98-50278
Y
MEN
Jonas, W.
AIIA-8.2.6
1998 Determination of the growth inhibition on Pseudokirchneriella subcapitata (former name: Ankistrodesmus bibraianus) Testsubstance: Benzoic
Acid.
NA 98 9408/1
GLP, unpublished
WAT98-50277
Y
MEN
Codes of owner
MEN:
Monograph
22 November 2000
Benzoic acid
Volume 3
Annex B
Summary, Scientific
Evaluation and Assessment
-iBenzoic acid – Contents
22 November 2000
Contents
B
Rapporteur Member State summary, evaluation and assement of the data and
information
B.1
Identity ................................................................................................................... 3
B.1.1
B.1.1.1
B.1.2.3
B.1.2.4
B.1.2.5
B.1.3
Identity of the active substance (Annex IIA 1 and 3.1) ........................................... 3
Annex I (Annex IIA 1.1) ......................................................................................... 3
Common name and synonyms (Annex IIA 1.3) ...................................................... 3
Chemical name (Annex IIA 1.4) ............................................................................. 3
Manufacturer's development code number (Annex IIA 1.5) ................................... 3
CAS, EEC and CIPAC numbers (Annex IIA 1.6)................................................... 3
Molecular and structural formulae, molecular mass (Annex IIA 1.7)..................... 4
Manufacturer or manufacturers of the active substance (Annex IIA 1.2) ............... 4
Method or methods of manufacture (Annex IIA 1.8).............................................. 4
Specification of purity of the active substance (Annex IIA 1. 9) ............................ 5
Identity of isomers, impurities and additives (Annex IIA 1.10).............................. 5
Analytical profile of batches (Annex IIA 1.11)....................................................... 5
Identity of the plant protection product (Annex IIIA 1) .......................................... 5
(Annex IIIA 1.3) ...................................................................................................... 5
Manufacturer or manufacturers of the plant protection product (Annex IIIA
1.2)........................................................................................................................... 5
Type of the preparation and code (Annex IIIA 1.5) ................................................ 6
Function (Annex IIA 3.1; Annex IIIA 1.6).............................................................. 6
Composition of the preparation (Annex IIIA 1.4) ................................................... 6
References relied on ................................................................................................ 6
B.2
Physical and chemical properties....................................................................... 11
B.2.1
B.2.2
B.2.3
Physical and chemical properties of the active substance (Annex IIA 2) ............. 11
Physical, chemical and technical properties of the plant protection products
(Annex IIIA 2) ....................................................................................................... 17
References relied on .............................................................................................. 21
B.3
Data on application and further information ................................................... 27
B.3.1
B.3.2
B.3.3
B.3.4
B.3.4.1
Data on application relevant to the active substance (Annex IIA 3.1 to 3.6) ........ 27
Data on application relevant to the plant protection product (Annex IIIA 3)........ 27
Summary of data on application............................................................................ 27
Further information on the active substance (Annex IIA 3.7 to 3.9)..................... 31
Recommended methods and precautions concerning handling, storage,
transport or fire (Annex IIA 3.7) ........................................................................... 31
Procedures for destruction or decontamination (Annex IIA 3.8) .......................... 31
Emergency measures in the case of an accident (Annex IIA 3.9) ......................... 31
Further information on the plant protection product (Annex IIIA 4) .................... 31
Packaging (type, materials, size, etc.), compatibility of the preparation with
proposed packaging materials (Annex IIIA 4.1) ................................................... 31
Description of packaging....................................................................................... 31
Suitability of packages and closures...................................................................... 32
B.1.1.2
B.1.1.3
B.1.1.4
B.1.1.5
B.1.1.6
B.1.1.7
B.1.1.8
B.1.1.9
B.1.1.10
B.1.1.11
B.1.2
B.1.2.1
B.1.2.2
B.3.4.2
B.3.4.3
B.3.5
B.3.5.1
B.3.5.1.1
B.3.5.1.2
- ii Benzoic acid – Contents
B.3.5.1.3
B.3.5.2
B.3.5.3
22 November 2000
B.3.5.6.1
B.3.5.6.2
B.3.5.6.3
B.3.6
Resistance of the packaging material to its contents ............................................. 33
Procedures for cleaning application equipment and protective clothing............... 33
Re-entry periods, necessary waiting periods or other precautions to protect
man, livestock and the environment (Annex IIIA 4.3).......................................... 33
Recommended methods and precautions concerning handling, storage,
transport or fire (Annex IIIA 4.4) .......................................................................... 34
Procedures for use in the event of an accident ...................................................... 34
Procedures for destruction or decontamination of the plant protection
product and its packaging (Annex IIIA 4.6) .......................................................... 35
Neutralisation procedures...................................................................................... 35
Safe disposal of the plant protection product and its packaging ........................... 35
Other methods for disposal.................................................................................... 35
B.4
Proposals for the classification and labelling.................................................... 39
B.4.1
B.4.3
Proposals for the classification and labelling of the active substance (Annex
IIA 10) ................................................................................................................... 39
Proposals for the classification and labelling of preparations (Annex IIIA
12.3 and 12.4)........................................................................................................ 39
B.5
Methods of analysis ............................................................................................. 43
B.5.1
B.5.5
B.5.5.1
B.5.5.2
B.5.6
Analytical methods for formulation analysis (Annex IIA 4.1; Annex IIIA
5.1)......................................................................................................................... 43
Analytical methods for formulation analysis (technical active substance)
(Annex IIA 4.1) ..................................................................................................... 43
Method for the determination of pure active substance in the active
substance as manufactured .................................................................................... 43
Methods for the determination of significant and / or relevant impurities and
additives (e.g. stabiliser) in the active substance as manufactured ....................... 43
Specificity, linearity, accuracy and repeatability................................................... 43
Analytical methods for formulation analysis (plant protection product)
(Annex IIIA 5.1) .................................................................................................... 43
Analytical methods (residue) for plants, plant products, foodstuffs of plant
and animal origin, feedingstuffs (Annex IIA 4.2.1; Annex IIIA 5.2).................... 44
Analytical methods (residue) soil, water, air (Annex IIA 4.2. 2 to 4.2.4;
Annex IIIA 5.2) ..................................................................................................... 44
Analytical methods (residue) for body fluids and tissues (Annex IIA 4.2.5;
Annex IIIA 5.2) ..................................................................................................... 44
Evaluation and assessment .................................................................................... 44
Formulation analysis ............................................................................................. 44
Residue analysis .................................................................................................... 45
B.6
Toxicology and metabolism ................................................................................ 49
B.6.1
Absorption, distribution, excretion and metabolism (toxicokinetics) (Annex
IIA 5.1) .................................................................................................................. 50
Acute toxicity including irritancy and skin sensitization (Annex IIA 5.2)............ 56
Short-term toxicity (Annex IIA 5.3)...................................................................... 61
B.3.5.4
B.3.5.5
B.3.5.6
B.4.2
B.5.1.1
B.5.1.1.1
B.5.1.1.2
B.5.1.1.3
B.5.1.2
B.5.2
B.5.3
B.5.4
B.6.2
B.6.3
- iii Benzoic acid – Contents
B.6.3.1
B.6.3.1.1
B.6.3.1.2
B.6.3.2
B.6.3.3
B.6.3.4
B.6.3.5
B.6.4
B.6.5
B.6.5.1
B.6.5.1.1
B.6.5.1.2
B.6.5.2
B.6.5.2.1
B.6.5.2.2
B.6.5.2.3
B.6.6
B.6.6.1
B.6.6.2
B.6.6.2.1
B.6.6.2.2
B.6.6.2.3
B.6.6.2.4
B.6.6.3
B.6.7
B.6.8
B.6.8.1
B.6.9
B.6.9.1
B.6.9.2
B.6.9.3
B.6.9.4
B.6.9.5
B.6.9.6
B.6.9.7
B.6.9.8
B.6.9.9
B.6.9.10
B.6.9.11
B.6.10
B.6.10.1
B.6.10.2
B.6.10.3
B.6.10.4
B.6.11
22 November 2000
Studies, Rat............................................................................................................ 61
Oral studies............................................................................................................ 61
Inhalative study, Rat .............................................................................................. 67
Oral studies, Mouse............................................................................................... 67
Oral studies, Cat .................................................................................................... 69
Oral studies, Dog................................................................................................... 70
Oral studies, Guinea pig ........................................................................................ 71
Genotoxicity (Annex IIA 5.4) ............................................................................... 71
Long-term toxicity and carcinogenicity (Annex IIA 5.5) ...................................... 75
Long-term toxicity................................................................................................. 76
Oral Studies, Rat.................................................................................................... 76
Oral Study, Mouse................................................................................................. 77
Carcinogenicity...................................................................................................... 77
Oral Studies, Rat.................................................................................................... 77
Oral Studies, Mouse .............................................................................................. 78
Other carcinogenicity tests .................................................................................... 79
Reproductive toxicity (Annex IIA 5.6).................................................................. 80
Reproduction ......................................................................................................... 81
Developmental toxicity ......................................................................................... 81
Rat ...................................................................................................................... 81
Rabbit .................................................................................................................... 84
Mouse .................................................................................................................... 84
Hamster ................................................................................................................. 84
Other teratogenicity tests ....................................................................................... 85
Delayed neurotoxicity (Annex IIA 5.7)................................................................. 86
Further toxicological studies (Annex IIA 5.8)....................................................... 86
Summarized description of investigations ............................................................ 86
Medical data and information (Annex IIA 5.9)..................................................... 88
Acute experiments with human volunteers ........................................................... 88
Subacute / subchronic experiments with human volunteers ................................. 89
Test for irritancy on human volunteers.................................................................. 89
Experiences with medical use of benzoic acid/benzoates ..................................... 90
Non-immune immediate contact reactions (NIICRs) of benzoic
acid/benzoates ....................................................................................................... 90
Medical surveillance on manufacturing plant personal......................................... 93
Direct observation, e.g. clinical cases and poisoning incidents............................. 93
Observations on exposure of the general population and epidemiological
studies if appropriate ............................................................................................. 93
Diagnosis of poisoning (determination of active substance, metabolites),
specific signs of poisoning, clinical tests) ............................................................. 94
Proposed treatment: first aid measures, antidotes, medical treatment................... 94
Expected effects of poisoning ............................................................................... 94
Summary of mammalian toxicology and proposed ADI, AOEL, ARfD and
drinking water limit (Annex IIA 5.10) .................................................................. 94
Summary of mammalian toxicology ..................................................................... 94
Calculation of the Acceptable Daily Intake (ADI) ................................................ 98
Acceptable Operator Exposure Level (AOEL)...................................................... 99
Acute Reference Dose (ARfD).............................................................................. 99
Acute toxicity including irritancy and skin sensitization of preparations
(Annex IIIA 7.1) .................................................................................................... 99
- iv Benzoic acid – Contents
22 November 2000
B.6.11.1
B.6.11.2
B.6.11.3
B.6.11.4
B.6.11.5
B.6.11.6
B.6.12
B.6.13
Acute oral toxicity ............................................................................................... 100
Acute dermal toxicity .......................................................................................... 101
Acute inhalation toxicity ..................................................................................... 101
Skin Irritation - Rabbit ........................................................................................ 102
Eye Irritation - Rabbit.......................................................................................... 102
Skin sensitization................................................................................................. 104
Dermal absorption (Annex IIIA 7.3) ................................................................... 104
Toxicological data on non active substances (Annex IIIA 7.4 and point 4 of
the introduction) .................................................................................................. 104
B.6.14
Exposure data (Annex IIIA 7.2) .......................................................................... 104
B.6.14.1 Operator exposure ............................................................................................... 105
B.6.14.1.1 German model ..................................................................................................... 106
B.6.14.1.2 EASE model ........................................................................................................ 106
B.6.14.2 Worker exposure ................................................................................................. 109
B.6.14.3 Bystander exposure ............................................................................................. 109
B.6.15
References relied on ............................................................................................ 109
B.7
Residue data....................................................................................................... 149
B.7.1
B.7.17
Metabolism, distribution and expression of residues in plants (Annex IIA
6.1; Annex IIIA 8.1) ............................................................................................ 149
Metabolism, distribution and expression of residues in livestock (Annex IIA
6.2; Annex IIIA 8.1) ............................................................................................ 149
Definition of the residue (Annex IIA 6.7; Annex IIIA 8.6)................................. 149
Use pattern........................................................................................................... 149
Identification of critical GAPs............................................................................. 149
Residues resulting from supervised trials (Annex IIA 6.3; Annex IIIA 8.2)....... 149
Effects of industrial processing and/or household preparation (Annex IIA
6.5; Annex IIIA 8.4) ............................................................................................ 150
Livestock feeding studies (Annex IIA 6.4; Annex IIIA 8.3) ............................... 150
Residues in succeeding or rotational crops (Annex IIA 6.6; Annex IIIA 8.5) .... 150
Proposed pre-harvest intervals for envisaged uses, or withholding periods, in
the case of post-harvest uses (Annex IIA 6.8; Annex IIIA 8.7) .......................... 150
Community MRLs and MRLs in EU Member States (Annex IIIA 12.2) ........... 150
Proposed EU MRLs and justification for the acceptability of those residues
(Annex IIA 6.7; Annex IIIA 8.6)......................................................................... 150
Proposed EU Import tolerances and justification for the acceptability of
those residues ...................................................................................................... 151
Basis for differences, if any, in conclusion reached having regard to
established or proposed Codex MRLs................................................................. 151
Estimates of potential and actual dietary exposure through diet and other
means (Annex IIA 6.9; Annex IIIA 8.8).............................................................. 151
Summary and evaluation of residue behaviour (Annex IIA 6.10; Annex IIIA
8.9)....................................................................................................................... 151
B.8
Environmental fate and behaviour.................................................................. 155
B.8.1
B.8.2
Route and rate of degradation in soil (Annex IIA 7.1.1; Annex IIIA 9.1.1)........ 155
Adsorption, desorption and mobility in soil (Annex IIA 7.1.2, 7.1.3; Annex
IIIA 9.1.2) ............................................................................................................ 155
B.7.2
B.7.3
B.7.4
B.7.5
B.7.6
B.7.7
B.7.8
B.7.9
B.7.10
B.7.11
B.7.12
B.7.13
B.7.14
B.7.15
B.7.16
-vBenzoic acid – Contents
B.8.3
B.8.4
B.8.5
B.8.6
22 November 2000
B.8.6.1
B.8.6.2
B.8.7
B.8.8
B.8.9
B.8.10
Predicted environmental concentrations in soil (Annex IIIA 9.1.3).................... 156
Fate and behaviour in water (Annex IIA 7.2.1; Annex IIIA 9.2. 1, 9.2.3) .......... 156
Impact on water treatment procedures (Annex IIIA 9.2.2).................................. 157
Predicted environmental concentrations in surface water and in ground
water (Annex IIIA 9.2.1, 9.2.3) ........................................................................... 157
Surface water ....................................................................................................... 157
Ground water....................................................................................................... 157
Fate and behaviour in air (Annex IIA 7.2.2; Annex IIIA 9.3) ............................. 157
Predicted environmental concentrations in air (Annex IIIA 9.3) ........................ 158
Definition of the residue (Annex IIA 7.3) ........................................................... 158
B.9
Ecotoxicology ..................................................................................................... 163
B.9.1
B.9.1.1
B.9.1.2
B.9.2
B.9.2.1
B.9.2.2
B.9.2.3
B.9.2.4
B.9.3
B.9.3.1
B.9.3.2
B.9.4
B.9.5
B.9.6
B.9.7
B.9.8
B.9.10
B.9.11
Effects on birds (Annex IIA 8.1; Annex IIIA 10.1)............................................. 163
Toxicity (Annex IIA 8.1, Annex IIIA 10.1)......................................................... 163
Risk assessment for birds .................................................................................... 163
Effects on aquatic organisms (Annex IIA 8.2; Annex IIIA 10.2)........................ 163
Acute toxicity to fish ........................................................................................... 163
Acute toxicity to aquatic invertebrates ................................................................ 164
Effects on algal growth........................................................................................ 164
Risk assessment for aquatic organisms ............................................................... 165
Effects on other terrestrial vertebrates (Annex IIIA 10.3)................................... 165
Toxicity to wild mammals (Annex IIIA 10.3)..................................................... 165
Risk assessment for wild mammals..................................................................... 165
Effects on bees (Annex IIA 8.3.1; Annex IIIA 10.4)........................................... 165
Effects on other arthropod species (Annex IIA 8.3.2; Annex IIIA 10.5) ............ 165
Effects on earthworms (Annex IIA 8.4; Annex IIIA 10.6.1)............................... 165
Effects on other soil non-target macro-organisms (Annex IIIA 10.6.2).............. 166
Effects on soil non-target micro-organisms (Annex IIA 8.5; Annex IIIA
10.7)..................................................................................................................... 166
Effects on other non-target organisms (flora and fauna) believed to be at risk
(Annex IIA 8.6) ................................................................................................... 166
Effects on biological methods of sewage treatment (Annex IIA 8.7) ................. 166
B.10
Appendices ......................................................................................................... 171
B.10.1
B.10.2
Appendix I: Standard terms and abbreviations ................................................... 171
Appendix II: Specific terms and abbreviations ................................................... 183
B.9.9
Annex B
Benzoic acid
B-1: Identity
-3Benzoic acid – Annex B.1: Identity
22 November 2000
B.1 Identity
B.1.1 Identity of the active substance (Annex IIA 1 and 3.1)
B.1.1.1
Annex I (Annex IIA 1.1)
Menno Chemie-Vertriebs-Ges.mbH
Langer Kamp 104
D-22850 Norderstedt
Germany
Contact person: Jan Nevermann
Tel No.: +49 40 5253024
Fax No.: +49 40 5253027
B.1.1.2
Common name and synonyms (Annex IIA 1.3)
Common name (ISO, accepted): benzoic acid
B.1.1.3
Chemical name (Annex IIA 1.4)
Chemical name IUPAC: benzoic acid
Chemical name CA:
benzoic acid
B.1.1.4
Manufacturer's development code number (Annex IIA 1.5)
Benzoic acid
B.1.1.5
CAS, EEC and CIPAC numbers (Annex IIA 1.6)
CAS:
CIPAC:
EINECS:
ELINCS:
65-85-0
622
2006182
not available
B.1.1.6
22 November 2000
Molecular and structural formulae, molecular mass (Annex IIA 1.7)
Molecular formula:
Structural formula:
C7H6O2
O
OH
Molecular mass:
B.1.1.7
122.12
Manufacturer or manufacturers of the active substance (Annex IIA 1.2)
CVH Chemie-Vertrieb GmbH & Co. Hannover KG
Podbielskistr. 22
D-30163 Hannover
Germany
Phone:
Fax:
+49 511 628151
+49 511 625334
B.1.1.8
Method or methods of manufacture (Annex IIA 1.8)
Benzoic acid is manufactured by liquid-phase oxidation of toluene employing various cobalt
catalysts. Figure B.1.1-1 gives a general flow diagram. The syntheses conditions are: 308 to
790 kPa and 130 to 160 °C. The by-products water, formic acid, acetic acid and CO2 are volatile at these conditions and could be distilled like excess toluene. Benzoic acid is crystallised
with a yield over 90% and a purity over 99%. The substance is used for pharmaceutical formulations.
H2O
formic acid
acetic acid
toluene
CO2
air
toluene
cobalt
liquid phase reactor
308-790 kPa
130-160 °C
toluene
recycle
distillation
and/or
crystallization
benzoic acid
tar
Figure B.1.1-1:
General flow diagram of liquid-phase toluene oxidation (Williams,
1978)
B.1.1.9
22 November 2000
Specification of purity of the active substance (Annex IIA 1. 9)
The active substance benzoic acid has pharmaceutic quality. The purity as well as the limits of
the impurities are defined by the German pharmacopoeia (current revision DAB 10, 1991):
Purity:
99.0-100.5 %
B.1.1.10 Identity of isomers, impurities and additives (Annex IIA 1.10)
Isomers:
None
Impurities: Cinnamic acid:
Ash:
Additives: None
max. 0.1%
max. 0.001%
max. 0.1%
not detectable
B.1.1.11 Analytical profile of batches (Annex IIA 1.11)
Analytical profiles of batches are not required, because the maximum content of impurities
does not exceed 1 g/kg. The active substance has pharmaceutic quality. The purity as well as
the limits of the impurities are defined by the German pharmacopoeia (current revision DAB
10, 1991):
Purity:
Cinnamic acid:
Ash:
99.0-100.5 %
max. 0.1%
max. 0.001%
max. 0.1%
not detectable
B.1.2 Identity of the plant protection product (Annex IIIA 1)
B.1.2.1
(Annex IIIA 1.3)
Proposed trade names:
B.1.2.2
Menno-Florades
M&ENNO-Florades
Manufacturer or manufacturers of the plant protection product (Annex IIIA
1.2)
A.F.P. GmbH
Otto Brenner-Str. 16
D-21337 Lueneburg
Phone: +49 4131 55085
Fax: +49 4131 81131
Contact person: Dr. W. Hahn
B.1.2.3
22 November 2000
Type of the preparation and code (Annex IIIA 1.5)
Soluble liquid (SL)
B.1.2.4
Function (Annex IIA 3.1; Annex IIIA 1.6)
Bactericide, virucide, viroicide, fungicide
B.1.2.5
Composition of the preparation (Annex IIIA 1.4)
Confidential information, see Annex C.
B.1.3 References relied on
Annex
point/
reference
number
Author(s)
AIIA-1
Freitag, D.,
Ballhorn, L.,
Geyer, H.,
Korte, F.
AIIA-1.3;
AIIA-1.4;
AIIA-1.7
Anonym
Year Title
report no.
published or not
1985 Environmental hazard profile of organic chemicals.
not GLP,published
Chemosphere, 14, 10, 1985, 1589-1616
CHE98-00884
not GLP,published
Data
Owner
protection
claimed
Y/N
N
-
N
-
CHE98-00890
AIIA-1.3;
AIIA-1.4;
AIIA-1.6;
AIIA-1.7;
AIIA-1.8;
AIIA-1.10;
AIIA-2.1;
AIIA-2.2;
AIIA-2.3;
AIIA-2.4;
AIIA-2.6;
AIIA-4.1
Anonym
not GLP,published
Relevance., 1993
CHE98-00891
N
-
AIIIA-1.4
Anonym
1986 Isopropylalkohol.
not GLP,published
DAC, 2. Ergänzung 90, 1986, 1-5
BEI96-00497
N
-
Annex
point/
reference
number
Author(s)
AIIIA-1.4
Anonym
22 November 2000
Year Title
report no.
published or not
1996 Lieferspezifikation für Ameisensäure 99%.
not GLP,published
Data
Owner
protection
claimed
Y/N
N
-
N
-
N
-
N
-
BEI96-00499
AIIIA-1.4
Anonym
1994 Spezifikation und Kenndaten für Monoethylenglykol.
not GLP,published
BEI96-00501
AIIIA-1.4
Anonym
1994 EG - Sicherheitsdatenblatt für Monoethylenglykol.
not GLP,published
BEI96-00502
AIIIA-1.4
Anonym
1993 Sicherheitsdatenblatt für Ameisensäure techn. ca.
98%.
not GLP,published
BEI96-00500
AIIIA-1.4
Anonym
1995 Sicherheitsdatenblatt für IsopropylalkoholCosmetic.
not GLP,published
Shell Chemicals
BEI96-00498
N
-
AIIIA-1.4
Anonym
1995 Sicherheitsdatenblatt für N-Propanol.
not GLP,published
BASF
BEI96-00496
N
-
AIIIA-1.4
Anonym
1995 Produktinformation für KNA-Cumolsulfonat 40.
not GLP,published
Hüls AG
BEI96-00493
N
-
AIIIA-1.4
Anonym
1994 EG-Sicherheitsdatenblatt für KNACumolsulfonat 40.
not GLP,published
N
-
BEI96-00494
Annex
point/
reference
number
Author(s)
AIIIA-1.4
Anonym
22 November 2000
Year Title
report no.
published or not
1993 Sicherheitsdatenblatt für Mersolat W 93.
not GLP,published
Data
Owner
protection
claimed
Y/N
N
-
N
-
BEI96-00492
AIIIA-1.4
Anonym
1996 Angaben zum Beistoff Mersolat W 93.
not GLP,published
BEI96-00490
AIIIA-1.4
Klokkers
1996 Information zum Beistoff N-Propanol.
not GLP,published
BASF AG
BEI96-00495
N
-
AIIA-1.7;
AIIA-2.1;
AIIA-2.4
Anonym
- Grundlfg. 1991.
not GLP,published
N
-
CHE98-00889
Codes of owner
Annex B
Benzoic acid
B-2: Physical and chemical properties
- 11 Benzoic acid – Annex B.2: Physical and chemical properties
22 November 2000
B.2 Physical and chemical properties
B.2.1 Physical and chemical properties of the active substance (Annex IIA 2)
The following information on physical and chemical properties of the active substance has been taken from the literature. Because benzoic acid is a
well known substance the tests were not repeated according to GLP.
Table B.2.1-1:
Section
(Annex
point)
B.2.1.1.1
(IIA 2.1)
B.2.1.1.2
(IIA 2.1)
B.2.1.1.3
(IIA 2.1)
B.2.1.2
(IIA 2.2)
B.2.1.3.1
(IIA 2.3)
Summary of the physical and chemical properties of the active substance benzoic acid
Study
Purity
(w/w)
Method
Results
Comment /
Conclusion
Melting point, of
purified active
substance
Boiling point of
purified active
substance
Temperature of
decomposition or
sublimation
n.s.
n.s.
122.4 °C
acceptable
Williams (1978)
CHE9800847
n.s.
n.s.
249.2 °C
acceptable
Williams (1978)
CHE9800847
n.s..
n.s.
acceptable
Anonym (1993)
CHE9800891
n.s..
n.s.
acceptable
Anonym (1972)
CHE9800848
n.s.
n.s..
acceptable
Anonym (1993)
CHE9800891
Relative density
of purified active
substance
Vapour pressure
of purified active
substance
Begin of sublimation at
> 100 °C, at app. 150 °C formation of anhydride, at app.
370 °C decarboxylation
1.312 g/cm3
0.11 – 0.53 Pa (20 °C)
Reference
Section
(Annex
point)
B.2.1.3.2
(IIA 2.3)
B.2.1.4.1
(IIA 2.4)
B.2.1.4.2
(IIA 2.4)
B.2.1.4.3
(IIA 2.4)
B.2.1.5.1
(IIA 2.5)
Study
Volatility,
Henry's lawconstant of purified
active substance
Appearance:
physical state
Appearance:
colour
Appearance:
odour
Spectra of purified active substance
Purity
(w/w)
n.s.
n.s.
n.s.
n.s.
22 November 2000
Method
Results
Comment /
Conclusion
Calculated from
vapour pressure
and solubility in
water
Visual assessment
Visual assessment
Visual assessment
UV-VIS
0.0046 – 0.022 Pa m³ mol-1
(20 °C)
acceptable
Anonym (1993)
CHE9800891
crystalline solid
acceptable
white
acceptable
odourless to slightly benzoinor benzaldehyde-like
Wave length: Molar extinction
279.0 nm: 729
271.5 nm: 893
227.5 nm:11900
The structure of benzoic acid
is confirmed by all spectra.
acceptable
Williams (1978)
CHE9800847
Williams (1978)
CHE9800847
Williams (1978)
CHE9800847
Anonym (1998)
CHE9800885
IR
NMR
MS
B.2.1.5.2
(IIA 2.5)
Spectra for impurities of toxicological, ecotoxicological or environmental concern
n.a.
n.a.
Not required because the active substance contains no
impurities of toxicological
concern
acceptable
acceptable
acceptable
Reference
Anonym (1998)
CHE9800886
CHE9800887
CHE9800888
Section
(Annex
point)
B.2.1.6
(IIA 2.6)
22 November 2000
Study
Purity
(w/w)
Method
Solubility in water of purified
active substance
food quality
EEC A 6.
B.2.1.7
(IIA 2.7)
Solubility in organic solvents of
the active substance as manufactured (25 °C)
n.s.
n.s.
B.2.1.8
(IIA 2.8)
Partition coefficient of purified
active substance
n.s.
n.s.
B.2.1.9.1
(IIA 2.9)
Hydrolysis rate
of purified active
substance
n.a.
n.a.
Results
Comment /
Conclusion
Reference
2.9 g/l (20 °C, pH: 2.94)
3.4 g/l (25 °C)
pH 5: 5 g/l (20 °C)
pH 9: 15 g/l (20 °C)
acceptable
Kellner (1998)
CHE9800892
Solubility [g/100 g solvent]
acetone:
55.6
benzene:
12.17
4.14
CCl4:
chloroform: 15.02
ethanol:
58.4
ethyl ether 40.8
hexane:
0.94 (17 °C)
methanol:
71.5 (23 °C)
toluene:
10.6
log Pow = 1.87
The effect of pH on the
n-octanol/water partition coefficient was not determined
because the pKa-value is over
2
Stable – taking account of the
chemical structure (aromatic
monocarbon acid) hydrolysis
at pH 5 – 9 will not occur.
acceptable
Williams (1978)
CHE9800847
Freitag et al.(1985)
CHE9800884
acceptable
Section
(Annex
point)
B.2.1.9.2
(IIA 2.9)
22 November 2000
Study
Purity
(w/w)
Method
Results
Comment /
Conclusion
Direct phototransformation in
purified water of
purified active
substance
Quantum yield of
direct photodegradation
Dissociation constant (pKa) of
purified active
substance
Stability in air,
indirect phototransformation
n.a.
n.a.
Not required (no absorption at
λ > 290 nm)
acceptable
n.a.
n.a.
Not required (no absorption at
λ > 290 nm)
acceptable
n.s.
n.s.
pKa = 4.2
acceptable
n.a.
n.a.
acceptable
B.2.1.11.1 Flammability of
(IIA 2.11) active substance
as manufactured
B.2.1.11.2 Auto-flammabi(IIA 2.11) lity of active substance as manufactured
B.2.1.12
Flash point of the
(IIA 2.12) active substance
as manufactured
n.s.
n.s.
Taking into account the type
of formulation and the kind of
application contamination of
air following use according to
the GAP is not expected.
Ignition temperature in air:
573 °C
n.a.
n.a.
acceptable
n.s.
n.s.
Due to the chemical structure
and the vapour pressure no
auto-flammability properties
are expected
> 40 °C (about 121-131 °C,
sublimation)
B.2.1.9.3
(IIA 2.9)
B.2.1.9.4
(IIA 2.9)
B.2.1.10
(IIA 2.10)
acceptable
acceptable
Reference
Williams (1978)
CHE9800847;
Anonym (1993)
CHE9800891
Williams (1978)
CHE9800847
Williams (1978)
CHE9800847
Section
(Annex
point)
B.2.1.13
(IIA 2.13)
B.2.1.14
(IIA 2.14)
B.2.1.15
(IIA 2.15)
Study
22 November 2000
Purity
(w/w)
Method
Explosive properties of active
substance as
manufactured
Surface tension
n.a.
n.a.
According to the chemical
structure explosive properties
are not expected.
n.s.
n.s.
130 °C: 31 ± 1.3 mN/m
150 °C: 30 ± 1.3 mN/m
170 °C: 27 ± 1.5 mN/m
Oxidising properties of active
substance as
manufactured
n.s.
n.s.
According to the chemical
structure oxidising properties
are not expected.
n.s.: not specified
n.a.: not applicable
Results
Comment /
Conclusion
Reference
acceptable
Acceptable, although Williams (1978)
the study was obviCHE9800847
ously not performed
according to EEC
A 5.
acceptable
22 November 2000
B.2.1.16: Summary of of data presented under points B.2.1.1 to B.2.1.15
Benzoic acid is a crystalline white odourless solid with a melting point of 122 °C and a
boiling point of 249 °C. The density is 1.321 g/cm3. The vapour pressure of benzoic acid is
reported to be 0.11 – 0.53 Pa (20 °C), Henry’s Law constant was calculated to be 0.00460.022 Pa m3 mol-1. Solubility in distilled water is 2.9 g/l (pH = 2.94). Benzoic acid is less
soluble under acidic conditions (free acis) and more soluble under alkaline conditions (as
salt). The active substance is soluble in polar organic solvents as acetone, methanol, ethyl
ether and ethanol in the range of 41-72 g/100 g. The solubility decreases in non-polar solvents
like toluene (10.6 g/100 g) or n-hexane (0.94 g/100 g). The log POW values is 1.87. Taking
account of the chemical structure (aromatic monocarbon acid) hydrolysis at pH 5 – 9 will not
occur. The active substance has no explosive or oxidising properties. When benzoic acid is
heated to 370 °C, it is irreversible decomposed to benzene and carbon dioxide, with a small
fraction (2-8 %) decomposing into phenol and carbon monoxide.
22 November 2000
B.2.2 Physical, chemical and technical properties of the plant protection products (Annex IIIA 2)
Product name: Menno Florades (containing 90 g/l benzoic acid, SL)
Table B.2.2-1:
Section
(Annex
point)
B.2.2.1.1
(IIIA 2.1)
B.2.2.1.2
(IIIA 2.1)
B.2.2.1.3
(IIIA 2.1)
B.2.2.2.1
(IIIA 2.2)
Summary of the physical, chemical and technical properties of the plant protection product
Study
Appearance:
colour
Appearance:
odour
Appearance:
physical state
Explosive properties
Method
Results
Comment/Conclusion
visual assessment
amber
Acceptable
olfactory assessment
visual assessment
slightly alcoholic and acidic
Acceptable
liquid
Acceptable
B.2.2.2.2
(IIIA 2.2)
Oxidising properties EEC A 17 is not
applicable to liquids
B.2.2.3.1
(IIIA 2.3)
Flash point
EEC A 9
B.2.2.3.2
(IIIA 2.3)
Flammability
n.a.
Due to the chemical structure Acceptable
of the active substance and
formulants no explosive
properties are expected
(shock, friction, pressure).
Due to the chemical structure Acceptable
of the active substance and
formulants no oxidising are
expected.
28 °C
Study not performed according to GLP,
acceptable.
Not relevant for liquids
Reference
Hahn (1994),
CHE9800853
Gericke and Schlorff (1996),
CHE9800854
Section
(Annex
point)
B.2.2.3.3
(IIIA 2.3)
Study
Auto-flammability
B.2.2.4.1
(IIIA 2.4)
Acidity/alkalinity
B.2.2.4.2
(IIIA 2.4)
B.2.2.5.1
(IIIA 2.5)
B.2.2.5.2
(IIIA 2.5)
pH
B.2.2.5.3
(IIIA 2.5)
B.2.2.6.1
(IIIA 2.6)
B.2.2.6.2
(IIIA 2.6)
B.2.2.7.1
(IIIA 2.7)
B.2.2.7.2
(IIIA 2.7)
B.2.2.7.3
(IIIA 2.7)
B.2.2.8.1
(IIIA 2.8.1)
Surface tension
22 November 2000
Method
EEC A 15
CIPAC MT 75
(glass electrode)
Results
The fomulation has an
auto.ignition temperature of
435 °C.
Due to the pH value of the
neat preparation of 5.8 the
test was not performed.
pH (CIPAC water D, 1%) = 2.64
Kinematic viscosity
Dynamic viscosity
Comment/Conclusion
Acceptable
Reference
Angly (2000),
PHY2000-664
Study not performed acAFP (1996), CHE9800855
cording to GLP, acceptable.
Study not performed acAFP (1996), CHE9800855
cording GLP, acceptable.
Brockfield viscometer (OECD
114)
EEC A5
6.9 mPa s
53.4 mN/m
Acceptable
d204 = 1.0
Acceptable
Bulk (tap) density
EEC A 3 (pyknometer)
n.a.
Schulz (2000),
PHY2000-663
AFP (1996), CHE9800855
Storage stability
CIPAC MT 46
Acceptable
AFP (1996), CHE9800856
Low temperature
stability
Shelf-life
CIPAC MT 39
Physically and chemically
stable
stable
Acceptable.
AFP (1996), CHE9800857
GIFAP Monograph 17
n.a.
Chemically and physically
stable for at least 2 years
n.a. for SL formulation
Acceptable
AFP (1998), CHE9800858
Relative density
Wettability
Section
(Annex
point)
B.2.2.8.2
(IIIA 2.8.2)
B.2.2.8.3.1
(IIIA 2.8.3)
B.2.2.8.3.2
(IIIA 2.8.3)
B.2.2.8.4
(IIIA 2.8.4)
B.2.2.8.5
(IIIA 2.8.5)
B.2.2.8.6.1
(IIIA 2.8.6)
B.2.2.8.6.2
(IIIA 2.8.6)
B.2.2.8.6.3
(IIIA 2.8.6)
B.2.2.8.7.1
(IIIA 2.8.7)
B.2.2.8.7.2
(IIIA 2.8.7)
B.2.2.8.8.1
(IIIA 2.8.8)
Study
Method
22 November 2000
Results
Comment/Conclusion
Persistent foaming
n.a.
Suspensibility
n.a.
Spontaneity of dispersion
Dilution stability
n.a.
CIPAC MT 41
Dry sieve test
n.a.
The application solution is
Acceptable
stable. Concentrations of 2, 4
and 5 % were tested. No insoluble or precipitated particles were observed during 18
h.
Particle size distribution
Dust content
n.a.
n.a.
Friability and attrition
Emulsifiability,
emulsion stability
and re-emulsifiability
Stability of dilute
emulsion
Flowability
n.a.
n.a.
n.a.
n.a.
Reference
Kellner (2000),
PHY2000-665
Section
(Annex
point)
B.2.2.8.8.2
(IIIA 2.8.8)
B.2.2.8.8.3
(IIIA 2.8.8)
B.2.2.9.1
(IIIA 2.9)
B.2.2.9.2
(IIIA 2.9)
B.2.2.10
(IIIA 2.10)
Study
Pourability (rinsability)
Dustability
Physical compatibility with other
products
Chemical compatibility with other
products
Adherence and distribution to seeds
Method
22 November 2000
Results
Comment/Conclusion
n.a.
n.a.
n.a.
Not required because mixing acceptable
is not recommended for the
preparation
Not required because mixing acceptable
is not recommended for the
preparation
n.a. no seed dressing inacceptable
tended
n.a.
n.a.
Reference
22 November 2000
B.2.2.11: Summary and evaluation of data presented under points B.2.2.1 to B.2.2.10
(IIIA 2.11)
The preparation Menno-Florades is a clear slightly amber coloured liquid, which can be diluted with water to the required application concentration of 1 to 4%.
Due to the content of organic solvents the preparation is flammable with a flash point of
28 °C. The preparation is stable after storage at low and high temperatures and has a shelf live
of at least 2 years. Its technical properties indicate no particular problems when used as recommended.
Annex
point/
reference
number
Author(s)
AIIA-1.3;
AIIA-1.4;
AIIA-1.6;
AIIA-1.7;
AIIA-1.8;
AIIA-1.10;
AIIA-2.1;
AIIA-2.2;
AIIA-2.3;
AIIA-2.4;
AIIA-2.6;
AIIA-4.1
Anonym
AIIA-1.7;
AIIA-2.1;
AIIA-2.4
Anonym
Year Title
report no.
published or not
not GLP, published
Relevance., 1993
CHE98-00891
- Grundlfg. 1991.
not GLP, published
Data
Owner
protection
claimed
Y/N
N
-
N
-
CHE98-00889
AIIA-2.1
Williams, A.E.
1978 Benzoic Acid.
not GLP, published
Kirk-Othmer, Enzcyclopedia of Chemical Technology, 3rd Ed, 1978, 778-792
CHE98-00847
N
-
AIIA-2.1;
AIIA-2.3
Informatics Inc.
PB-221 208
not GLP, published
PB-221 20, 1972
CHE98-00848
N
-
Annex
point/
reference
number
Author(s)
AIIA-2.5
Anonym
AIIA-2.5
Anonym
AIIA-2.5
Year Title
report no.
published or not
1998 Benzoic Acid -NMR Spectrum.
CHE98-00887
22 November 2000
Data
Owner
protection
claimed
Y/N
Y
MEN
1998 Benzoic Acid - MS Spectrum.
CHE98-00888
Y
MEN
Anonym
1998 Benzoic Acid - IR Spectrum.
CHE98-00886
Y
MEN
AIIA-2.5
Anonym
1966 Benzoic Acid - UV Spectrum.
CHE98-00885
Y
MEN
AIIA-2.5;
AIIIA-5.1
Hahn
CHE98-00862
Y
MEN
AIIA-2.6
Kellner, G.
1998 Determination of the Water Solubility of Benzoic Acid at pH 5.2 and pH 9.0.
CHEMCON PROJECT NO.CC98B05
CHE98-00892
Y
MEN
AIIA-2.9
Ware, G. W.,
1980 Photodecomposition of DDA.
Crosby, D. G.
not GLP, published
and Giles, J. W.
Arch. Environm. Contam. Toxicol., 9, 1980,
135-146
LUF2000-207
N
-
AIIIA-2.1
Hahn
1994 Untersuchungsbericht Flammpunktbestimmung
nach DIN 51755 Produkt Menno Florades - AFP
GmbH.
CHE98-00852
Y
MEN
AIIIA-2.2
Hahn
1994 Report - Determination of the Flash Point - Method: DIN 51755.
CHE98-00853
Y
MEN
22 November 2000
Annex
point/
reference
number
Author(s)
Year Title
Data
Owner
protection
report no.
claimed
published or not
Y/N
2000 Determination of the Auto-Ignition Temperature
Y
MEN
(Liquids and Gases) of MENNO Florades according to EC Council Directive 92/69/EEC, Part.
A. 15.
2000.4048.AFG
GLP, unpublished
PHY2000-664
AIIIA-2.3
Angly, H.
AIIIA-2.3
Gericke, K. and
Schlorff, S.
1996 Analysenbericht: HH-0245a.
CHE98-00854
Y
MEN
AIIIA-2.4
AFP GmbH
1996 Menno Florades Batch No. 9507.
CHE98-00855
Y
MEN
AIIIA-2.5
AFP GmbH
1996 Menno Florades Batch No. 9507 Prüfung der
Lagerstabilität bei 54 °C (+/-2) für 14 Tage.
CHE98-00856
Y
MEN
AIIIA-2.5
Schulz, H.
2000 Determination of the Surface Tension of MENNO florades in Aqueous Solution.
IF-100/22588-00
GLP, unpublished
PHY2000-663
Y
MEN
AIIIA-2.6
AFP GmbH
1996 Menno Florades Batch No. 9507 Test on Storage
Stability at 0 °C (+/-1) over 7 days.
CHE98-00857
Y
MEN
AIIIA-2.7
Hahn
1998 Stability Test over 29 months Menno Florades
Batch No. 9601, manufactured 18.1.1996.
CHE98-00858
Y
MEN
AIIIA-2.8.4
Keller, G.
2000 Determination of the Dilution Stability of
MENNO Florades.
ChemCon Project No. CC00C07
PHY2000-665
Y
MEN
Codes of owner
MEN:
Annex B
Benzoic acid
B-3: Data on application
and further information
- 27 Benzoic acid – Annex B.3: Data on application and further information
22 November 2000
B.3 Data on application and further information
B.3.1 Data on application relevant to the active substance (Annex IIA 3.1
to 3.6)
Benzoic acid acts by contact as fungicide, bactericide, virucide and viroicide and thus can be
used for disinfection. It is intended to be used in horticulture (floriculture) for the disinfection
of surfaces (i.e. the surfaces on which plants in pots or other culture vessels stand as well as
culture- and storerooms), culture vessels and equipment (e.g. knives) in glasshouses or
similarly protected areas.
The active substance occurrs naturally in several fruits and in resin. It is commonly used for
conservation of food or cosmetics for example. From this field of work some information on
the mode of action is available. It is known that benzoic acid inhibits the bacterial cell
multiplication (Verschueren, 1977). The cellular uptake of for example amino-acids, organic
acids and phosphate is inhibited and results in uncoupling of both substrate transport and
oxidative phosphorylation from the electron transport system (Freese et al., 1973).
Furthermore, the citric acid cycle is inhibited. Effective is the undissociated acid (low pH).
Resistance or cross-resistance has not been observed.
B.3.2 Data on application relevant to the plant protection product (Annex
IIIA 3)
It is intended to use plant protection products based on benzoic acid in horticulture
(floriculture) in glasshouses or similarly protected cultivation areas and in the field.
The product acts by contact against fungi, bacteria, viruses and viroids and thus is used for
disinfection of surfaces (i.e. the surfaces on which plants in in pots or other culture vessels
stand as well as culture- and storerooms), culture vessels and equipment (e.g. knives).
Depending on the organisms to be controlled, the product has to be diluted to a concentration
from one to four percent. Surfaces have to be watered after the last use, equipment and culture
vessels are disinfected by dipping before and after use respectively. For further details of the
application rate see chapter B.03.3.
Used for disinfection of surfaces, culture vessels and equipment the plant protection product
does not cause phytotoxic reactions.
B.3.3 Summary of data on application
Benzoic acid acts effectively against fungi, bacteria, viruses and viroids. Therefore it can be
used for disinfection, an important measure in plant protection.
The active substance occurrs naturally in fruits and reisin and is commonly used for
conservation.
22 November 2000
The plant protection product “MENNO Florades” which is already authorized in Germany, is
of great importance in practice, especially because disinfection with this product includes also
viruses and viroids. At the moment, diseases caused by these organisms cannot be treated.
No phytotoxic effects have been observed on plants which had contact to materials disinfected
with the plant protection product.
22 November 2000
Crop and/
or situation
(a)
Member
State
or
Country
Product
name
F
G
or
I
(b)
Pests or
Group of pests
controlled
(c)
Formulation
Type
Application
(d-f)
Conc
of as
(i)
method
kind
(f-h)
growth
stage &
season
(j)
after the
last use
number
min max
(k)
1
interval
between
applications
(min)
n.a.
Surfaces
Germany
Menno
Florades
G
+
I
Virus
(ArMV, PFBV,
PLCV, PLPV,
TBRV, TSWV)
SL
90 g/l
watering
Surfaces
Germany
Menno
Florades
G
+
I
Virus
(TMV, ToMV)
SL
90 g/l
watering
after the
last use
1
Culture vessels
Germany
Menno
Florades
G
+
I
Virus
(ArMV, PFBV,
PLCV, PLPV,
TBRV, TSWV)
SL
90 g/l
soaking
after the
last use
Culture vessels
Germany
Menno
Florades
G
+
I
Virus
(TMV, ToMV)
SL
90 g/l
soaking
Equipment (eg
knives)
Germany
Menno
Florades
G
+
I
Virus
(ArMV, PFBV,
PLCV, PLPV,
TBRV, TSWV)
SL
90 g/l
Equipment (eg
knives)
Germany
Menno
Florades
G
+
I
Virus
(TMV, ToMV)
SL
90 g/l
kg as/hl
min max
water
l/ha
min max
PHI
(days)
(l)
Remarks
(m)
kg as/ha
min max
0.09 kg
(1 % solution)
2000 20000
1.8 - 18 kg n.a.
watering (16 h)
ebb/flood benches:
0.2 l/m2
other surfaces:
2.0 l/m2
n.a.
0.36 kg
(4 % solution)
2000 20000
7.2 - 72 kg n.a.
watering (16 h)
ebb/flood benches:
0.2 l/m2
other surfaces:
2.0 l/m2
n.a.
n.a.
0.09 kg
(1 % solution)
n.a.
n.a.
n.a.
soaking (16 h)
after the
last use
n.a.
n.a.
0.36 kg
(4 % solution)
n.a.
n.a.
n.a.
soaking (16 h)
dipping
before
the use
n.a.
n.a.
0.18 kg
(2 % solution)
n.a.
n.a.
n.a.
dipping
(3 minutes)
dipping
before
the use
n.a.
n.a.
0.27 kg
(3 % solution)
n.a.
n.a.
n.a.
dipping
(3 minutes)
Crop and/
or situation
(a)
Member
State
or
Country
Product
name
F
G
or
I
(b)
Pests or
Group of pests
controlled
(c)
22 November 2000
Formulation
Type
Application
(d-f)
Conc
of as
(i)
method
kind
(f-h)
growth
stage &
season
(j)
after the
last use
number
min max
(k)
1
interval
between
applications
(min)
n.a.
Surfaces
Germany
Menno
Florades
G
+
I
Bacteria and fungi
SL
90 g/l
watering
Culture vessels
Germany
Menno
Florades
G
+
I
Bacteria and fungi
SL
90 g/l
soaking
after the
last use
n.a.
Equipment (eg
knives)
Germany
Menno
Florades
G
+
I
Bacteria and fungi
SL
90 g/l
dipping
before
the use
Equipment (eg
knives)
Germany
Menno
Florades
G
+
I
Viroids
SL
90 g/l
dipping
before
the use
(i) g/kg or g/l
kg as/hl
min max
water
l/ha
min max
PHI
(days)
(l)
Remarks
(m)
kg as/ha
min max
0.09 kg
(1 % solution)
2000 20000
1.8 - 18 kg n.a.
watering (16 h)
ebb/flood benches:
0.2 l/m2
other surfaces:
2.0 l/m2
n.a.
0.09 kg
(1 % solution)
n.a.
n.a.
n.a.
soaking (16 h)
n.a.
n.a.
0.09 kg
(1 % solution)
n.a.
n.a.
n.a.
dipping
(3 minutes)
n.a.
n.a.
0.09 kg
(1 % solution)
n.a.
n.a.
n.a.
dipping
(3 minutes)
22 November 2000
B.3.4 Further information on the active substance (Annex IIA 3.7 to 3.9)
B.3.4.1
Recommended methods and precautions concerning handling, storage, transport or fire (Annex IIA 3.7)
Handling, storage and transport:
Handling:
Observe the usual precautions for handling chemicals.
Storage:
Keep only in original container.
Do not store together with animal feed stocks or foodstuffs.
Keep container tightly closed. Suitable for any general chemical storage area.
Transport:
Domestic (D.O.T)
Fire:
Use alcohol foam, dry chemical or carbon dioxide. Water may be ineffective. Fire fighters
should wear proper protective equipment and self-contained breathing apparatus with full
facepiece operated in positive pressure mode
B.3.4.2
Procedures for destruction or decontamination (Annex IIA 3.8)
Because of the manufacturing process benzoic acid does not contain any halogens. Benzoic
acid is a common used substance with a natural occurrence. Therefore detailed instructions for
safe disposal are not necessary. The substance is harmless.
B.3.4.3
Emergency measures in the case of an accident (Annex IIA 3.9)
Steps to be taken in the event of a spill or discharge:
Wear suitable protective clothing, carefully sweep up and remove
Decontamination of water:
A decontamination of water is not necessary because benzoic acid is in natural wide spread
and an ubiquity chemical substance. The main effect will be a decrease in the pH value, alkaline substances can counteract the effect (Verschueren, 1977, CHE 98-849).
B.3.5 Further information on the plant protection product (Annex IIIA 4)
B.3.5.1
B.3.5.1.1
Packaging (type, materials, size, etc.), compatibility of the preparation with
proposed packaging materials (Annex IIIA 4.1)
Description of packaging
1 litre-flask (HDPE)
Lenght
Width
Height
71.5 mm
90.5 mm
209.5 mm
Volume
No. of openings
Size of opening
Type of closure
Type of seal
22 November 2000
1070 mL
1
20 mm (inner diameter)
screw cap
conus
10 litre-container (HDPE)
Lenght
200 mm
Width
232 mm
Height
322 mm
Volume
11 litre
No. of openings
1
Size of opening
44 mm (inner diameter)
Type of closure
screw cap
Type of seal
Alveocel
30 litre-container (HDPE)
Lenght
370 mm
Width
297 mm
Height
420 mm
Volume
34.2 litre
No. of openings
1
Size of opening
53.5 mm (inner diameter)
Type of closure
screw cap
Type of seal
Alveocel
220 litre-drum
Diameter
Height
Volume
No. of openings
Size of opening
Type of closure
Type of seal
B.3.5.1.2
584 mm (max)
935 mm
227 Litre
2
2“ and 3/4“
screw cap
Lupolen
Suitability of packages and closures
Strength, leakproofness and resistance to normal transport and handling are ensured by the
certificates given to the following packaging materials:
10 litre-container
Certificate no. 8018/3H1
issued on 01.09.1993 by Deutsche Bundesbahn (German Railway), Zentralamt Minden
(CHE98-859)
22 November 2000
30 litre-container
Certificate no. 8249/3H1,
issued on 19.05.1989 by Deutsche Bundesbahn (German Railway), Zentralamt Minden
(CHE98-860)
220 litre-drum
Certificate No. 9640/1H1
issued on 30.05.1995 by Bundesanstalt für Materialforschung und -prüfung (BAM), Berlin
(CHE98-861)
All packages are certified for transport goods with a much higher degree of danger than the
preparation Menno-Florades.
B.3.5.1.3
Resistance of the packaging material to its contents
The active substance and the formulants are well-known chemicals. Any packaging material
specified for acids and for halogen free organic solvents is suitable for packaging the preparation. Therefore, no special packaging material is necessary for Menno-Florades.
The used packaging material HDPE is suitable for acidic compounds and organic solvents as
alcohols.
B.3.5.2
Procedures for cleaning application equipment and protective clothing
Cleaning with tap water is recommended if necessary. All formulants are water soluble or
miscible. Any household detergent may be used to intensify the cleaning procedure. Practical
experience shows that no residues remain on washed surfaces.
Protective clothing may, if allowed by the manufacturer, be washed in a household washing
machine without special precautions. Because washing powder usually is slightly alkaline, the
removal of benzoic acid as salt is easily accomplished.
B.3.5.3
Re-entry periods, necessary waiting periods or other precautions to protect
man, livestock and the environment (Annex IIIA 4.3)
Not required on the basis of the available information about the active substance, the preparation and the intended uses.
For further details see:
- pre-harvest interval for each relevant crop
see chapters B.7.4 and B.7.10
- re-entry period for livestock to areas to be grazed
- re-entry period for man to crops, building or spaces treated
see chapter B.6.14
- withholding period from animal feeding stuffs
- waiting period between application and handling to treated products
22 November 2000
- waiting period between last application and sowing or planting succeeding crops
see chapter B.7.9
B.3.5.4
Recommended methods and precautions concerning handling, storage, transport or fire (Annex IIIA 4.4)
While the active substance benzoic acid does not impose greater risks to man and environment, some of the formulants are flammable liquids. Precautions have to be taken to avoid
sparks, electrostatic discharge or open fire when handling the preparation.
During storage and transport local regulations for handling water miscible flammable liquids
with a flash point of 28° C and an auto ignition temperature of > 360° C have to be observed.
Standard protective clothing for handling organic solvents (alcohols) and organic acids is suitable and sufficient (e.g. rubber gloves). The preparation is irritating to the eyes, therefore
safety goggles should be worn.
Because the active substance and the formulants are chemicals with well-known properties,
special testing to evaluate the suitability and effectiveness of the protective clothing and
equipment against Menno-Florades is not necessary.
The generation of waste is minimised by selling the preparation in different sizes to allow the
end user to buy just as much Menno-Florades as he needs. Surplus may be stored without decline in effectiveness until the following season. Packaging material may be recycled after
rinsing with water. Used packaging material does not need special precautions and may be
handed over to any plastic recycling system.
In the event of fire, combustion products do not impose special risks because the preparation
is free of halogen and contains only small amounts of sulphur.
B.3.5.5
Procedures for use in the event of an accident
Spilled preparation generally is of low risk for man and environment. The main risk is the
flammability of the organic solvents. Therefore, precautions have to be taken to avoid sparks,
electrostatic discharge or open fire when cleaning up the spilled preparation. Safety goggles
should be worn to protect the eyes. Greater amounts of spillage should be contained with adsorbent or sand. Areas, vehicles and buildings may be decontaminated with plenty of water.
Damaged packaging, adsorbents and other materials may be either burned in an incinerator or
deposited in accordance with local regulations.
Emergency workers and bystanders should use standard protection (rubber gloves, eye goggles). First aid is symptomatic. The main risk is not posed by the active substance but by the
flammability of the organic solvents.
B.3.5.6
B.3.5.6.1
22 November 2000
Procedures for destruction or decontamination of the plant protection product
and its packaging (Annex IIIA 4.6)
Neutralisation procedures
The preparation contains some free acid which may be neutralised with any kind of alkali.
However, this procedure is not recommended for small and large quantities because the surplus of alkali poses at least the same risk than the free acids which are only slightly acidic.
The best way to handle accidental spillage is to dilute the preparation with water. This minimises the risk of ignition as well as the risk of skin and eye irritation.
B.3.5.6.2
Safe disposal of the plant protection product and its packaging
The preparation should be disposed of in an incinerator in accordance with local regulations.
Packaging should after cleansing with water recycled in a plastic recycling system.
B.3.5.6.3
Other methods for disposal
No other methods available.
Annex
point/
reference
number
Author(s)
Year Title
report no.
published or not
1973 Function of Lipophilic Acids as Antimicrobial
Food Additives.
not GLP,published
Nature 241, 321-325, 1973
BIO1999-473
Data
Owner
protection
claimed
Y/N
N
-
AIIA-3
Freese, E.,
Sheu, C.W.,
Galliers, E.
AIIA-3
Verschueren, K. 1977 Handbook of environmental data on organic
chemicals.
not GLP,published
Van Nostrand Reinhold Company, 1977
BIO1999-472
N
-
AIIA-3
Verschueren, K. 1977 Handbook of Environmental Data on Organic
Chemicals.
not GLP,published
N
-
CHE98-00849
Annex
point/
reference
number
Author(s)
AIIIA-4.1
Anonym
AIIIA-4.2
Anonym
AIIIA-4.3
Wieser, K.E.
Year Title
report no.
published or not
1993 1. Nachtrag zur 1. Neufassung zum Zulassungsschein Zulassungs-Nr. 8018/3H1 - Deutsche
Bundesbahn Bundesbahn-Zentralamt Minden
(Westf).
CHE98-00859
Data
Owner
protection
claimed
Y/N
N
MEN
1989 1. Neufassung zum Zulassungsschein Zulassungs-Nr. 8249/3H1 - Deutsche Bundesbahn
Bundesbahn-Zentralamt Minden (Westf).
CHE98-00860
N
MEN
1995 3. Neufassung zum Zulassungsschein - Nr.
9640/1H1 Bundesanstalt für Materialforschung
und -Prüfung (BAM).
CHE98-00861
N
MEN
Codes of owner
MEN:
22 November 2000
Annex B
Benzoic acid
B-4: Proposals for the
classification and labelling
- 39 –
Benzoic acid – Annex B.4: Proposals for the classification and labelling
22 November 2000
B.4 Proposals for the classification and labelling
B.4.1 Proposals for the classification and labelling of the active substance
(Annex IIA 10)
A proposal in accordance with the latest classification and labelling guidance under Directive
67/548/EEC (i.e. in the 18th ATP published as Directive 93/21/EEC) is not possible because
not all of the original studies are available. The proposal is made on the basis of all respective
data available.
Benzoic acid
Hazard symbol:
Xi
Irritant
Risk phrases:
R 41
Reasons for classification
For justification of R 41 see B.6.2 (Table B.6.2-5: eye irritation).
B.4.2 Proposals for the classification and labelling of preparations (Annex
IIIA 12.3 and 12.4)
The following is proposed in accordance with Directive 78/631/EEC in combination with the
latest classification and labelling guidance under Directive 67/548/EEC (i.e. in the 18th ATP
published as Directive 93/21/EEC):
Menno-Florades
Hazard symbol:
Xi
Irritant
Risk phrases:
R 41
Reasons for classification
For justification of R 41 see B.6.11.5 (Eye irritation).
Remarks
Concerning the possible sensitizing properties, no test was performed. It is considered not
nessecary on the basis of the available information about the active substance, the
preparation and the intended uses.
- Persons who react sensitive to pseudoallergic substances have to check for benzoic
acid/benzoates. If these are the causative substances in their individual case they should
avoid contact with them.
- The classification with Xi, R 41 for the active ingredient and the preparation is also
proposed by the notifier.
Annex B
Benzoic acid
B-5: Methods of analysis
- 43 Benzoic acid – Annex B.5: Methods of analysis
22 November 2000
B.5 Methods of analysis
B.5.1 Analytical methods for formulation analysis (Annex IIA 4.1; Annex
IIIA 5.1)
B.5.1.1
B.5.1.1.1
Analytical methods for formulation analysis (technical active substance) (Annex IIA 4.1)
Method for the determination of pure active substance in the active substance
as manufactured
The active substance is analysed by using the method C 17.2, an isocratic HPLC elution on a
reversed stationary phase (Spherisorb 5 ODS) with UV detection (245 nm) (Hahn (1996),
CHE98-862).
B.5.1.1.2
Methods for the determination of significant and / or relevant impurities and
additives (e.g. stabiliser) in the active substance as manufactured
Benzoic acid does not contain toxicological, ecotoxicological or environmental relevant impurities in quantities above 10 g/kg. The purity of the active substance has a pharmaceutical
quality and contains no additive.
B.5.1.1.3
Specificity, linearity, accuracy and repeatability
The enclosed analytical method C 17.2 is a common used and standard method. Therefore, the
specificity, linearity, accuracy, repeatability, and interference are proved in the practice very
often.
Determination on the method validity and linearity was submitted and is acceptable.
The method C 17.2 contains a statistical evaluation. The Linearity (y = 90463,38 x + 457,754)
as well as accuracy and repeatability (4.67 %) are in an acceptable range.
B.5.1.2
Analytical methods for formulation analysis (plant protection product) (Annex
IIIA 5.1)
The preparation contains only one active substance and no other compounds with strong UVabsorption. Possible interferences are separated by HPLC. The method meets any
requirements on specificity. No CIPAC method is available for benzoic acid at the moment.
(Spherisorb 5 ODS). Mobile phase: methanol/0.03 mol/l H3PO4 (50:50, V/V) (Hahn (1996),
CHE98-862).
22 November 2000
B.5.2 Analytical methods (residue) for plants, plant products, foodstuffs
of plant and animal origin, feedingstuffs (Annex IIA 4.2.1; Annex
IIIA 5.2)
Relevant residues of benzoic acid in food of plant and animal origin are not expected to occur.
The setting of MRL is not necessary and a residue relevant to MRL is not defined (cf.
Point B.7.3, Definition of the residue; Point B.7.12, Proposed EU MRL and justification for
the acceptability of those MRL). Therefore, residue analytical methods for the determination
of the active substance in food of plant and animal origin for enforcement purposes are not
required.
B.5.3 Analytical methods (residue) soil, water, air (Annex IIA 4.2. 2 to
4.2.4; Annex IIIA 5.2)
Due to the ubiquitous occurence in soil and the kind of application relevant residues in the
environmental compartments arising from the use of benzoic acid are not expected to occur
(cf. Point B.8.9, Definition of the residue). Therefore, residue analytical methods for the
determination of the active substance in soil, water and air are not required.
As an additional information a publication dealing with the determination of organic acids in
soil extracts was submitted (Baziramakenga et al., 1994). Free organic acids from soil samples
were extracted with distilled water. Extraction of the bound acid fraction was performed using
100 mM NaOH; after acidification (pH 2.5) the analytes were partitioned into ethyl acetate.
Following evaporation to dryness the extract was redissolved in distilled water. Quantification
was performed using ion chromatography with UV detection (254 nm). The stationary phase
was an ion exchange OmniPac Pax-100 column, the mobile phase consisted of deionized
water, 80 % acetonitrile and 1 M NaCl + 4 mM NaOH. Recoveries from fortification
experiments were not reported. The limit of detection was stated to be 202 nM (= 25 µg/l), the
relative standard deviation of 10 injections was found to be 0.71 %.
Another publication (Jalal and Read, 1983) considering the organic acid composition of
heathland soil was submitted. Individual organic acid concentrations were determined using
gas chromatography; however further information about the applied analytical method is not
contained in the article.
B.5.4 Analytical methods (residue) for body fluids and tissues (Annex IIA
4.2.5; Annex IIIA 5.2)
Methods for the determination of residues in body fluids and tissues are not required since the
active substance is not classified as toxic or highly toxic.
B.5.5 Evaluation and assessment
B.5.5.1
Formulation analysis
22 November 2000
The preparation contains only one active substance and no other compounds with strong UVabsorption. Possible interferences are separated by HPLC. The method meets any
requirements on specificity. No CIPAC method is available for benzoic acid at the moment.
(Spherisorb 5 ODS). Mobile phase: methanol/0.03 mol/l H3PO4 (50:50, V/V) (Hahn (1996),
CHE98-862).
B.5.5.2
Residue analysis
Relevant residues in food of plant and animal origin and in the environmental compartments
arising from the application of benzoic acid according to the GAP are not expected to occur.
The setting of MRL is not necessary and no residue is defined, neither with relevance to MRL
nor with relevance to the environment (cf. Point B.7.3, Definition of the residue; Point B.7.12,
Proposed EU MRL and justification for the acceptability of those MRL; Point B.8.9,
Definition of the residue). Therefore, residue analytical methods for the determination of the
active substance in food of plant and animal origin for enforcement purposes as well as for
soil, water and air are not required. Methods for the determination of residues in body fluids
and tissues are not required since the active substance is not classified as toxic or highly toxic.
Annex
point/
reference
number
Author(s)
AIIA-1.3;
AIIA-1.4;
AIIA-1.6;
AIIA-1.7;
AIIA-1.8;
AIIA-1.10;
AIIA-2.1;
AIIA-2.2;
AIIA-2.3;
AIIA-2.4;
AIIA-2.6;
AIIA-4.1
Anonym
AIIA-2.5;
AIIIA-5.1
Hahn
Year Title
report no.
published or not
not GLP, published
Relevance., 1993
CHE98-00891
CHE98-00862
Data
Owner
protection
claimed
Y/N
N
-
Y
MEN
Annex
point/
reference
number
AIIA-4.2
AIIA-4.2
Author(s)
Year Title
Data
Owner
protection
report no.
claimed
published or not
Y/N
Baziramakenga, 1995 Determination of organic acids in soil extracts by
N
R.; Simrad, R.R.
ion chromatography.
and Leroux,
not GLP, published
G.D.
MET1999-141
Jalal, M.A.F.
and Read, D.J.
fungitoxicity.
not GLP, published
Plant and Soil, 70, 1983, 273 - 286
MET1999-140
Codes of owner
MEN:
22 November 2000
N
-
Annex B
Benzoic acid
B-6: Toxicology and metabolism
- 49 Benzoic acid – Annex B.6: Toxicology and metabolism
22 November 2000
B.6 Toxicology and metabolism
Bridging concept
Benzoic acid and its salts are widely spread natural compounds in the environment. They are
generated in plant and animal metabolism and therefore a constituent in many foodstuffs (up
to ca 40 mg/kg food, IPCS, 1999).
Benzoic acid and benzoates are used as therapeutic substances in human and veterinary medicine. Because of its antimicrobial activity, benzoic acid is commonly used as preservative in
food, cosmetics and pharmaceuticals.
The worldwide industrial production volume is some 100 000 tons per year. The intended use
as plant protection product for disinfection in horticulture amounts to less than 0.0001% of the
total production.
Benzoic acid is the active ingredient considered in this monograph. However, in the
toxicological part of the evaluation, benzoates are included because a considerable part of data
was generated with these substances. Particularly sodium benzoate has been used in many
experiments because of the low water solubility of benzoic acid at neutral pH. Additionally,
for some experiments it was not definitely stated whether benzoic acid or benzoates were
used. Regarding the great similarity of the toxicological profile, benzoic acid and its salts can
in general be considered together.
The monograph on the active ingredient is based on literature which is very heterogeneous. In
several studies – especially in short-term and long-term studies - only one or two doses and
only few parameters were tested. Results were often insufficiently reported. Otherwise, also
publications with reduced relevance contribute to the toxicological characterization of benzoic
acid and benzoates.
Already evaluated information in review articles was barely used because some toxicological
results are described in nearly all reviews but others are only mentioned in one or the other
and so the emphasis for some observations varies from review to review. Additionally,
because information on the study design is helpful for the judging of findings, all original
publications accessible (including the very old, often marked by high accuracy) are shortly
described and assessed.
Regarding the overall conclusions on the toxicological properties of benzoic acid/benzoates in
this monograph, they resemble those drawn in other evaluations (e.g. JECFA, 1974, 1983,
1996; FDA 1972, BIBRA, 1989; MAK-Comission, 1985, 1995; GDCh-Advisory Committee
on Existing Chemicals of Environmental relevance (BUA), IPCS, 1999, 1. Draft). The ADI
derived in this monograph is in agreement with the ADI of JECFA (1974) and the decision of
FDA (1972) to accept benzoic acid as a GRAS (Generally Recognized As Safe) direct food
substance is absolutely agreed.
Toxicological studies according to current test guidelines are only available for the
preparation Menno-Florades.
However, the toxicological properties of the active ingredient are altogether possible to assess
from the available literature. Taking into account the natural occurrence of benzoic acid and
benzoates in the environment and the long and extensive experience with the use of these substances as dietary supplement, further testing is not necessary.
22 November 2000
The RMS concludes that an exemption from the requirement of toxicological studies for the
active ingredient according to current standard test guidelines is justified. No further studies
have to be submitted.
B.6.1 Absorption, distribution, excretion and metabolism (toxicokinetics)
(Annex IIA 5.1)
Summary
acid/sodium benzoate in organs and tissues is not to be expected. In contrast, benzoic acid
and extent of benzoate-metabolism in both organs.
plant products.
Absorption and distribution
Gastrointestinal absorption
After oral ingestion of benzoic acid/sodium benzoate, the gastrointestinal absorption is rapid
and virtually complete in humans, rats, dogs and hamsters (Bridges et al., 1970, Hall and
James, 1980, Jones, 1982). In humans, the peak plasma concentration is reached within 1 to 2
22 November 2000
hours (Kubota et al., 1988, Kubota & Ishizaki, 1991). Benzoates are not bound to proteins in
blood (Knoefel & Huang, 1956).
The rapidity of absorption was substantiated by perfusion experiments with stomach, small
intestine and colon of the rat (Schanker et al., 1957, 1958, 1959). In these experiments, it was
also shown that the absorption is based on simple diffusion of the unionized molecule. The
dependence of this process on pH was indicated in perfusion experiments with rat jejunum
(Högerle & Winne, 1983).
Percutaneous absorption
Because of the immense use of benzoic acid/sodium benzoate as preservative in cosmetics and
the suitability of benzoic acid as reference substance, many investigations dealed with the
percutaneous absorption in several animal species as rat (Rougier et al., 1983), rhesus monkey
(Wester & Maibach, 1976, Bucks et al., 1990), dog (Hunziker et al., 1978), pig (Carver &
Rivier, 1989), guinea pig (Anderson et al., 1980, Moon et al., 1990) and in humans (Feldmann
& Maibach, 1970, Wester & Maibach, 1976, Hunziker et al., 1978, Roskos et al., 1989). In
vitro investigations were also performed (Franz, 1975, Bronaugh & Stewart, 1985, Nathan et
al., 1990, Parry et al., 1990). Results obtained in vivo until ca 1989 were summarized by
Maibach & Wester (1989) in a review article.
After application of 4 µg benzoic acid per cm2 (total area 13 cm2) to the ventral surface of the
forearm of six human volunteers for 24 hours, the total absorption was 42.6% (SD 16.5%),
measured by urinary excretion over 5 days (Feldmann & Maibach, 1970). Wester & Maibach
(1976) compared absorption rates for humans (total area 13 cm2) and rhesus monkeys (total
area 6 cm2) and revealed similar results for both species (table B.6.1-1).
Table B.6.1-1:
Percutaneous absorption of benzoic acid in humans and rhesus
monkeys
Species
Dose (µg/cm2)
Total amount absorbed (µg/cm2)
Total percentage absorbed (%/cm2)
* () number of volunteers or animals
3.0 (6)*
1.1
37.0
Human
400 (7)
102.8
25.7
2000 (7)
288.0
14.4
Rhesus monkey
400 (3)
2000 (3)
134.4
348.0
33.6
17.4
For pigs, Carver & Riviere (1989) corrected the total percutaneous absorption (40 µg/cm2,
total area 5 cm2) by inclusion of the fecal excretion. The absorption after measurement of
urinary excretion alone was 23.7% (SD 2.7%). The corrected absorption after measurement of
the total excretion accounted for 25.7% (SD 2.4%).
Aging appears to decrease the percutaneous absorption of benzoic acid in humans. After
application of 4 µg benzoic acid/cm2 for 24 hours (total area 2.5 cm2) to volunteers, the
surface recovery was 45.6% in the group of 22-40-olds and 61.4% in the group of 65-86-olds
(Roskos et al., 1989).
Damage to the skin before application of benzoic acid nearly doubled the absorption. In an in
vitro experiment with human and rat skin (4 µg benzoic acid/cm2 in a lotion of 5 mg/cm2,
total area 0.32 cm2, 24 hours), the total absorption through the intact skin was 27.5% and
19.9%, through the damaged skin 57.7% and 40.4%, respectively (Bronaugh & Stewart,
1985). Damaging the skin of guinea pigs before application of 4 µg benzoic acid/cm2 for 24
hours in vivo led to a total absorption of ca 70% in the damaged skin versus an absorption rate
of 34.2% in the intact skin (Moon et al., 1990).
22 November 2000
The hypothesis that bioavailability of a chemical following multiple topical exposure may be
accurately predicted from the results of a single exposure was tested on four female rhesus
monkeys (Bucks et al., 1990). Doses of 4 µg benzoic acid/cm2 (first and eighth dose 14Clabelled) were applied to exactly the same site on the abdomen every 24 hours for 14 days.
The site was not washed between dosings. The absorption rates were compared with the
absorption rate after a single application. In the single dose experiment, the absorption rate
was 66±19%. In the multiple dose experiments, the absorption rate was 85±19% after the
initial dose and 89±19% after the eighth dose. In all cases, the excretion was essentially
complete within 24 hours. No significant change in the percutaneous absorption was found
after multiple dosing.
For practical reasons and due to the heterogeneous results in the different species, an overall
dermal absorption of 100% was assumed and taken for operator calculations.
Inhalative absorption
No data were available regarding absorption in the lower respiration tract.
From perfusion experiments performed by Huang et al. (1985) some absorption through the
nasal epithelium can be expected.
The in situ nasal absorption was tested with 1.5 mmolar sodium benzoate solution in a pH
range from 2.4 to 7.2. The absorption was found to depend on the pH of the perfusate with the
benzoate anion being absorbed at a rate approaching 25% of that of benzoic acid. From
similar perfusion experiments for testing of absorption enhancers for nasal drugs, Pujara et al.
(1995) indicated that benzoic acid (25 mmolar) caused more cellular pertubation at pH 3.2
than at pH 5.2. The degree of pertubation was measured by determination of total protein and
enzyme activities (LDH and 5’-nucleotidase) in the perfusate.
Distribution between maternal animal and fetus
After sc administration of 1.15 mg/kg bw benzoic acid to rats at 10 to 12 days of gestation, the
compound readily penetrated the placental barrier. Because of higher brain to plasma ratios in
the fetuses than in the maternal animals, the authors concluded that the blood-brain barrier is
less effective for benzoic acid in the fetuses than in the mother animals (Maickel &
Snodgrass, 1973).
Excretion and bioaccumulation
The excretion of benzoic acid/sodium benzoate with urine is rapid and virtually complete in
humans, rats, hamsters and dogs (Bignani, 1924, Bernhard et al., 1955, Lang & Lang, 1956,
Schachter, 1957, Barnes, 1959, Bridges et al., 1970, Riihimäki, 1979, Hall & James, 1980,
Kubota et al., 1988, Akira et al., 1993) but seems less effective in other species as ferrets and
subhuman primates (Bridges et al., 1970).
Fecal excretion appears to be a minor route of elimination. After intraperitoneal
administration of 10 mg/kg bw 14C-benzoic acid to various species, less than 5% of the
radioactivity was found in the feces within 72 hours (Huckle et al., 1981).
After oral and subcutaneous administration of ca 200 mg/kg bw 14C-benzoic acid to one rat
each, ca 90% appeared in the urine, < 1% in the expired air and 2% remained in the carcass
(Bernhard et al., 1955). The administration of oral doses of 10 and 100 µg/kg bw, and 1, 10,
100 and 1000 mg/kg bw of 14C-benzoic acid diluted with unlabeled sodium benzoate to rats
22 November 2000
resulted in an excretion of 80% to 100% with the urine within 24 hours. At the dose of 10
µg/kg bw ca 3% were exhaled as 14CO2 (Jones, 1982).
Given ca 250 mg/kg bw 14C-sodium benzoate intraperitoneally to rats, practically quantitative
excretion occurred in the urine within one to two days. Less than 4% of the radioactivity
appeared in the feces, up to 0.009% in the organs and 0.3% in the skin including fat (ether
extract). All radioactivity in the tissues was identified as parent material (Lang & Lang, 1956).
Sodium benzoate (equivalent to 50 mg/kg bw benzoic acid) intraperitoneally administered to
bile duct cannulated rats resulted in 99% urinary and 1% biliary excretion within 24 hours
(Hirom et al., 1976).
A human volunteer (58 kg) eliminated ca 80% of a single oral dose of 5 g benzoic acid in six
hours via urine (Quick 1931). In another experiment (Schachter, 1957), single oral doses of
6.9, 13.9, 34.7 and 69.3 mmoles (1, 2, 5, 10 g) sodium benzoate were given to a healthy man
(60 kg) with at least a two week interval between two successive doses. This resulted in a
complete elimination of each dose within 10 to 11 hours. A single dose of 20 mg/kg bw
sodium benzoate was orally administered to human volunteers (3 men). Within 5 hours a
percentage of 89% was urinary excreted with a maximal excretion rate in the first hour. (Fujii
et al., 1991). Even after repeated administration of 2 g sodium benzoate to human volunteers
for 8 days, 2 or 3 days were sufficient for total elimination (Bordas et al., 1925).
In subhuman primates (rhesus monkey, squirrel monkey, marmoset) the urinary excretion
ranged from 32% to 78% within 24 hours when 14C-sodium benzoate was orally administered
(1, 40 or 50 mg/kg bw). Reasons for this relatively low urinary excretion rates were not given
(Bridges et al., 1970, Hall & James, 1980).
Besides the data of Lang & Lang (1956, see above) no other data on tissue retention could be
found in the available literature but because of the high rate and extent of elimination in the
most species investigated, no accumulation is to be expected.
Metabolism
Hippuric acid and benzoyl-glucuronic acid are the two main urinary metabolites of benzoic
acid/sodium benzoate in mammals (Williams, 1959, Amsel & Levy, 1969, Fujii et al., 1991
among others). These metabolites result from conjugation reactions of benzoic acid with
glycine or glucuronic acid (figure B.6.1-1). Under normal living conditions, the urinary
excretion of hippuric acid in man is estimated to be 1.0-2.5 g/day (Stein et al., 1954) which
would correspond to the conversion of 0.8 to 2.0 g of sodium benzoate or 0.7 to 1.7 g of
benzoic acid in the human body per day. However, it was determined that a normal adult can
produce enough glycine to conjugate 0.9 to 1.3 g benzoic acid per hour (Quick, 1932).
In the experiment of Schachter (1957, see above), at the top dose, the maximum excretion rate
was 130.5 µmoles/min (17 mg/min) as hippuric acid and 5.5 µmoles/min (0.67 mg/min) as
benzoyl-glucuronic acid. Calculated for one day, this would mean the excretion of ca 20 g
benzoic acid.
The maximum rate of biotransformation of benzoic acid to hippuric acid varied between 17.2
and 28.8 mg/kg bw per hour among six healthy male volunteers to whom successive oral
doses of 40, 80 and 160 mg/kg bw sodium benzoate were administered at least one week apart
(Kubota & Ishizaki, 1991). The mean value of 23.0 mg/kg bw per hour was fairly close to that
22 November 2000
provided by a daily maximum dose of 500 mg/kg bw (21 mg/kg bw per hour) recommended
in the treatment of hyperammonemia (see B.6.8 and B.6.9.4).
The dose was entirely excreted as hippuric acid in a human volunteer (1 mg/kg bw) and in a
rhesus monkey (20 mg/kg bw) within 24 hours (Bridges et al., 1970). In rabbits, rats and pigs
benzoic acid is almost entirely excreted as hippuric acid , too (e.g. Thabrew et al., 1980),
whereas other species as marmosets (Hall & James, 1980), dogs (acc. to Barnes, 1959: ca
75%) and ferrets (acc. to Bridges et al., 1970: ca 20%) excrete also considerable quantities of
benzoyl-glucuronic acid.
In rats, over the wide range of oral doses from 10 µg/kg bw to 1000 mg/kg bw, all benzoic
acid was excreted solely as hippuric acid (Jones, 1982). In the very young rats, the proportion
excreted as hippuric acid appears to be reduced. Baines et al. (1978) administered 14C-sodium
benzoate to adult rats and recovered hippuric acid in the urine in nearly equivalent amounts
compared to the administered doses. In neonatal rats, ca 20% of the urinary radiolabel was
identified as benzoyl-glucuronic acid.
Under the influence of protein and energy deficiency, rats excreted less hippuric acid (62% to
85%) and more benzoyl-glucuronic acid (14% to 37%) (Thabrew et al., 1980). On the other
hand, cats lack the possibility to form benzoyl-glucuronic acid and if the capacity for hippuric
acid conjugation is saturated, the substance will build up to a toxic level (Bedford & Clarke,
1972, see also B.6.2 and B.6.3).
Important factors which affect the tolerance for benzoic acid/sodium benzoate are the
incorporated amount of these substances, the availability of an adequate glycine concentration
and the rate for both, the conjugation reaction and the excretory process (e.g. Kingsbury,
1923, Quick, 1931, De Vries & Alexander, 1948, Wan & Riegelman, 1972, Palekar & Kalbag,
1991). Griffith and Lewis (1923) found a marked increase of the synthesis and elimination of
hippuric acid in rabbits at simultaneous administration of ca 1000 mg/kg bw benzoic acid
(given as sodium benzoate, 1700 to 2120 mg per animal) and glycine (1 to 5 equivalents of the
benzoate doses, not clearly given in the original publication). When rats were fed 1.5%
sodium benzoate in the diet for 40 days, they excreted ca 95% as hippuric acid. As the
benzoate was increased to 3.0%, only ca 73% of the total benzoic acid were excreted as
hippuric acid. Additional glycine (0.39% to 1.56%) at this dose level raised the elimination as
hippuric acid again up to 96% to 99% (Griffith, 1929). In contrast, in a sheep (47 kg,
abomasal infusion over 24 hours) increasing the dose of benzoic acid caused a progressive fall
of the conjugation reaction in spite of simultaneous administration of glycine (Martin, 1966,
see also B.6.2).
Schreier et al. (1954) and Armstrong et al. (1955) indicated by their experiments that benzoic
acid is also generated in intermediary metabolism. Humans and rats receiving a special diet
excreted 1 to 3 mg/kg bw/d hippuric acid. In rats, this amount was not affected by fasting
(Armstrong et al., 1955). Phenylalanine can serve as precursor for the endogenous formation
of benzoic acid (Altman et al., 1954, Armstrong et al., 1955, Bernard et al., 1955).
The major sites of conversion of benzoic acid to hippuric acid and benzoyl-glucuronic acid are
the liver and the kidney. Marked species differences exist concerning the rate and extent of
benzoate-metabolism in both organs (Kao et al., 1978 among others). As already shown in the
classic experiments by Bunge and Schmiedeberg (1876) (perfusion of dog kidney) and
Snapper et al. (1924) (perfusion of dog, sheep and human kidney) and corroborated later (e.g.
22 November 2000
Quick, 1932), the formation of hippuric acid in the dog takes entirely place in the kidney. In
sheep, it may depend on the amount of benzoic acid (Snapper et al., 1924, Martin, 1966).
At comparable plasma concentrations of intravenously given benzoic acid to rabbits, the
formation of hippuric acid in the kidney and in the liver greatly varied from animal to animal.
A monkey was found to metabolize benzoic acid only in the liver (Wan & Riegelman, 1972).
In homogenates of 110 specimens of human liver and 67 specimens of human renal cortex, the
rate of conjugation of benzoic acid with glycine was measured. The mean rates of reaction
were 254± 90.5 nmol/min per g liver (range: 94.4 to 564 nmol/min) and 321±99.3 nmol/min
per g kidney (range: 63.3 to 542 nmol/min).While the conjugation rate was greater in the renal
cortex than in the liver, the larger mass and strategic anatomical position of the liver were
considered to make it quantitatively the more important organ with respect to glycine
conjugation (Temellini et al., 1993).
In vitro experiments indicated that after percutaneous absorption of benzoic acid a small
amount can also be converted to hippuric acid in the skin (Nathan et al., 1990).
Figure B.6.1-1
Conjugation reactions of Benzoic acid
COOH
Gly
Benzoic acid
ATP
CoA
H 2O
Gly
C
O
Hippuric acid
Gly : Glycine
Gluc: Glucuronic acid
Gluc
UTP
H 2O
Gluc
C
O
Benzoyl-glucuronic acid
22 November 2000
B.6.2 Acute toxicity including irritancy and skin sensitization (Annex IIA
5.2)
Summary
Acute toxicity testing with benzoic acid/benzoic salts was performed in several animals
benzoic compound was used.
LD50, oral:
LD50, dermal:
> 0.026 mg/l (1 h, rat).
LC50, inhalative:
mg/kg bw. It is not irritating to skin and eyes. No data on sensitizing effects are available.
The values derived in acute toxicological investigations are summarized in tables B.6.2-1 to
B.6.2-6.
Table B.6.2-1:
Test substance
Benzoic acid
Sodium benzoate
Benzoic acid
Acute oral toxicity studies with benzoic acid/benzoic salts
Species
rat
Test substance
Benzoic acid
Benzoic acid
LD50: 2000 – 2500 mg/kg bw
rat
LD50: 4100 (3720 - 4440) mg/kg bw
- fasted
LD50: 2100 mg/kg bw 1)
- not fasted LD50: 3450 mg/kg bw 1)
LD50: 3140 (2860 - 3440 mg/kg bw
LD50: 2370 mg/kg bw
mouse
LD50: 1940 (1740-2170) mg/kg bw
rabbit
lowest lethal dose: ca 1500 mg/kg bw
dog
Benzoic acid
Sodium benzoate
Benzoic acid /
Benzoic salt
cat
Benzoic acid
1) Calculated as benzoic acid
Table B.6.2-2:
Result
LD50: 1700 – 3040 mg/kg bw
Reference
Fassett & Irish,1962
Bio-Fax, 1973
Ignat’ev, 1965
Smyth & Carpenter, 1948
Deuel et al., 1954
Deuel et al., 1954
Loeser, 1977
Mc Cormick & Speaker, 1973
Abe, 1984
Rost et al., 1913
Rost et al., 1913
Ellinger, 1923
Acute dermal toxicity studies with benzoic acid
Species
rabbit
rabbit
LD50: > 10000
LD50: > 5000
Result
mg/kg bw
mg/kg bw
Reference
Bio-Fax, 1973
Moreno, 1977
Table B.6.2-3:
Acute inhalative toxicity studies with benzoic acid
Test substance
Benzoic acid
Table B.6.2-4:
Species
rat
Result
LC50: > 0.026 mg/l (1 h)
Reference
Bio-Fax, 1973
Acute toxicity studies with benzoic acid/benzoic salts, other routes
Test substance
Sodium benzoate
Route
iv
Species
rat
Benzoic acid
Sodium benzoate
Benzoic acid /
Benzoic salt
ip
ip
mouse
guinea pig
sc
rabbit
Table B.6.2-5:
22 November 2000
Result
LD50: 1714 ±124 mg/kg bw
Reference
Hager et al., 1942
LD50: 1460 mg/kg bw
Caujolle & Meynier, 1958
lowest lethal dose: 1400 mg/kg bw Chassevant & Garnier, 1905
lowest lethal dose: ca 2000 mg/kg
Ellinger, 1923
bw
Skin and eye irritation studies with benzoic acid/benzoic salts
Study
Test substance
Skin irritation
(intradermal)
sodium benzoate
(quantification of
irritating response by (1-20%)
a radioactive
indicator)
benzoic acid (500
Skin irritation
mg dry powder)
sodium benzoate
Skin irritation
(dry powder)
Skin irritation
benzoic acid
(appl. for 4 h, semi- (500 mg,
occlusive dressing)
moistened)
Skin irritation
sodium benzoate
(OECD 404)
benzoic acid (100
Eye irritation
mg dry powder)
sodium benzoate
Eye irritation
(dry powder)
Eye irritation
benzoic acid
benzoic acid
Eye irritation
(paste)
benzoic acid
Eye irritation
(ca 77 mg)
Eye irritation
sodium benzoate
(OECD 405)
Species
Result
Reference
dose-dependent irritating
(at 1% response not
significant)
Stol et al., 1988
rabbit
irritating
Bio-Fax, 1973
rabbit
not irritating
Loeser, 1977
rabbit
minimally irritating
RCC Notox, 1988
rabbit
not irritating
RCC Notox, not dated
rabbit
irritating
Bio-Fax, 1973
rabbit
not irritating
Loeser, 1977
rabbit
moderately irritating
Bayer, 1978
rabbit
mildly irritating
Suberg, 1986
rabbit
severely irritating
(Draize score 35) (R 41)
RCC Notox, 1988
mildly irritating
RCC Notox, not dated
rat
rabbit
Table B.6.2-6:
22 November 2000
Skin sensitization studies with benzoic acid
Study
Ear swelling test
(0.2-20% topical appl. onto earlope) 1)
M & K test
(10% intradermal injection, 20% topical
induction and challenge)
Buehler test
(20% induction and challenge)
GPMT
(20% induction and challenge)
Mouse ear swelling test, (MEST)
(20%, induction and challenge)
Local lymph node assay, LLNA) 2)
(5, 10, 20%, four topical inductions)
Species
Result
Reference
dose-dependent swelling
Lahti & Maibach, 1984
guinea pig
within 30-40 min, reversible
guinea pig not sensitizing
Gad et al., 1986
Gad et al., 1986
Gad et al., 1986
mouse
not sensitizing
Gad et al., 1986
mouse
not sensitizing
Gerberick et al., 1992
1) Animal model test for nonimmunologic contact urticaria (NICU) in men. At the maximum of swelling (after 40 min)
histological examination showed: dermal edema, slight infiltration of heterophils (neutrophils in men), eosinophils and some
lymphocytes in the venules.
2) Animal model test for contact sensitizing substances to replace tests with guinea pigs. Measurement of proliferative
activity in the draining lymph nodes by quantifying the incorporation of radiolabelled thymidine into the proliferative cells.
Proliferative activity correlates with the severity of elicitation reaction.
Data on clinical observations and pathological findings:
Data on clinical symptoms in acute toxicity testing of benzoic acid/sodium benzoate come to a
large number from investigations performed at the last turn of the century in only few animals
but the course of poisoning was often recorded very detailed. The data available are
summarized below. Altogether, the picture of poisoning is characterized by convulsions,
hyperaesthesia, disturbed respiration and changed body temperature.
Macroscopic pathological examinations were summarized by Ellinger (1923). He pointed out
that hyperemia, hemorraghia, erosion and even necrosis in the gastric mucosa occurred not
only after parental application but also after intravenous, inhalative and subcutaneous
application. More recent macroscopic pathological examinations are only available for cats
(Bedford & Clarke, 1972, see below).
Rats:
Reference:
Loeser, E., 1977
Animals:
10 male rats per group
Initial body weight: 154-178 g
Application:
Oral (gavage), 2000-4000 mg/kg bw sodium benzoate
Clinical observations: Diarrhoe, marked diuresis, emaciation, sedation, death within 2-3
days.
Reference:
Hager, G.P. et al., 1942
Animals:
Five white rats per group
Body weight:
90-150 g
Application:
Intravenous, 1200-2290 mg/kg bw sodium benzoate
Clinical observations: Symptoms within few minutes after injection; heightening of CNS
reflexes, tremor, clonic and often tetanic convulsions, death during
remission, mostly within 30 min and 1 hour. Survivors showed none
22 November 2000
of the nervous manifestations but salivation, vomiting, diarrhoea and
marked diuresis (some animals).
Reference:
Bio-Fax, 1973
Application:
Inhalative (1 h), 0.026 mg/l benzoic acid
Clinical observations: Inactivity, lacrimation
Macroscopic
pathological findings: No findings
Mice:
Reference:
Caujolle, M. F. & D. Meynier, 1958
Animals:
20 mice per group
Body weight:
Ca 20 g
Application:
Intraperitoneal, benzoic acid doses near LD50 (1460 mg/kg bw)
Clinical observations: Hyperaesthesia, hypothermia, no convulsions, death within 1 day
Reference:
Abe, S. et al., 1984
Animals:
10 mice per group
Application:
Oral, 1206-3000 mg/kg bw benzoic acid
Clinical observations: Sedation, slow respiration, then gasping, lacrimation, ptosis, loss of
righting reflex, clonic convulsions, jumping, tail reaction, death within
10-120 minutes.
Dogs:
Reference:
Lucas, D.R., 1909
Animal:
One dog
Body weight:
3.5 kg
Application:
Oral (animal fasted for 24 h), 1 g sodium benzoate (ca 300 mg/kg bw)
Clinical observations: Within 30 min muscular weakness, nausea, apathy, difficult breathing,
continuing for 6 hours
Application:
Next day: 4 g sodium benzoate (ca 1200 mg/kg bw)
Clinical observations: Within 60 min extreme weakness, extremely reduced and difficult
breathing, after 75 min tonic-clonic convulsions, after 2 h 20 min
death.
Reference:
Animals:
Initial body weight:
Application:
Rost. E. et al., 1913
Four dogs
1.8-7.8 kg
Single oral doses (gavage) on different days within 3 weeks with
different feeding conditions, 1.8-7.8 g sodium benzoate (ca 1000-2200
mg/kg bw)
Clinical observations: At ca 1000 mg/kg bw: No findings
At ca 1200-2200 mg/kg bw: Vomiting; after re-intake of the vomit:
aggressiveness, halluzination and in one animal death
Application:
Three oral doses (gavage) to the remaining 3 dogs within 1 hour (not
fasted), 4-6.9 g sodium benzoate (2880 mg/kg bw)
Clinical observations: Vomiting; intermittent convulsions and death in one animal which did
not vomit the second and third portion.
22 November 2000
Rabbits:
Reference:
Animals:
Application:
Rost. E. et al, 1913
Three rabbits
2.07-2.65 kg
Three single oral doses (gavage) on different days within 3 weeks to
not fasted animals, 4.1-7.2 g sodium benzoate (ca 1700-2440 mg/kg
bw as benzoic acid)
From ca 2000 mg/kg bw: Refused food intake, convulsions similar to
that of dogs, death
Application:
Single dose to fasted animals (1 or 2 days), 3.7-7.2 g sodium benzoate
(ca 1220-2440 mg/kg bw as benzoic acid)
From ca 1500 mg/kg bw: Tremor, side position, convulsions similar to
that of dogs, death.
Guinea pigs:
Reference:
Chassevant, A. & M. Garnier, 1905, cited in Ellinger, A., 1923
Application:
Intraperitoneal, 1400 mg/kg bw sodium benzoate
Clinical observations: Crouched position without movement, without tremor, without loss of
muscle tone, piloerection, extreme hypothermia, death by respiratory
paralysis within 5-7 hours.
Sheep:
Reference:
Animal:
Body weight:
Application:
Martin, A.K., 1966
One seven year old Scottish blackface sheep
75 kg
Rumen infusion of 79.7 g benzoic acid within 24 hours (1100 mg/kg
bw)
Clinical observations: Refused food intake, muscular weakness, tremor, accelerated
respiration, death on the third day.
Cats:
Reference:
Rationale:
Bedford, B. & M.A. Clarke, 1972
Suspected poisoning in a cattery, benzoic acid content in the cat meat:
2.39% (Bedford, B. & M.A. Clarke, 1971)
Animal number:
Four cats
Body weight:
1.06-1.7 kg
Application:
Feeding of 120 g meat with 1% benzoic acid (doses consumed: 450890 mg/kg bw)
Clinical observations: Onset ca 14 hours after food intake, duration of syndrome 18-176
hours; salivation, aggressiveness, hyperaesthesia, apprehension,
hypothermia collapse, death within 32 and 192 hours. One cat which
gradually consumed the food (890 mg/kg bw benzoic acid) exhibited
disturbed coordination, extreme aggressiveness, hyperaestesia,
hyperthermia, convulsions but recovered thereafter.
Necroscopy:
Gastro-intestinal-tract: Mouth and tongue ulcerated, retention of feces
and urine, no visible abnormalities in stomach and intestines
Liver: Pale, centrilobular vacuolation, hepatic and Kupffer cells
Histopathology:
Remark:
22 November 2000
swollen, cytoplasm foamy and granular, infiltration of inflammatory
cells into the portal tract
Kidney: Distension of kidney glomeruli with widespread herniation of
proximal tubules into Bowman’s capsule
Lung: edematous, areas of emphysema and hemorraghia
Heart: Myocardial foci of cell infiltration and degeneration
Central nervous system: no abnormalities
The higher toxicity in cats than in other species was attributed by the
authors to the lack of capacity in cats for glucuronidation of benzoic
acid.
B.6.3 Short-term toxicity (Annex IIA 5.3)
Summary
For reasons pointed out in the preface, in this monograph all accessible publications for shortterm toxicity are shortly described and assessed, including those with reduced relevance.
In several studies, only one or two doses and only a few parameters were tested. The
predominant aim in most experiments was to demonstrate effects and not to find out a
NOEL/NOAEL. Therefore, the noted NOELs were mostly derived by the rapporteur. It is
noted, if a study or publication is not relevant for deriving a NOEL.
mouse, cat, guinea-pig and dog.
decreased.
was observed.
be derived from all relevant short-term and chronic toxicity/carcinogenicity studies on rats
together since no single study according to a current test guideline is available. This NOEL
can serve for the calculation of ADI and AOEL.
B.6.3.1
Studies, Rat
B.6.3.1.1
Reference:
Oral studies
Griffith, W.H., 1929
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
22 November 2000
40 days (some animals up to 100 days); sodium benzoate
0-1.5-2-2.25-2.5-2.75-3-3.25-3.5-3.75% (with and without supplement
of glycine)
Oral (in the diet)
White rat
4-19 males
45-60 g
Yes
Clinical signs, body weight change, growth rate during restricted
feeding, food consumption and efficiency, survival rate
Decreased growth rate at 2% in the diet, occasionally mortality at
2.5%, above 3% severely depressed growth rate and mortality of more
than 50% of the animals with and without restriction of feeding,
mortality preceded by restlessness, uncoordinated movement, tremor,
convulsions, severe eye inflammation; addition of glycine lowered the
toxic effects
The NOEL is at 1.5% sodium benzoate in the diet (ca 750 mg/kg
bw/d).
White, A., 1941
Ca 40 days, 4 males up to 23 weeks; sodium benzoate
0-5% (ca 0-2500 mg/kg bw/d)
Oral (in the diet)
Rat (no more data given)
106 males
75-85 g
115 males
Clinical signs, body weight change, food consumption, survival rate
Markedly decreased growth rate and food consumption, occasionally
restlessness, irritability, tremor
No NOEL.
Comment: In this study sodium benzoate was taken as a reference
compound concerning body weight depression, for comparing with
other compounds (e.g. growth-stimulating substances).
Harshbarger, K.E., 1942
4-5 weeks; sodium benzoate (with and without supplement of glycine)
0-1-3% (ca 0-500-1500 mg/kg bw/d)
Oral (in the diet)
White rat
Only inexact information
Not reported, (age: about 4 weeks)
Yes
At 3% in the diet clinical signs of toxicity (increased irritability,
uncoordinated movement, convulsions), mortality (2/8 rats, within 720 days), decreased body weight gain; addition of glycine reduced the
toxicity
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
22 November 2000
Development of tolerance to sodium benzoate (tested with 3% in the
diet), when animals previously received 1% or 3% in the diet
The NOEL is at 1% sodium benzoate in the diet (ca 500 mg/kg bw/d).
Smyth, H.F. & Ch.P. Carpenter, 1948
30 days; sodium benzoate
Range from 16 to 1090 mg/kg bw/d
Oral (in the diet)
Rat, Sherman
5/sex/group
Ca 120 g
Yes
Body weight change, food consumption, survival rate, histology
(adrenal, upper intestine, kidney, liver, spleen, testis)
No adverse effect
No effect up to 1090 mg/kg bw/d.
Deuel, H.J. et al., 1954
13 weeks; sodium benzoate
0-1-2-4-8% (ca 0-500-1000-2000-4000 mg/kg bw/d)
Oral (in the diet)
Rat, Sherman
4-5/sex/group
No data given
Yes
Body weight change, food consumption, survival rate, liver and kidney
weight, histopathological examination of liver and kidney
At 8% in the diet mortality (4/8 rats, death within 13 days), decreased
growth rate (ca. 30% below control) with no change in food intake,
significantly higher kidney and liver weights, histopathological lesions
in kidney and liver (not specified)
No effect at 4% sodium benzoate in the diet in this study (ca 2000
mg/kg bw/d).
Remark: In comparison with other studies, the dose of 4% in the diet
unlikely is a NOEL.
Kieckebusch, W. & K. Lang, 1960
Depending on mortality; sodium benzoate
0-5% (ca 0-3750 mg/kg bw/d)
Oral (in the diet)
Rat, a strain from Farbwerke Bayer AG, Elberfeld
28 young and 5 adult rats
62-70 g and 221-232 g
The same as in the chronic/reproduction study by Kieckebusch (1960)
Body weight change, food consumption, survival rate, urine protein
and glucose, gross pathology
Mortality: 100% (young animals within 2-3 weeks, adult within 4-5
weeks), reduced body weight and food consumption
No NOEL.
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
22 November 2000
Kowalewski, K., 1960
3 weeks; sodium benzoate (with and without supplement of glycine)
0-5% (ca 0-2500 mg/kg bw/d)
Oral (in the diet)
Rat, Sprague Dawley
10-15 males/group
130-136 g
Yes
Body weight change, levels of lipids (liver) and electrolytes (muscle)
Reduced body weight gain, decrease in liver phospholipids, decrease
in potassium of skeletal muscle; addition of glycine reduced the toxic
effects
No NOEL.
Kramer, M. & R. Tarjan, 1962
0-1.5% (ca 0-750 mg/kg bw/d), day 20 to 30: 3% (ca 1500 mg/kg
bw/d), (carotene supplement after 4 weeks for 2 or 4 weeks)
Oral (in the diet)
Rat, Wistar
10 males/group
Not reported, (age: 8 weeks)
Yes
Body weight change, food consumption, vitamin A content of the liver
and kidney after 6 or 8 weeks, histology (no further information)
Reduced body weight gain and food consumption, when the
concentration of sodium benzoate was transiently increased to 3%
No influence on the vitamin A content of the liver and kidney
No effect at 1.5% sodium benzoate in the diet (ca 750 mg/kg bw/d).
Fanelli, G.M. & S.L. Halliday, 1963
0-2-5% (ca 0-2002/2357-5686 mg/kg bw/d for males and 02171/2396-7780 mg/kg bw/d for females; for 2% minimal/maximal
uptake is noted)
Oral (in the diet)
Rat, Sherman
6/sex/group
40-50 g
Yes
At 5% in the diet hyperexcitability, urinary incontinence, convulsive
seizures, 100% mortality after the second week, decreased growth rate
(also at 2%, but significant for males only), accompanied by lower
food consumption
No NOEL.
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
22 November 2000
Kreis, H. et al., 1967
1-5 days 3% (then 19-30 days control diet) and - other groups - 1, 2
and 5 weeks 1.1% in the diet; benzoic acid
0-1.1-3% (ca 0-550-1500 mg/kg bw/d)
Oral (in the diet)
Rat, Royal Wistar
5-10 males/group
About 60 g
Yes
Clinical signs, body weight change, food consumption, survival rate,
pathohistology (heart, liver, kidney, brain, different staining methods)
At 3% in the diet mortality (50% of the animals within 5 days),
increased irritability, restlessness, agressiveness, ataxia, tonic-clonic
convulsions
After 5 days morphological findings in all brains (necrosis of
parenchymal cells, stratum granulosum of the fascia dentata and cortex
of the lobus piriformis), after 19-30 days without benzoic acid brain
damage still evident and body weight reduced
At 1.1% in the diet (5 weeks) no findings except decreased body
weight change and food consumption
No NOEL. The discussion reveals, that 1% benzoic acid in the diet (ca
500 mg/kg bw/d) may be the threshold for toxic effects.
Bio-Fax, 1973
(cited in BUA, 1995)
4 weeks; benzoic acid
0-760-3800-7600 ppm (ca 0-65-324-648 mg/kg bw/d)
Oral (in the diet)
Rat (no more data given)
10 males/group
120 g
Yes
autopsy
No adverse effect
The NOEL is at 7600 ppm benzoic acid (ca 648 mg/kg bw/d).
Corthay, J. et al., 1977
7 days; benzoic acid (another group received hippuric acid, the main
metabolite of benzoic acid: 531 ppm)
0-362 ppm (ca 0-18 mg/kg bw/d)
Oral (in the diet)
Rat, Wistar
4 males/group
250-300 g
Yes
Hepatic microsomal enzymes (microsomal proteins, cytochrome P450, N-demethylation of aminopyrine, p-hydroxylation of aniline)
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
22 November 2000
No increase of drug-metabolizing enzymes, neither with benzoic acid
nor hippuric acid
No effect at 362 ppm benzoic acid (ca 18 mg/kg bw/d).
The dose is extremely low, the study is therefore not relevant for
deriving a NOEL.
Sodemoto, Y. & M. Enomoto, 1980
Preliminary study for the carcinogenicity study, see B.6.5.2.1
0-0.5-1-2-4-8% (ca 0-250-500-1000-2000-4000 mg/kg bw/d)
Oral (in the diet)
Rat, Fischer 344
10/sex/group
110-150 g, (age: 4-5 weeks)
10/sex
Clinical signs, body weight change, survival rate, pathohistology
(autopsy and histology of various organs)
At 4% and 8% sodium benzoate in the diet 100% mortality within 4
weeks, significantly reduced body weights; hypersensitivity;
histological examination revealed atrophy of the spleen and lymph
nodes
At 0.5, 1 and 2% in the diet 3, 2 and 1 males respectively died of
pneumonia (not compound or dose related)
According to the authors, the MTD is at 2% sodium benzoate in the
diet (ca 1000 mg/kg bw/d), the highest dose level for the
carcinogenicity study. For the occurence of hypersensitivity no doserelationship is given. No other adverse effects were described.
Fujitani, T., 1993
0-1.81-2.09-2.4% (ca 0-1358-1568-1800 mg/kg bw/d)
Oral (in the diet)
Rat, F344/Ducrj
6/sex/group
Yes
Clinical signs, body weight change, survival rate, organ weights (liver,
heart, kidney, spleen, lung, thymus), clinical chemistry (broad
spectrum), histological examination of liver and kidney
Mainly at 2.4% in the diet convulsions and mortality in 1/6 males;
depressed body weight gain; higher serum levels of albumin, total
protein and gamma-glutamyl-transpeptidase, lower levels of
cholesterol and cholinesterase; increased relative kidney and liver
weights; liver: eosinophilic foci around portal vein, enlarged
hepatocytes with glassy cytoplasm; some findings evident only in
males
The NOEL is at 1.81% sodium benzoate in the diet (ca 1358 mg/kg
bw/d).
B.6.3.1.2
Inhalative study, Rat
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
B.6.3.2
22 November 2000
IRDC (International Research and Development Corp.), 1981
(cited in BUA, 1995, there only abstract available)
4 weeks (6 hours/day, 5 days/week); benzoic acid
0-0.025-0.25-1.2 mg/l
Inhalative (dust aerosol with an equivalent aerodynamic diameter of
4.7 µm)
Rat, Sprague Dawley
10/sex/group
No data given
Yes
Body weight change, survival rate, platelets, organ weights,
pathohistology (only those parameters are noted, that showed effects,
no further information)
At 0.25 and 1.2 mg/l: Irritation of the upper respiratory tract,
decreased absolute and relative weights of the kidney
At 1.2 mg/l: Death of 1 animal/sex, decreased body weight, decrease
in platelets, decreased absolute and relative weights of the liver and
trachea/lung
Without dose-relation: High incidence of slight multifocal and
generalized interstitial fibrosis and inflammatory cell infiltrate in all
treated animals
Because of the lack of data, no conclusions can be drawn.
Oral studies, Mouse
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Loncin, M., 1967
3 days; benzoic acid
1220 mg/kg bw/d
Oral (gavage)
Mouse (no more data given)
5 males/group
16 g
Yes
Body weight change, survival rate
Decrease of body weight, mortality within 3 days (2/5)
No NOEL.
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Shtenberg, A.J. & A.D. Ignat’ev, 1970 and Ignat’ev, A.D., 1965
80 mg/kg bw/d
Oral (gavage)
White mouse, cross-bred
50/sex
8-10 g
Yes, but no number of animals given
Clinical signs, body weight change, food and water consumption,
survival rate, susceptibility to stress (different parameters, e.g.
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
22 November 2000
tolerance to CCl4 (test on detoxifying capacity of the liver), tolerance
to food restriction, both at the end of the exposure period)
Reduced body weight gain; reduced survival rate only in connection
with reduced tolerance to CCl4 or food restriction
Available data are not sufficient to justify conclusions from this study.
Toth, B., 1984
Preliminary study for the carcinogenicity study, see B.6.5.2.2
0.5-1-2-4-8% (no data given for the compound consumption)
Oral (in the drinking water)
Mouse, Albino swiss
4/sex/group
No
Body weight change, water consumption (no data given), survival rate,
pathohistology
At 8% in the drinking water all animals died within 3 weeks
At 4% 6/8 animals died during the experimental period, body weight
was significantly decreased (no further data given)
2% sodium benzoate in the drinking water was found to be suitable for
the carcinogenicity study.
Schafer, E.W. & W.A. Bowles, 1985
3 days (+ 4 days observation); benzoic acid
1250 mg/kg bw/d (25 wheat seeds/animal/d treated with 2% benzoic
acid) and alternatively laboratory rodent pellets ad lib. (less preferred
by mice)
Oral (on wheat seeds)
Deer mouse
5/group
20 g (average)
No
Survival rate, repellency
No repellent effect
Lethal dose for half of the animals: > 1250 mg/kg bw/d
The study is not relevant for deriving a NOEL.
Fujitani, T., 1993
0-2.08-2.5-3% (ca 0-3012-3750-4500 mg/kg bw/d)
Oral (in the diet)
Mouse, B6C3F1
5 males and 4-5 females/group
Yes
Clinical signs, body weight change, survival rate, organ weights (liver,
heart, kidney, spleen, lung), clinical chemistry (broad spectrum),
histological examination of liver and kidney
Findings:
Conclusion:
B.6.3.3
22 November 2000
Mainly at 3% in the diet hypersensitivity and convulsions, mortality
(2/5 females), higher serum levels of cholesterol and phospholipids,
increased kidney and liver weights; hepatocytes: eosinophilic
cytoplasm, enlargement, vacuolation and necrosis
Most findings evident only in males
NOEL at 2.08% sodium benzoate in the diet (ca 3012 mg/kg bw/d).
Oral studies, Cat
Reference:
Rationale:
1. Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
2. Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Bedford, B. & M.A. Clarke, 1972
Suspected poisoning in a cattery, benzoic acid content of 2.39% in the
cat meat (Bedford, B. & M.A. Clarke, 1971)
Therefore carrying out the following experiments with 5 heterogenous
groups
1 x in the food (observation up to 2 months); benzoic acid (see also
B.6.2)
0-1% (doses consumed: 450-890 mg/kg bw)
Oral (in the diet)
Cat (no more data given)
4/group
1.06-1.7 kg, (age: 7 months)
Body weight: 3.6-3.8 kg, (age: 16 months)
Clinical signs, survival rate, blood chemistry (urea, SAP, SALAT),
pathohistology (including central nervous system)
Aggressiveness, hyperaesthesia, convulsions (onset 14-16 h after
beginning of the feeding), mortality (2/4 32-192 h after beginning of
the feeding); abnormal histological findings in the liver, kidney, lung,
mouth and heart muscle
One cat recovered (890 mg/kg bw), the fourth was without symptoms
(450 mg/kg bw)
The single dose of 1% benzoic acid in the diet revealed effects in cats.
3 days (2 cats) and 4 days (2 cats); benzoic acid
0-0.5% (daily dose rate: 300-420 mg/kg bw, total doses consumed:
910-1260 mg/kg bw)
Oral (in the diet)
4/group
1.42-2 kg, (age: 7.5-8.5 months)
Body weight: 3.6-3.8 kg, (age: 16 months)
Clinical signs, survival rate, blood chemistry (urea, SAP, SALAT),
pathohistology (including central nervous system)
Hyperaesthesia, apprehension, depression (48-92 hours after the first
feeding), mortality (2/4 within 85-120 hours after the first feeding);
abnormal biochemical and histological findings in the liver and kidney
Two cats recovered (300 mg/kg bw/d)
No NOEL.
3. Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
4. Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
B.6.3.4
22 November 2000
0-0.25% (daily dose rate: 130-160 mg/kg bw, total doses consumed:
3000-3680 mg/kg bw)
Oral (in the diet)
4/group
3.2-4 kg, (age: 12-18 months)
Body weight: 3.6-3.8 kg, age: 16 months
Clinical signs, survival rate, blood chemistry (urea, SAP, SALAT)
No adverse effect
The NOEL is at 0.25% benzoic acid in the diet (130-160 mg/kg bw/d).
0-100-200 mg/kg bw/d
Oral (in the diet)
4/group
1.7-2.3 kg, (age: 9-10 months)
Body weight: 3.6-3.8 kg, age: 17 months (the same group as above,
but 1 month older)
Clinical signs, survival rate, blood chemistry (urea, SAP, SALAT)
No adverse effect
The NOEL for the cat is 200 mg/kg bw/d (benzoic acid); higher dose
levels revealed signs of acute (central nervous system) and cumulative
toxicity and damage of kidney and liver, but no abnormality of the
brain and spinal cord was detected by histological examination. 200
mg/kg bw/d is the lowest relevant NOEL from all available short-term
and chronic studies with benzoic acid or sodium benzoate. The reason
for the particular sensitivity of cats is a defective glucuronic acid
system. In contrast with other species, in the cat only hippuric acid is
formed, no reserve detoxication system is available.
This investigation (without guideline) performed on one species with a
peculiar metabolism is not suitable for deriving a reference dose.
Oral studies, Dog
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Rost, E. et al., 1913
Up to 250 days; sodium benzoate
Up to 7 g/animal/d (ca 1000 mg/kg bw/d), for a few dogs up to 12
g/animal/d (ca 1700 mg/kg bw/d) until death; the application pattern
differed from dog to dog with gradually increasing doses
Oral (in the diet)
Dog, Fox Terrier
17 (sex not given)
4-8 kg
No
Findings:
Conclusion:
B.6.3.5
22 November 2000
The LOELs for individual dogs ranged from 860 to 1500 mg/kg bw/d.
Overall, at ca 1000 mg/kg bw/d (ca 7 g/dog/d) and above decreased
body weight gain and food consumption, and mortality occurred,
preceded by vomiting, uncoordinated movement, ataxia, tono-clonic
and epileptiform convulsions
At even slightly lower doses no adverse effect was observed
The NOEL for the most sensitive dog was at ca 800 mg/kg bw/d (ca 6
g/dog/d) sodium benzoate.
Oral studies, Guinea pig
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Kluge, H., 1933
65 days; benzoic acid + sodium benzoate
0-150 mg/kg bw/d (sum of both compounds)
Oral (by pipette)
Guinea pig (no more data given)
4/group
Young animals (no more data)
Yes
Clinical signs, body weight change, survival rate
No adverse effect
No effect at 150 mg/kg bw/d (benzoic acid + sodium benzoate); the
study is not relevant for deriving a NOEL.
B.6.4 Genotoxicity (Annex IIA 5.4)
Summary
evident.
22 November 2000
Table B.6.4-1: Summary of in vitro mutagenicity studies: Point mutation (Ames test)
Test System
Test object
Conc./Dose
Remarks
Result
Reference
Reverse mutation
S. typh.TA 98, 100,
0.01-1 mg/plate
BA*
neg.
McCann et al.,
assay
1535, 1537
activ. s.**
1975
Reverse mutation
S. typh.TA 98, 100,
0.1 mg/plate
BA
neg.
Milvy & Garro,
assay
1535, 1537, 1538
(activ. s.?)
1976
Reverse mutation
S. typh.TA 98, 100,
0.1 mg/plate
hippuric acid neg.
Milvy & Garro,
assay
1535, 1537, 1538
(activ. s.?)
1976
Reverse mutation
S. typh.
NFI***
BA and SB* neg.
Commoner,
assay
activ. s.
1976
Reverse mutation
S. typh.TA 98, 100,
up to 3.6 µg/plate, BA
neg.
Cotruvo et al.,
assay
1535, 1536, 1537, 1538 ozonation of BA
activ. s.
1977
Reverse mutation
S. typh.TA 98, 100,
0.04 –2.5 mg/plate BA
neg.
Anderson &
assay
1535, 1537
activ. s.
Styles, 1978
Reverse mutation
S. typh.TA 98, 100, 1537 NFI
SB
neg.
Ishidate &Yoassay
activ. s.
shikawa,1980
Reverse mutation
S. typh.TA 98, 100
NFI
SB
neg.
Kawachi et al.,
assay
activ. s.
1980
Reverse mutation
S. typh.TA 100
0.0001-1mg/plate BA
neg.
Rapson et al.,
assay
1980
Reverse mutation
S. typh.
NFI
BA and SB
neg.
Morita et al.,
assay
activ. s.
1981
Reverse mutation
S. typh.
NFI
BA
neg.
Rideg, 1982
assay
(abstract)
Reverse mutation
S. typh.TA 98, 1535
0.1-5 µmol/plate
hippuric acid neg.
Wiessler et al.,
assay
activ. s.
1983
Reverse mutation
S. typh.TA 92, 94, 98,
up to 10 mg/plate
BA
neg.
Ishidate et al.,
assay
100, 1535, 1537
activ. s.
1984
Reverse mutation
S. typh.TA 92, 94, 98,
up to 3 mg/plate
SB
neg.
Ishidate et al.,
assay
100, 1535, 1537
activ. s.
1984
Reverse mutation
S. typh.TA 97, 98, 100,
0.033-10 mg/plate BA
neg.
Zeiger et al.,
assay
1535, 1537
activ. s.
1988
Reverse mutation
S. typh.TA 98, 100
ozonation: weight BA
pos.
Matsuda et al.,
assay
ratio BA/ozon: 1:0- activ. s.
(TA
1991
(method: Yahagi)
1:0.5-1:1-1:6
NFI
100)
Reverse mutation
S. typh.TA 98, 100,
0.033-10 mg/plate SB
neg.
Prival et al.,
assay
1535, 1537, 1538
activ. s.
1991
Reverse mutation
E.coli WP2
0.033-10 mg/plate SB
neg.
Prival et al.,
assay
activ. s.
1991
* BA = benzoic acid; *** NFI = no further information available * SB = sodium benzoate; ** test with activation
system
Table B.6.4-2:
Test System
Reombination
assay
Recombination
assay
22 November 2000
Summary of in vitro mutagenicity studies: Recombination/DNA
damage
Test object
S. cerevisiae D3
B. subtilis H17, M45
Conc./Dose
up to 0.18% ozonation of BA
1%
NFI***
Remarks
BA*
activ. s.**
BA
Recombination
B. subtilis
NFI
SB*
assay
activ. s.
Recombination
B. subtilis
NFI
SB
assay
Recombination
- S9: 20 mg/plate
SB
assay
+ S9: 16 mg/plate activ. s., NFI
Recombination
NFI
BA
assay
Recombination
NFI
SB
assay
DNA damage
S. typh.
up to 1.67 mg/ml
BA
(Umu test)
TA 1535/pSK 1002
activ. s.
Lambda prophage
E. coliWP2s (lambda)
max. 0.106
BA
induction
(microscreen)
mg/well
* BA = benzoic acid, * SB = sodium benzoate, ** test with activation system,
*** NFI = no further information available, **** pos. only without activ.
Table B.6.4-3:
Result
Reference
neg.
Cotruvo et al.,
1977
neg.
KhoudokormoffGistBrocades, 1978
(abstract)
pos.
Kawachi et al.,
****
1980
neg.
Morita et al.,
1981
incon- Ishizaki &
clusiv. Ueno, 1989
pos.
Nonaka, 1989
(abstract)
pos.
Nonaka, 1989
(abstract)
neg.
Nakamura et al.,
1987
neg.
Rossman et al.,
1991
Summary of in vitro mutagenicity studies: Chromosome aberrations
Test System
Test object
Conc./Dose
Remarks Result
Cytogenetic assay
(anaphase preparat.)
Chromosome aberration test
* BA = benzoic acid,
human embryonic lung
cells (WI-38)
human lymphocytes
0.01-1 mg/ml
SB*
neg.
0.001-0.1 mg/ml
BA*
neg.
Chinese hamster cells
(DON)
(CHL)
(CHL)
hamster lung fibroblast
cells
(CHL)
(CHL)
(CHL)
(CHL)
* SB = sodium benzoate,
1 x 10-3 to 1 x 10-2 M
SB
pos.
139 mg/ml (only high- SB
est dose given)
10 mg/ml
SB
no data given
up to 1.5 mg/ml
SB
activ s.**
BA
up to 2 mg/ml
SB
up to 1.5 mg/ml
BA
up to 2 mg/ml
SB
Reference
Litton Bionetics,
1974
Zhurkov, 1975
Abe & Sasaki,
1977
pos.
Ishidate &
Odashima, 1977
pos.
Ishidate & Yoshikawa 1980
pos. *** Kawachi et al.,
1980
pos.
Ishidate et al.,
1984
pos.
Ishidate et al.,
1984
inconIshidate, 1988
clusive
pos.
Ishidate, 1988
** test with activation system, *** pos. only without activ.
Table B.6.4-4:
Summary of in vitro mutagenicity studies: Chromosome aberrations
(SCE)
Test System
SCE
22 November 2000
Test object
Conc./Dose
SB
BA*
neg.
BA
neg.
SCE
1-10 mmol/l
(CHO)
human lymphoblastoid cells 1-30 mmol/l
(transformed by EpsteinBarr virus)
human lymphocytes
up to 2 mmol/l
BA
neg.
SCE
human lymphocytes
SB
pos.
SCE
SCE
1 x 10mmol/l
SB*
Result
inconclusive
neg.
SCE
1–10 mmol/l
(DON)
hamster lung fibroblast cells NFI**
Remarks
Reference
Abe & Sasaki,
1977
Kawachi et al.,
1980
Oikawa et al.,
1980
Tohda et al.,
1980
Jansson et al.,
1988
Xing & Zhang,
1990
* BA = benzoic acid, * SB = sodium benzoate, ** NFI = no further information available
Table B.6.4-5:
Summary of in vivo mutagenicity studies
Test System
Cytogenetic assay
(bone marrow)
Test object
rat, Sprague Dawley,
5 males/group
Host-mediated
assay (S. typh.TA
1530)
mouse, ICR, 8-10
males/group
Host-mediated
mouse, ICR, 8-10
assay (S. typh.G 46; males/group
S. cerevisiae D3)
Chromosome aberration
(bone marrow)
Dominant lethal
assay
rat
rat, random-bred, 5
males/group
Conc./Dose
0-50-500-5000 mg/kg
bw, via gavage
1. single application
2. for 5 days
0-50-500-5000 mg/kg
bw, via gavage
2. for 5 days
0-50-500-5000 mg/kg
bw, via gavage
2. for 5 days
3.
NFI***
0-50-500-5000 mg/kg
bw, via gavage
2. for 5 days
Remarks
Result
Reference
SB* sacrifice: neg.
Litton Bionetics,
1. after 6-48 h
1974
2. after 6 h
SB*
(neg.)
**
Litton Bionetics,
1974
SB
neg.
Litton Bionetics,
1974
SB
neg.
Kawachi et al.,
1980
SB
neg.
Litton Bionetics,
1974
* SB = sodium benzoate
** elevation of mutant frequency with S. typh.TA 1530 at 500 mg/kg bw after the single application
*** NFI = no further information available
Table B.6.4-6:
Test System
Mutation rate
Mammalian-cell
transformation test
22 November 2000
Summary of other mutagenicity studies
Test object
Conc./Dose
Remarks
Result
Reference
SB*
BA*
neg.
neg.
Njagi, 1978
Purchase et al.,
1978
Mammalian-cell
transformation test
Drosophila, fruit fly
NFI**
NFI
human diploid lung fibroblasts or liver derived
cells (Chang)
Syrian hamster kidney
NFI
cells
BA
neg.
Purchase et al.,
1978
Mutation rate
Silk worm
NFI
SB
neg.
Cytological effects,
e.g. inhib. of DNA
synth., anaphase
bridges, micronucl.
Influence on phagocyte-induced mutation in bacteria
Vicia faba root meristems
5-50000 mg/kg
SB
pos.
Kawachi et al.,
1980
Njagi & Gopalan, 1982
SB
Weitzman &
SB
inhibits Stossel, 1982
mutations
signific.
pos.
Xing & Zhang,
1990
phagocytic human leuco- 2.5 mmol/l
cytes + S. typh.TA 100
Sister chromatid
Vicia faba root tip cells
exchange
* BA = benzoic acid, * SB = sodium benzoate
** NFI = no further information available
1-10 mmol/l
SB
B.6.5 Long-term toxicity and carcinogenicity (Annex IIA 5.5)
Summary
For reasons pointed out in the preface, in this monograph all accessible publications for longterm toxicity and carcinogenicity are shortly described and assessed, even those with reduced
relevance.
drinking water.
Including the results from the chronic toxicity studies the conclusion can be drawn that no
carcinogenic effect is evident for benzoic acid or sodium benzoate in the available literature.
be derived from all relevant short-term and chronic toxicity/carcinogenicity studies on rats
together since no single study according to a current test guideline is available. This NOEL
can serve for the calculation of ADI and AOEL.
B.6.5.1
22 November 2000
Long-term toxicity
B.6.5.1.1
Oral Studies, Rat
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Marquardt, P., 1960
0-1.5% (ca 0-1125 mg/kg bw/d)
Oral (in the diet)
Rat, Wistar and Osborne-Mendel
Wistar: 30 and 20 males (2 strains), 20 females (1 strain); OsborneMendel: 20 males
50-60 g, (age: ca 5 weeks), (only data for Wistar)
Wistar: 13 and 10 males (2 strains), 12 females (1 strain); OsborneMendel: 10 males
Mortality (only in one Wistar strain): 15/50 at 1.5% benzoic acid in
the diet, control group: 3/25; decreased body weight change and food
consumption in all the strains
No NOEL.
Combined chronic/reproduction study
Generation 1 and 2: lifelong; generation 3: 16 weeks; generation 4:
until breeding; benzoic acid
0-0.5-1% (ca 0-375-750 mg/kg bw/d)
Oral (in the diet)
20/sex/group
40-50 g
20/sex
Clinical signs, body weight change, food consumption (protein
efficiency), survival rate, organ weights (brain, heart, liver, spleen,
kidney, testes), parameters concerning reproduktion, histology
No adverse effect
Significant prolongation of life at 0.5% in the diet
The NOEL is at 1% benzoic acid in the diet (ca 750 mg/kg bw/d).
0-40 mg/kg bw/d
Oral (via an undefined paste prior to feeding)
Rat, Wistar
10/sex
100-120 g
Clinical signs, food and water consumption, survival rate, several
blood parameters, tolerance to one lethal dose of sodium benzoate
given terminally
Findings:
Conclusion:
B.6.5.1.2
Development of tolerance to benzoic acid (mortality rate in control
animals given one lethal dose of 3600 mg/kg bw sodium benzoate at
termination: 100 %, mortality rate in the animals fed the test
compound for 72 weeks prior one lethal dose of 4000 mg/kg bw
sodium benzoate: 25 %)
Oral Study, Mouse
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
B.6.5.2
22 November 2000
0-40 mg/kg bw/d
Oral (via an undefined paste prior to feeding)
White mouse, cross-bred
25/sex
10-20 g
Clinical signs, body weight change, food and water consumption,
survival rate, several blood parameters, susceptibility to stress
(different parameters, e.g. tolerance to food restriction at the end of the
exposure period), tumour rates
Reduced survival rate in connection with food restriction, reduced
body weight gain; increased tumour rate after application of the
combination benzoic acid/sodium bisulphite (this leads to the Ehrlich
ascites mouse carcinoma test, performed by Dinerman, A.A. & A.D.
Ignat’ev, 1966, see B.6.5.2.2)
Carcinogenicity
B.6.5.2.1
Oral Studies, Rat
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Sodemoto, Y. & M. Enomoto, 1980
18-24 months; sodium benzoate
Scheduled sacrifice of several animals from each group for
morphological examination in the middle of the experimental period,
no further data
0-1-2% (ca 0-500-1000 mg/kg bw/d)
Preliminary 6 week toxicity study (0-0.5-1-2-4-8% in the diet), see
B.6.3.1
Oral (in the diet)
Rat, Fischer 344
50 males and 52 females/group (no number given for the intermediate
sacrifice)
110-150 g, (age: 4-5 weeks)
25 males and 43 females (no number given for the intermediate
sacrifice)
Parameters:
Findings:
Conclusion:
B.6.5.2.2
22 November 2000
pathohistology (autopsy and histology of various organs), tumour rates
No adverse effect
Mortality rate overall was 14-15% for all groups up to 16 months, all
dead animals showing pneumonia with abscess; after 16 months
mortality rate increased significantly due to hemorrhagic pneumonia,
probably induced by mixed infection, but no difference between
treated and control groups was evident:
Average survival time at the 0%, 1% and 2% dietary concentration
was 81.3 (+ 23.1), 68.7 (+ 15.7) and 74.9 (+ 16.3) weeks for males and
71.9 (+ 17.7), 87.4 (+ 20) and 81.4 (+ 22.3) weeks for females,
respectively
Comments of the rapporteur:
- In the figures 3 and 4 of the publication, showing curves of the body
weight change, males and females obviously were exchanged by
mistake
– There is a lack of information on the intermediate scheduled
sacrifice
– Overall, there is enough information and survival rates up to 16
months are sufficient for the following conclusion
Neither hypersensitivity occurring in the preliminary short-term study
nor other lesions were reported. No carcinogenic effect in Fischer rats
from sodium benzoate up to 2% in the diet (ca 1000 mg/kg bw/d) was
evident in this study.
Oral Studies, Mouse
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Toth; B., 1984
Lifelong; sodium benzoate
0-2% (average uptake: 0-124 mg/d for males, 0-119 mg/d for females;
no data given for body weights)
Preliminary 6 week toxicity study (0.5-1-2-4-8% in the drinking
water), see B.6.3.2
Oral (in the drinking water)
Mouse, Albino swiss
50/sex
Not reported, (age: 39 days)
99/sex
Clinical signs, body weight change, water consumption, survival rate,
complete pathohistology (including the brain), tumour rates
No adverse effect on survival rates or on the other parameters
No carcinogenic effect in Albino swiss mice from sodium benzoate at
2% in the drinking water was evident in this study
NOEL for other lesions also at 2% in the drinking water (ca 120
mg/mouse/d).
B.6.5.2.3
22 November 2000
Other carcinogenicity tests
Hosino, L., 1940 a, b (cited in Hosino, L. in Hartwell, J.L.,1951)
Carcinogenicity test on rabbits
When benzoic acid was applicated sc or iv (no dose given) for 40 days, no carcinogenic effect
was found. No further data given.
Dinerman, A.A. & A.D. Ignat’ev, 1966
Ascites mouse carcinoma test
With this test, the effect of benzoic acid and other food additives on the development of
malignant processes was studied in Mongrel mice of both sex. The test was performed,
because an increased tumour rate occurred after application of the combination benzoic
acid/sodium bisulphite (see B.6.5.1.2, Shtenberg, A.J. & A.D. Ignat’ev, 1970 and Ignat’ev,
A.D., 1965).
Those mice, that received benzoic acid presented a higher percentage of tumours, a shorter life
length and a larger amount of ascetic fluid. No further information.
Odashima, S., 1980
Overview mutagenicity/carcinogenicity
Summarized results are presented for several compounds to establish a correlation between
mutagenic and carcinogenic effects. Sodium benzoate was noted with negative results in longterm studies with doses of 1% and 2% sodium benzoate in the diet (mice: 104 weeks, rats: 108
weeks). For the carcinogenicity studies no further data and no references were given, but the
long-term rat study obviously represents the study published by Sodemoto and Enomoto, 1980
(see B.6.5.2.1).
Hatanaka, J. et al., 1982
Screening test in fish
The toxicity and carcinogenicity of several compounds, for which data in mice and rats were
known, were tested in Medaka, a small aquarium fish. Sodium benzoate was incorporated into
the diet (4 groups, 10000-80000 ppm, ca 50 fish/group, daily diet consume of 50 fish: 800 mg;
control group: 25/sex) and fed for 24 weeks; daily observation, terminal autopsy and histology
were done. Mainly, known carcinogens (application periods up to 24 weeks, 20-50 fish/group)
induced liver cell carcinoma, preneoplastic nodules or other hepatotoxic effects. Sodium
benzoate was one of the test compounds, which neither revealed liver tumours nor
preneoplastic stages, but 12/50 fish died at 40000 ppm and 13/50 at 80000 ppm from week 12
to 24. Bile duct proliferation occurred at 80000 ppm. All mentioned findings were not
observed in control fish. The authors concluded that this fish test could be established as a
useful alternative to screening tests in mammals, however further studies would be necessary.
Jagota, S.K. & Dani, H.M. (1985)
Microsomal degranulation test
A method for the detection of carcinogens indicated by degranulation of microsomes (loss of
there ribosomes) is tested. Benzoic acid (no concentration given) was used as a known non
carcinogen. Eight known carcinogens caused a high percentage of microsomal degranulation,
whereas benzoic acid together with 6 other known non carcinogens failed to cause this effect.
22 November 2000
The authors recommended the technique as a quick, inexpensive and accurate screening for
the prediction of environmental carcinogens.
Gupta, M.M. & Dani, H.M. (1986)
Microsomal degranulation test
In this screening test for possible carcinogens, benzoic acid in a concentration of 20 µg/ml
was found to be positive (degranulation ≥ 5% in relation to controls considered as positive;
benzoic acid: ca 9%; for comparison: dimethylnitrosamine: ca 20%). Data for the control experiments and exact evaluation criteria were not given in this publication. The authors suggested to use the test as one among others in screening testing.
Ito, N. et al., 1989
Liver foci test (DEN-PH model)
The enhancing effect of sodium benzoate on induction of preneoplastic liver foci was
measured in F 344 rats by comparing the glutathion S-transferase positive foci in liver slices
of treated and control animals.
Study design: A single ip injection of diethylnitrosamine in one group and saline in a second
group, respectively, was followed by repeated treatment with sodium benzoate (no dose given)
from week 2 up to termination; the third group only recieved a single ip dose of
diethylnitrosamine (200 mg/kg bw); hepatectomy at week 3; sacrifice at week 8. The effect
was positive with sodium benzoate.
Spustova, V. & Oravec, C. (1989)
In vitro test with mouse ascites tumor strains with benzoate
Ascites mouse carcinoma test with hippurate
In an in vitro test with several mouse ascites tumor strains, an antitumor effect of benzoate
and its main metabolite hippurate was found. The concentration range was 0.5 to 5.0 mmolar.
The growth of ascites tumors implanted into mice four days before administration of hippurate
(1000 mg/kg bw ip, twice daily, 4 days) could be reduced. The authors suggested to investigate the possible clinically relevant antitumor effect of hippurate further.
B.6.6 Reproductive toxicity (Annex IIA 5.6)
Summary
For reasons pointed out in the preface, in this monograph all publications accessible for the
evaluation of reproduction and developmental toxicity are shortly described and assessed,
even those with reduced relevance.
22 November 2000
rabbits, mice and hamsters. up to the highest tested doses of 175, 250, 175 and 300 mg/kg
these species.
B.6.6.1
Reproduction
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
B.6.6.2
Combined chronic/reproduction study
Generation 1 and 2: lifelong; generation 3: 16 weeks; generation 4:
until breeding; benzoic acid
0-0.5-1% (ca 0-375-750 mg/kg bw/d)
Oral (in the diet)
20/sex/group
40-50 g
20/sex
Clinical signs, body weight change, food consumption (protein
efficiency), survival rate, organ weights (brain, heart, liver, spleen,
kidney, testes), parameters concerning reproduction, histology
No adverse effect; significant prolongation of life at 0.5% in the diet
The NOEL is at 1% benzoic acid in the diet (ca 750 mg/kg bw/d).
Developmental toxicity
B.6.6.2.1
Rat
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Kimmel, C.A. et al., 1971
A single dose at day 9 of gestation, termination at day 20 of gestation;
benzoic acid
One group: 510 mg/kg bw benzoic acid, the other groups: 510 mg/kg
bw benzoic acid and 2 hours later 250 or 500 mg/kg bw acetylsalicylic
acid (a known teratogen)
Oral (by gavage)
Rat, Wistar, Albino Farms
7-10 females/group
200-250 g
6 females
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
22 November 2000
Implantation and resorption rate, survival rate,
abnormality/malformation rate; concentration of acetylsalicylic acid in
maternal serum, and in fetuses with and without pretreatment by
benzoic acid
After application of benzoic acid alone the survival and malformation
rates (100% and 3%) were comparable with the rates in the vehicle
control group (90% and 4%); historical control data: 96% and 1%.
Benzoic acid increased the concentration and persistence of
acetylsalicylic acid in maternal serum, and in fetuses.
The teratogenic effect of acetylsalicylic acid after 250 and 500 mg/kg
bw was enhanced by pretreatment with benzoic acid from rates of 21%
and 76% after acetylsalicylic acid alone to rates of 43% and 91%.
The authors concluded, that benzoic acid prolonged the excretion time
of acetylsalicylic acid, resulting in a longer exposition time for the
fetuses
No teratogenic effect at 510 mg/kg bw benzoic acid, applicated at day
9 of gestation.
Minor, J.L. & B.A. Becker, 1971
(Only an abstract available)
Day 9-11 or 12-14 of gestation; sodium benzoate
0-100-315-1000 mg/kg bw/d
ip
Rat, Sprague-Dawley, females
No data given
No data given
Yes: sodium chloride, but no number given
Fetal body weight, in utero survival rate, gross pathology
At 1000 mg/kg bw/d at both application dates decreased fetal body
weight and in utero survival rate; gross anomalies (no further
information)
According to the abstract, at 315 mg/kg bw/d sodium benzoate no
effects were observed in this study.
No more conclusions can be drawn.
FDR Lab., 1972
Day 6-15 of gestation; observation until day 20 of gestation; sodium
benzoate
0-1.75-8-38-175 mg/kg bw/d
Oral (by gavage)
Rat, Wistar, females
No data given
No data given
Yes
Maternal toxicity (no more data given), nidation rate, survival rate,
abnormalities of soft and skeletal tissues
No adverse effect
The NOEL is at 175 mg/kg bw/d sodium benzoate.
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
22 November 2000
Onodera, H. et al., 1978
During the whole gestation period; sodium benzoate
0-1-2-4-8% (ca 0-500-1000-2000-4000 mg/kg bw/d)
Oral (in the diet)
Rat, Wistar
12-18 females
No data given, (15-17 weeks old)
15 females
Body weight, food consumption, implantation rate, perinatal survival
rate, organ weights of 8 week old offspring, abnormality/malformation
rate (visceral and skeletal)
At 4% and 8% decreased body weight gain and food consumption of
the mothers, decreased weight of fetuses (gestation day 20), shortly
after birth 100% mortality of the offspring; increased incidences of
abnormalities/malformations of organs (eye, kidney, brain) and
skeletal system
At 1% and 2% no statistically significant difference in organ or
skeletal abnormalities
Number of fetuses with abnormalities at 0%, 1%, 2%, 4% and 8% was
0/41, 1/33, 1/41, 12/36 and 11/26, respectively; at 1%, the fetus
showed bilateral anophthalmia, at 2%, the fetus showed unilateral
pyelectasis; at 4% and 8% high incidences of eye and kidney
abnormalities were evident
Remark of the rapporteur:
At 2% sodium benzoate in the diet slight reduction of food intake of
mothers and survival rate of 8 week old offspring
The isolated findings at 1% and 2% sodium benzoate in the diet are
not regarded as compound related. The NOEL is at 1% sodium
benzoate in the diet.
Crane, S.C. & P.A. Lachance, 1985
During the whole gestation and lactation period, pubs after weaning up
to day 45 of age; sodium benzoate
0-0.1-0.5-1% (ca 0-50-250-500 mg/kg bw/d)
Oral (in the diet)
Rat, Wistar
10 females/group
200-250 g
10 females
Body weight change, food consumption; spontaneous locomotor
activity (at day 6, 9, 12, 15, 18, 21 of age and thereafter continuously
up to termination); brain levels of serotonin, dopamine and
norepinephrine (at day 9, 15, 21 of age and at termination), brain
weight
No adverse effect
The NOEL is at 1% sodium benzoate in the diet.
B.6.6.2.2
Rabbit
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
B.6.6.2.3
FDR Lab., 1972
benzoate
0-2.5-12-54-250 mg/kg bw/d
Oral (by gavage)
Rabbit, Dutch-belted, females
No data given
No data given
Yes
No adverse effect
Mouse
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
B.6.6.2.4
22 November 2000
FDR Lab., 1972
benzoate
0-1.75-8-38-175 mg/kg bw/d
Oral (by gavage)
Mouse, CD-1, females
No data given
No data given
Yes
No adverse effect
Hamster
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
FDR Lab., 1972
benzoate
0-3-14-65-300 mg/kg bw/d
Oral (by gavage)
Golden hamster, outbred, females
No data given
No data given
Yes
Findings:
Conclusion:
B.6.6.3
22 November 2000
No adverse effect
Other teratogenicity tests
Teratogenicity screening tests, Hen
Reference:
Duration:
Dose:
Application:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Reference:
Duration:
Dose:
Species/Strain:
Animal number:
Control group:
Parameters:
Findings:
Conclusion:
Verrett, M.J. et al.,1980
Single injection; sodium benzoate
Up to 5 mg/egg (only the highest of 5 doses is given)
Injection into the eggs; four test conditions: injection via the air cell or
via the yolk at preincubation (hour 0) or 96 hours after
Hen, Leghorn
Ca 25 chicken embryos/test condition (= ca 100/dose)
Ca 100/vehicle or untreated control
Concerning acute toxicity and teratogenicity
LD50 (injection via air cell at 96 hours): 4.74 mg/egg
No teratogenic effect with sodium benzoate
Ten of the simultaneously tested 79 compounds produced teratogenic
effects
No teratogenic effect up to a dose of 5 mg sodium benzoate/egg.
Remark: The authors propose this test for screening large numbers of
compounds.
Jelinek, R. & M. Peterka, 1985
Single injection; sodium benzoate
Up to 0.1 mg/embryo (injection into the eggs)
Hen, Ross I stock
A total of 120 chicken embryos for range finding and main test (days
of incubation: 1.5, 2, 3 or 4)
Yes, but no exact number given; however, basis data for abnormalities
of 5370 embryos were given
Concerning embryotoxicity and teratogenicity
No adverse effect
117 of the simultaneously tested 129 compounds produced
embryotoxic and/or teratogenic effects
No embryotoxic effect with sodium benzoate up to a concentration of
0.1 mg/embryo.
Remark: The authors propose this test for screening large numbers of
compounds.
22 November 2000
In vitro - teratogenicity screening test
Szydlowska, H. et al. (1980)
In this test the inhibition of histochemical reaction to SH groups in fixed liver sections of
Wistar rats was measured. Sodium benzoate was tested in a concentration of 14,41 mg/ml.
Thirty three other compounds (known teratogens and non-teratogens) were tested simultaneously. Sodium benzoate inhibited the histochemical reaction to SH groups.
The authors propose this test as a preliminary screening procedure for teratogenic properties.
B.6.7 Delayed neurotoxicity (Annex IIA 5.7)
guidelines are not available. There are no results in other studies which would indicate the
necessity of neurotoxicity testing.
In one study, the neuroexcitation potential of benzoic acid as a metabolite of toluene was
examined. Benzoic acid (2% solution) was intravenously administered to rats at a rate of ca 2
mg/min, resulting in a total dose of 108 mg. Somatosensory evoked potentials (SEP) and
electroencephalograms (EEG) were recorded from the somatosensory cortex with nasal
reference. The results were compared to tests with toluene, o-cresol and hippuric acid as the
main metabolite of benzoic acid. Neither benzoic acid nor hippuric acid did cause
neuroexcitation or changes in EEG (Mattson et al., 1989).
B.6.8 Further toxicological studies (Annex IIA 5.8)
Summary
A multitude of studies - biochemical studies, certain biological tests etc - with benzoic
acid/benzoates were performed from which some additional information could be obtained.
However, it would be beyond the scope of this monograph to refer to all these investigations.
Summarizing, it can be said that all metabolic processes in which glycine, ATP and coenzyme
A are involved might be affected by benzoates because the detoxication of benzoic
acid/benzoates requires these substances.
B.6.8.1
Summarized description of investigations
Findings in studies with benzoates touching on the matter of concern of this evaluation are
summarized in the following paragraphs. Data from in vitro carcinogenicity tests are quoted in
chapter B.6.5.2.3.
indicated benzoic acid as being a potential substrate of cytochrome P450 IIE (Parke & Lewis,
1992).
Because the detoxication of benzoates requires glycine, a reduction of the glycine level in the
body can occur (Simkin & White, 1957a, Simkin & White, 1957b, Palekar & Kalbag, 1991).
22 November 2000
This can result in a reduction of creatine (Brand & Harris, 1933 and Polonovski & Boy, 1941),
glutamine (Harris and Harris, 1949, Häussinger et al., 1989), glutamate (O’Connor et al.,
1989), N-acetylglutamate (O’Connor et al., 1989) and urea (O’Connor et al., 1989, Häussinger
et al., 1989). For the formation of N-acetylglutamate, glutamine and urea, ATP is essential
(Palekar et al., 1989) which is also required for the conversion of bencoic acid to its CoA ester
prior to the conjugation with glycine to hippuric acid (Kalpag & Palekar, 1988).
Benzoates can exert inhibitory effects on the oxidation of intermediary metabolites as glucose
(Kaplan et al., 1954), d-amino acids (Klein & Kamin, 1941), fatty acids (Avigan et al., 1955,
Kalpag & Palekar, 1988) and acids in the tricarboxylic acid cycle (Kaplan et al., 1954). At
least partly, the inhibitory effects could be caused by the formation of benzoyl CoA resulting
in a decrease of acetyl CoA.
Benzoates can cause a decrease in ATP, coenzym A and acetyl CoA and an increase in
ammonia in the liver. This was shown in experiments performed to solve the discrepancy
between the possibility to treat hyperammonemia in patients (see B.6.9.4) and the potentiation
of lethal effects of hyperammonemia in animal experiments (O’Connor et al., 1989, Kalbag &
Palekar, 1988, Palekar et al., 1989, Palekar & Kalbag, 1991).
In the experiments of Kalbag & Palekar (1988), the intraperitoneal administration of ca 1440
mg sodium benzoate/kg bw (10 mmol/kg bw) led to a reduction in hepatic ATP, coenzym A
and acetyl CoA down to ca 20%, 50% and 30% as compared to control rats and an increase of
ammonia up to ca 200%.
In another experiment of this group (Palekar & Kalbag, 1991), intraperitoneally administered
doses of ca 360, 720, 1080 and 1440 mg sodium benzoate/kg bw (2.5, 5, 7.5 and 10 mmol/kg
bw) caused decreases of glycine in plasma and liver (plasma: by 44%, 53%, 58%, 66%; liver:
by 47%, 50%, 58%, 60%, respectively) within 2 hours.
Because glycine enters the liver mitochondria passively down its concentration gradient, the
authors concluded that a decrease in the glycine level up to 50% in both liver and plasma may
limit its own rate of transport into mitochondria and further conjugation with benzoate which
could be a mechanism for the potentiation of hyperammonemia symptoms in animal
experiments.
As indicated by FDA (1972), benzoates can accelerate the in vitro autoxidation of
oxyhemoglobin by interaction with the hemeprotein. However from the review of the original
papers of Tsushima (1954) and White & Kerr (1957), their experimental designs has no
relevance for existing conditions in vivo.
In the spectrophotometrical measurements by Tsushima (1954), benzoates (0.61 to 1.42
molar) did accelerate the autoxidation of oxyhemoglobin (0.085%), obtained from a
supernatant of bovine erythrocytes.
Testing denaturating agents, White & Kerr (1957) observed a denaturation of hemoglobin by
1.7 molar sodium benzoate, spectrophotometrically measured at pH 8.5.
Benzoic acid (100 mmolar, for comparison: salicylic acid: 10 mmolar) caused an uncoupling
of oxidative phosphorylation from respiration in isolated rat liver mitochondria (Bosund,
1957). In experiments of Kalbag & Palekar (1988), sodium benzoate at concentrations of 0.5
to 2.0 mmolar failed to show any uncoupling activity.
22 November 2000
B.6.9 Medical data and information (Annex IIA 5.9)
Summary
B.6.9.1
Acute experiments with human volunteers
In an investigation of Bignani (1924), volunteers tolerated single oral doses of 21 to 42 g
benzoic acid and excreted it nearly completely within few hours.
When Gerlach (1909) took 10 g benzoic acid within 3.5 hours in a self-experiment, he did not
observe any effect on respiration, body temperature and pulse. In a second experiment on
himself with the ingestion of 0.5 or 1 g benzoic acid or sodium benzoate with breakfast, he
found no effect on total acidity of gastric juice, free HCl and digestion.
Single oral doses of 3 to 10 g sodium benzoate administered to male volunteers caused a
decrease of urea and uric acid in urine and an increase of uric acid (but not of urea) in blood
and plasma. No symptoms were reported (Swanson, 1925).
B.6.9.2
22 November 2000
Subacute / subchronic experiments with human volunteers
In experiments of Gerlach (1909), daily administration of 0.5, 1 and 2 g benzoic acid or 1 and
2 g sodium benzoate to volunteers for 6 consecutive days had no effect on total protein and on
the utilization of nitrogen and lipid components of the food. The daily intake of 1 g benzoic
acid or 1.5 g sodium benzoate for 44 days did not lead to any symptoms and had no influence
on body weight, body temperature, respiration and pulse. Daily intake of 1 g benzoic acid over
a period of about 90 days did also not cause unfavorable effects.
In other experiments undertaken by Lucas (1909), 12 men drank apple cider (1 to 2.5 l with an
average of 1.2 l) with 1 g/l sodium benzoate (0.1%) during one evening and noted a burning
taste of the cider. They suffered from symptoms as nausea, “fulness in the head”, headache,
nervousness, vomiting, itching of the skin, unusual perspiration, constipation and a decrease
in urine flow. A decrease in specific gravity of the urine and albuminuria were also evident.
Intake of 1 l cider (without apple pulp) with 2 to 3 or 5 g/l benzoic acid caused albuminuria
within 3 hours. The author stated elsewhere that he had ingested 6 g/d for three successive
days in milk on a full stomach without the slightest discomfort.
Twelve individuals were given benzoic acid in a total dosage of 35 g for 20 consecutive days
according to the following regimen: 1 g for 5 days, 1.5 g for 5 days, 2 g for 5 days and 2.5 g
for 5 days. Benzoic acid produced marked symptoms as discomfort, malaise, nausea,
headache, weakness, burning and irritation of the oesophagus and indigestion. Only 3
volunteers took the intended entire dose of 35 g (Wiley and Bigelow, 1908).
It seems not very likely that these strong symptoms occurred in so many volunteers at these
ingested amounts of benzoates – especially in the investigation of Lucas (1909) “offering” the
apple cider with 0.1% sodium benzoate. This concentration would have been the same or
barely higher than that which nowadays is usually added to foods and semi-luxury foods
(Germany: 0.005% - 0.5% and 0.05% - 0.1%, respectively; Baltes 1989).
According to Barnes (1959), the poisoning with benzoates at excessive doses in man is
comparable to salicylate poisoning, related to disturbances in the acid-base equilibrium rather
than to tissue damage.
B.6.9.3
Test for irritancy on human volunteers
Frosch and Kligman (1976) performed a so called chamber-scarification test for irritancy
(closed patch test) in young adult caucasoids, some of them obviously especially vulnerable to
irritants (no details given). Test substances were applied in a chamber to either scarified or
intact skin once daily for 3 days with readings made at 72 hours, i.e. 30 minutes after removal.
The lowest concentration of benzoic acid which caused some irritancy without scarification
was 30%, with scarification 7.5%. Benzoic acid was classified by the authors as moderately
irritant in this test.
22 November 2000
B.6.9.4 Experiences with medical use of benzoic acid/benzoates
Senator (1879) introduced benzoic acid and sodium benzoate for the treatment of rheumatic
arthritis. At first he applied doses of 4 to 6 g per day. Against the background of increased
clinical experience, the doses were heightened up to 10 to 25 g per day later on. No symptoms
were reported.
A test on liver function making use of the conversion of benzoic acid to hippuric acid was
developed by Quick (1932). In this test, usually 6 g of benzoic acid were orally given.
To increase the penicillin level in blood, 11 patients received daily doses of 12 g benzoic acid
(divided into 8 administrations each day) for five days (in one case for 14 days). No influence
on the blood urea nitrogen levels and on the endogenous creatinine clearance, i.e. no renal
impairment became evident under these conditions. About one third of the patients
complained of gastric burning and anorexia (Waldo et al., 1949).
The administration of sodium benzoate has been shown to be beneficial in patients suffering
from hyperammonemia related to Reye’s syndrome, some organic acidemias and genetic
effects in the urea cycle (Batshaw et al., 1981, Green et al., 1983, Brusilow & Maestri, 1996).
The protection against hyperammonemia is based on utilization of ammonia to reform glycine
that has been utilized in benzoate conjugation to hippurate. The doses are within the range of
125 to 500 mg/kg bw/day (Batshaw et al., 1981, Green et al., 1983, Takeda et al., 1983, Feillet
& Leonard, 1998). However, because of the considerable interpatient variability in benzoate
metabolism, parameters as glycine, benzoate, hippurate and/or ammonia levels in plasma and
urine have to be carefully monitored to avoid any toxic effect of benzoate (Green et al., 1983,
Palekar & Kalbag, 1991, Feillet & Leonard, 1998) (see also B.6.8).
B.6.9.5
Non-immune immediate contact reactions (NIICRs) of benzoic acid/benzoates
Benzoic acid and its salts are known as pseudoallergic substances which can cause syndromes
as urticaria (Michaelsson & Juhlin, 1973, Michaelsson et al., 1974, Thune & Granholt, 1975,
Doeglas, 1975, Ros et al., 1976, Warin & Smith, 1976, Warin & Smith, 1982, Lewis et al.,
1989, Pachor et al., 1989), asthma (Rosenhall & Zetterström, 1975, Freedman, 1977, Tarlo &
Broder, 1980, Ortolani, 1986) and rhinitis (Moneret-Vautrin, 1986, van Beyer et al., 1989).
The strength of reaction can vary from local redness and/or edema to generalized urticaria,
abdominal seizures and anaphylactic shock (Kinsey & Wright, 1944, Pevny et al., 1981,
Michils et al., 1991).
The pseudoallergic reactions mimic signs and symptoms of allergic disorders but without
underlying immunologic mechanisms (Juhlin et al., 1972, Freedman, 1977, Clemmensen &
Hjorth, 1982). Therefore they are termed as non-immune immediate contact reactions
(NIICRs) including non-immune contact urticaria (NICU), in contrast to immunological
contact urticaria which is mediated at least partly by specific IgE antibodies (Lahti &
Maibach, 1984).
In a maximization test - developed for humans and described in fullness by Kligman (1966) benzoic acid and related compounds did not show any sensitization potential in volunteers
(Leyden & Kligman, 1977).
22 November 2000
Investigations of Lahti (1980) indicated that NIICRs due to benzoates are not mediated by
histamine. The reactions may be mediated by other vasoactive substances. An altered
prostaglandine synthesis was proposed since benzoic acid is chemically related to
acetylsalicylic acid (Schaubschläger et al., 1991) and cross reactivity in NIICRs for bencoic
acid and salicylates has been described (Ros et al., 1976, Genton, 1985). Benzoates can also
have a direct influence on dermal vessels (Lahti, 1980).
Ultraviolet irradiation appears to reduce (Larmi, 1989) and infra-red and laser irritation (1064
nm) to increase (Larmi et al., 1989) the NIICRs induced by benzoic acid.
Intensive testing has been carried out to find the causative substance in people for whom a
sensitivity to pseudoallergic (or allergic) substances is known or at least suspected.
For skin testing of substances including benzoates, open epicutan tests as well as closed patch
and chamber tests are reported (Baird, 1945 (1/1)♦, Baer et al., 1955 (5/108), Hjorth, 1961
(10/103), Forsbeck & Skog, 1977 (3/5), Nethercott, 1984 (2/2), de Groot et al., 1986 (8/627),
Broeckx et al., 1987 (34/5202), Malanin & Kalimo, 1989 (6/23), Rademaker & Forsyth, 1989
(14/125), Brasch et al., 1993 (7/2045), Basketter and Wilhelm, 1996 among others).
A large amount of oral provocation tests (oral challenge tests) with benzoates are also
provided in the comprehensive literature (Juhlin et al., 1972 (3/7)♦, Michaelsson & Juhlin,
1973 (22/37), Michaelsson et al., 1974 (3/7), Warin & Smith, 1982 (7/56), Genton et al., 1985
(6/33), Kemp & Schembri, 1985 (1/14), Moneret-Vautrin, 1986 (2/17), Young et al., 1987,
van Beyer et al., 1989 (3/6), Vieluf et al., 1990 (4/19), Schaubschläger et al., 1991 (4/21),
Götz et al., 1994 (1/1), Vogt, 1999 (1/1) among others).
The number of patients reacting and the strength of reaction depend on the kind of test (Lahti,
1978, Lahti, 1980, Nethercott et al., 1984), the study design, the selection and number of
patients, the number of placebo controls and the criteria for judging the reactions
(Schaubschläger et al., 1991, Coverly et al., 1998).
Criteria of the study design are the used vehicle (e.g. Ylipieti & Lahti, 1989), the part of the
body where the substance is applied (Frosch et al., 1980, Larmi et al., 1989), the condition of
the skin (scarificed or not) (Lahti, 1980), the number and time of intervals between the
applications (Michaelsson et al., 1974) and the time of judging the reactions (Warin & Smith,
1982).
In skin tests, the mostly used concentrations for benzoic acid and sodium benzoate are 5% and
10%; the mostly used vehicle is petrolatum (e.g. Lahti, 1980). In the oral provocation tests, in
general the doses vary between 10 to 500 mg sodium benzoate. As a rule, the substance is
administered in water (e.g. Genton et al., 1985) or gelatine capsules (e.g. Vieluf et al., 1990).
In some investigations, the administration of the substance was preceded by an elimination
diet (e.g. Kemp & Schembri, 1985).
According to estimations, 0.003% to 0.15% of the general population react sensitively to
pseudoallergic substances including benzoic acid/benzoates in food (Diehl, 1983). Sensitivity
to benzoates used in cosmetic products is also sometimes observable (Broeckx et al., 1987, de
♦ In parentheses the number of patients who reacted / number of patients tested for benzoates are given to get an
idea of the number of involved patients in these investigations.
♦ In parentheses the number of patients who reacted / number of patients tested for benzoates are given to get an
idea of the number of involved patients in these investigations.
22 November 2000
Groot et al., 1986). NIICRs to airborne benzoates in occupationally exposed persons were
occasionally reported (e.g. Nethercott et al., 1984).
Therefore two investigations quoted above which were dealing with unselected groups of the
general population are described more detailed:
Young et al. (1987) undertook a large scale study in the area of Wycombe, Great Britain
including questionnaires and interviewing. Persons for whom at the end of the interviewing
phase a real intolerance to certain substances could be assumed were included in an oral
provocation test after remaining on an elimination diet. The trial regime involved taking five
different low dose capsules during the first ten days, alternating with lactose placebo capsules
and then taking five high dose capsules, alternating with placebo during the next ten days. The
capsules contained combinations of chemicals, e.g. 50 mg aspirin and 10 mg sodium benzoate
(low dose) and 300 mg aspirin and 100 mg sodium benzoate (high dose).
The data of this study are summarized in table B.6.9-1.
Table B.6.9-1:
Summarized data of the large scale study in the area of Wycombe,
Great Britain
Stage of assessment
Questioning by Questionnaire
No. of individuals involved
30000 2)
(in 11388 households)
1223
132
Respondents 1)
18582
(62%)
Nonrespondents 1)
11418
(38%)
Called for interview
649 (53%)
574 (47%)
Entered into trial
81 (61%)
51 (39%)
Individuals who reacted to a
3
(4%)
combination of chemicals 3)
1) Respondents / non-respondents are these individuals who answered / not answered the questionnaires, took
part / took not part at the interview and participated / not participated at the trial until the end
2) Estimated
3) Two adults reacted to annatto, a natural colour. The reaction of one five-year-old child was doubtful because
of reacting to two food additives but to the placebo capsules as well.
No individual included in the oral provocation test reacted to the combination of aspirin and
sodium benzoate. Therefore, the planned testing for each of the two substances alone could be
omitted. That means, no person sensitively reacting to benzoates was found in this study.
In another investigation with unselected volunteers (200), double blind skin tests were run
with three known urticants, among these benzoic acid (Basketter and Wilhelm, 1996).
The substances were applied in chambers onto the skin for 20 min and assessed 30 min after
the initiation of the application. Benzoic acid was used in concentrations of 125 mM (1.5%,
306 µg/20 µl) and 500 mM (6.0%, 1220 µg/20 µl).
The NIICRs (mostly erythema) assessed ten minutes after direct contact of benzoic acid with
the skin are summarized in table B.6.9-2. No significant correlation between age or sex and
the degree of NIICR was found.
Table B.6.9-2:
22 November 2000
Skin reactions with benzoic acid in an unselected population
Erythema / edema score 1)
Urticant
0
1
2
3
4
5
6
7
Benzoic acid (125 mM) 53/175 44/19
41/5
25/1
26/0
10/0
1/0
0/0
Benzoic acid (500 mM) 43/164 35/30
41/5
31/1
39/0
9/0
2/0
0/0
1) Number of individuals with each grade of erythema / edema
2) Erythema / edema grading:
0: nothing visible
1: a marginal reaction, not sufficient to be classified as “slight”
2: perceptible erythema / edema (swelling)
3: higher grade than “perceptible”, not sufficient to be classified as “distinct”
4: distinct erythema / edema (swelling)
5: higher grade than “distinct”, not sufficient to be classified as “well developed”
6: well developed, may extend beyond site
7: higher grade than “well developed”, not sufficient to be classified as “strong”
8: strong, deep erythema / strong, “blisterlike” edema (swelling), both may extend beyond site
(detailed scheme in: Basketter and Wilhelm, 1996)
2)
8
0/0
0/0
In this study, 10 minutes after direct contact of benzoic acid with the skin a relatively large
group of unselected volunteers reacted at the used concentrations. This again indicates the big
influence of the study design on the result.
B.6.9.6
Medical surveillance on manufacturing plant personal
Standard precautions according to national law for chemical plants are sufficient.
B.6.9.7
Direct observation, e.g. clinical cases and poisoning incidents
There is no information on poisoning incidents.
Clinical cases in connection with the known pseudoallergic reactions (non-immune immediate
contact reactions, NIICRs) of benzoic acid/benzoates: see B.6.9.5.
B.6.9.8
Observations on exposure of the general population and epidemiological studies if appropriate
Estimates of the mean intake of benzoates with food performed for consumers in China, Japan
and USA were in a range of 0.18 mg/kg bw/d to 14 mg/kg bw/d (12.6 to 980 mg per 70 kg
body weight) (IPCS, 1999). In this range is the average value of 312 mg benzoic acid (sum of
acid and salts) for the human daily intake per capita in USA (quoted by the notifier). Intake in
Europe is expected to be in the same range. From the use of benzoic acid as disinfectant in
horticulture any additional exposure of the general population can be excluded.
Studies (also epidemiological studies) in connection with the known pseudoallergic reactions
(non-immune immediate contact reactions, NIICRs) of benzoic acid/benzoates: see B.6.9.5.
B.6.9.9
22 November 2000
Diagnosis of poisoning (determination of active substance, metabolites), specific signs of poisoning, clinical tests)
Diagnosis in connection with the known pseudoallergic reactions (non-immune immediate
contact reactions, NIICRs) of benzoic acid/benzoates: see B.6.9.5.
B.6.9.10 Proposed treatment: first aid measures, antidotes, medical treatment
Symptomatic. Oral antacida or adsorbentia (e.g. aluminium hydroxide, magnesium-aluminium
hydrate, sodium hydrogen carbonate). Induction of vomiting may irritate the oesophagus mucosa and should be avoided. After ingestion of large amounts (> 30 g orally) pumping out the
stomach may be advised.
Contaminated skin should be washed with soap (alkaline preferred to neutral) or detergents.
B.6.9.11 Expected effects of poisoning
Information on expected effects was derived from animal studies, i.e. irritation of exposed
eyes can occur.
Information regarding the known pseudoallergic reactions (non-immune immediate contact
reactions, NIICRs) of benzoic acid/benzoates: see B.6.9.5.
B.6.10 Summary of mammalian toxicology and proposed ADI, AOEL,
ARfD and drinking water limit (Annex IIA 5.10)
B.6.10.1 Summary of mammalian toxicology
Biokinetics and metabolism
22 November 2000
acid/sodium benzoate in organs and tissues is not to be expected. In contrast benzoic acid
and extent of benzoate metabolism in both organs.
plant products.
Acute toxicity
Acute toxicity testing with benzoic acid / benzoic salts was performed in several animals
benzoic compound was used then.
LD50, oral:
LD50, dermal:
LC50, inhalative:
> 0.026 mg/l (1 h, rat).
mg/kg bw. It is not irritating to skin and eyes. No data on sensitizing effects were available.
Short-term toxicity
mouse, cat, guinea-pig and dog. The predominant aim in most experiments was to
demonstrate effects and not to find out a NOEL/NOAEL. Therefore, the noted NOELs were
mostly derived by the rapporteur.
decreased.
was observed.
22 November 2000
The overall NOEL has to be derived from all relevant short-term and chronic rat studies
together, i.e. 1% benzoic acid in the diet corresponding to ca 500 mg/kg bw/d. This NOEL can
serve for the calculation of the ADI and AOEL.
Genotoxicity
evident.
Chronic toxicity/carcinogenicity
drinking water.
Including the results from the chronic toxicity studies, the conclusion can be drawn that no
carcinogenic effect is evident for benzoic acid or sodium benzoate from the available
literature.
be derived from all relevant short-term and chronic toxicity/carcinogenicity studies together
since no single study according to a current test guideline is available. This NOEL can serve
for the calculation of the ADI and AOEL. Most of these studies and relevant studies on other
species are summarized in table B.6.10-1.
Reproductive/developmental toxicity
rabbits, mice and hamsters up to the highest tested doses of 175, 250, 175 and 300 mg/kg
these species.
22 November 2000
Table 6.10-1:
Relevant oral short-term and long-term/carcinogenicity, reproduction
and developmental toxicity studies taken for risk assessment
Study
Short-term studies
Rat, 10 days, SB
Rat, 1-5 days,
1, 2, 5 weeks, BA
NOEL
1.81% (ca 1358 mg/kg
bw/d)
no NOEL at 1.1% (5
weeks)
Rat, 4 weeks, SB
Rat, 4 weeks, BA
Remark
Fujitani, 1993
1.1%: decreased body
weight change and food
consumption only
authors stated 1% as
threshold
2%: lowest dose tested
no NOEL at 2%
7600 ppm (ca 648 mg/kg
bw/d)
Rat, 4-5 weeks, SB
1.0% (ca 500 mg/kg bw/d) development of tolerance
to SB
Rat, 40 days, SB
1.5% (ca 750 mg/kg bw/d)
Rat, 10 weeks, SB
1.5% (ca 750 mg/kg bw/d)
Mouse, 10 days, SB
2.08% (ca 3012 mg/kg
bw/d)
Cat, 3, 4, 15, 23 days, BA 200 mg/kg bw/d (15 days) lowest NOEL*
Dog, up to 250 days, SB
Long-term studies
Rat, 72 weeks, BA
Rat, combined
chronic/reproduction
study, 4 generations, BA
Rat, carcinogenicity
study, 18-24 months, SB
Reference
Kreis et al., 1967
Fanelli & Halliday, 1963
Bio-Fax, 1973
Harshbarger, 1942
Griffith, 1929
Kramer & Tarjan, 1962
Fujitani, 1993
800 mg/kg bw/d
NOEL for the most
sensitive dog
Rost et al., 1913
no NOEL at 1.5% (ca
1125 mg/kg bw/d)
this dose tested only
Marquardt, 1960
2% (ca 1000 mg/kg bw/d)
significant prolongation of Kieckebusch & Lang,
life at 0.5%
1960
No evidence of
carcinogenicity at this
dose (highest dose tested)
No evidence of
carcinogenicity,
(only this dose tested)
Mouse, carcinogenicity,
2% in the drinking water
life-long, drinking water, (ca 120 mg/mouse/d)
SB
Developmental toxicity studies
Rat, appl. at day 9 of
510 mg/kg bw/d
only this dose tested
gestation, BA
gestation, SB
gestation, SB
BA: benzoic acid; SB: sodium benzoate
* This investigation on a species with a peculiar metabolism, performed without a
reference dose.
Sodemoto & Enomoto,
1980
Toth, 1984
Kimmel, 1971
Onodera et al., 1978
Crane & Lachance, 1985
guideline is no basis for a
22 November 2000
Neurotoxicity
guidelines are not available. They are not indicated by results in other studies. In one study
examining the neuroexcitation potential of benzoic acid no neuroexcitation or changes in EEG
were found.
Further data
It would be beyond the scope of this monograph to refer to the multitude of studies biochemical studies, certain biological tests etc - with benzoic acid/benzoates.
indicated benzoic acid as being a potential substrate of cytochrome P450 IIE. Because the
detoxication of benzoic acid/benzoates requires glycine, ATP and coenzyme A, metabolic
processes in which these physiological substances are involved might be affected by
benzoates. Benzoate did not uncouple the oxidative phosphorylation from respiration at
concentrations of 0.5 to 2.0 mmolar in isolated rat liver mitochondria.
Medical data
B.6.10.2 Calculation of the Acceptable Daily Intake (ADI)
Considering the toxicological profile of benzoic acid and benzoates, a risk for the consumer in
terms of acute toxicity, organtoxicity, genotoxicity, carcinogenicity and reproductive/
developmental toxicity is not discernable. There is no evidence of bioaccumulation.
According to the principles of Annex VI to Directive 91/414 EEC, the acceptable daily intake
should be established on the basis of the highest dose at which no adverse effect is observed
(NOAEL) in relevant studies in the most sensitive species.
22 November 2000
current test guideline is available. Considering the overall low toxicity of benzoic acid and
benzoates, an assessment factor of 100 is proposed and an ADI value of 5.0 mg/kg bw/d is
calculated.
The ADI derived in this monograph is in agreement with the ADI of JECFA (FAO, WHO
1974, 1996).
B.6.10.3 Acceptable Operator Exposure Level (AOEL)
According to the principles of Annex VI to Directive 91/414 EEC, the proposed acceptable
operator exposure level should be established on the basis of the highest dose at which no
adverse effect is observed (NOAEL) in relevant studies in the most sensitive species.
For the risk assessment of the user, applicator and producer as well as for the calculation of
the AOEL, the results of the short-term toxicity and/or reproduction/developmental toxicity
studies are considered to be most relevant.
current test guideline is available.
Due to the high level of gastrointestinal absorption, an additional correction factor is not
required.
Considering the overall low toxicity of benzoic acid and benzoates, an assessment factor of
100 is proposed and a systemic AOEL of 5.0 mg/kg bw/d is calculated.
B.6.10.4 Acute Reference Dose (ARfD)
Benzoic acid and its salts are widely spread natural compounds in the environment. No
residues in harvest products occur from the intended use. There is no relevant exposure of
operators, bystanders and workers. Therefore allocation of an ARfD is not nessecary.
B.6.11 Acute toxicity including irritancy and skin sensitization of
preparations (Annex IIIA 7.1)
The preparation Menno-Florades (company code MEN-23900-BVF-0-SL) is a clear slightly
amber coloured liquid, which can be diluted with water to the required application concentration of 1 to 4%. The preparation (pH value 5.8) as well as the application solution (pH value:
approximately 3) are slightly acidic which is a prerequisite for the efficacy as disinfectant in
horticulture. Menno-Florades contains 9% benzoic acid as the active ingredient.
Toxicological studies with Menno-Florades were conducted according to the methods described in the Commission Directive 92/69/EEC. The results of the experiments are outlined
in Table B.6.11-1. In the following chapters the individual tests are described in detail.
Table B.6.11-1
22 November 2000
Acute toxicity of Menno-Florades
Parameter
Acute oral LD50
Acute dermal LD50
Acute inhalation LC50
Skin irritation
Eye irritation
Skin sensitization
Species
rat
rat
rabbit
rabbit
-
Result
mg/kg bw or effect
>2000 mg/kg bw
>2000 mg/kg bw
not irritating
corrosive
(not sensitizing; see B.6.11.6)
Reference
Bien, 1994
Bien, 1994
not conducted
Bien, 1994
Bien, 1994
not conducted
In accordance with the Directive 78/631/EEC in combination with the latest classification and
labelling guidance under Directive 67/548/EEC (i.e. in the 18th ATP published as Directive
93/21/EEC) with regard to the low acute toxicity and the very slight skin irritancy but the corrosive properties to eyes, the classification/labelling of Menno-Florades with Xi (irritant) and
R 41 (risk of serious damage to eyes) is required.
B.6.11.1 Acute oral toxicity
Report:
Guidelines:
Deviations:
GLP:
Acceptance:
Bien, E. (1994): Acute Oral Toxicity Test of ”MENNO-Florades” in
Rats., IBR Forschungs GmbH, 29664 Walsrode, Germany, Project
No.: 10-04-0859/00-94, June 1994; experimental period: April 27,
1994 to May 16, 1994.
OECD 401 (equivalent to Directive 92/69/EEC B.1).
No deviations from Directive 92/69/EEC, B.1.
Yes.
The study is considered acceptable.
Material and methods:
Five male and five female Wistar rats (Hsd/Win:Wu, Fa. Harlan Winkelmann GmbH,
Borchen; body weight males: 233-254 g, females: 177-221 g) received a single oral dose of
Menno-Florades (Batch No.: 9401; 9.0% a.i.) administered by gavage undiluted at a dose level
of 2000 mg/kg bw (dose volume of 1.98 ml/kg bw). The pH value was 2.73. In each animal a
number of clinical-toxicological signs were evaluated according to a modified IrwinScreening procedure (Screening Methods in Pharmacology, R. A. Turner, 1965, p. 26). The
animals were examined at the following post treatment intervals: 10 min, 1 h, 2 h, 6 h, 24 h,
and thereafter once daily up to day 14. Body weights were recorded on the day of dosing (day
0), day 7 and at termination (day 14). Gross pathological examinations were performed on all
animals at the end of the 14-day observation period.
Findings :
No mortality occurred, and there were no clinical signs of toxicity observed
during the 14-day study period. All animals gained weight during the study, and no treatmentrelated macroscopic pathological changes were noted at necropsy.
Conclusion : The oral LD50 value of Menno-Florades was greater than 2000 mg/kg bw (limit
dose) for male and female rats. In accordance with current EC guidelines, no classification is
required.
22 November 2000
B.6.11.2 Acute dermal toxicity
Report:
Guidelines:
Deviations:
GLP:
Acceptance:
Bien, E. (1994): Acute Dermal Toxicity Test of ”MENNO-Florades”
in Rats., IBR Forschungs GmbH, 29664 Walsrode, Germany, Project
No.: 10-04-0860/00-94, June 1994; experimental period: April 27,
1994 to May 17, 1994.
Yes.
Material and methods:
Five male and five female Wistar rats (Hsd/Win:Wu, Fa. Harlan Winkelmann GmbH,
Borchen; body weight males: 247-274 g, females: 190-212 g) received a single dermal dose of
Menno-Florades (Batch No.: 9401; 9.0% a.i.) undiluted at a dose level of 2000 mg/kg bw
(dose volume: 1.98 ml/kg bw; area of treated skin: roughly 5 x 10 cm). The pH value was
2.73. The substance was held in contact with the skin for the 24-hour exposure period with a
porous gauze dressing and ElastoplastR (Beiersdorf). In each animal a number of clinicaltoxicological signs were evaluated according to a modified Irwin-Screening procedure
(Screening Methods in Pharmacology, R. A. Turner, 1965, p. 26). The animals were examined
at the following post treatment intervals: 10 min, 1 h, 2 h, 6 h, 24 h, and thereafter once daily
up to day 14. After patch removal, dermal irritation was evaluated once daily for 14 days
according to the scheme of Draize. Body weights were recorded on the day of dosing (day 0),
day 7 and at termination (day 14). Gross pathological examinations were performed on all
animals at the end of the 14-day observation period.
Findings :
No mortality occurred, and there were no clinical signs of toxicity observed
during the 14-day study period. The weight gains were reduced in 4 of 5 male animals as well
as in 4 of 5 female animals during the entire observation period. No signs of oedema were
observed in all animals and no signs of erythema in the males. In the female rats, there was a
very slight or well-defined erythema in 3 of 5 animals on day 1 p.a. A very slight erythema
was still apparent in these 3 females on day 2 p.a. and in 2 of these 3 animals also on day 3
and 4 p.a. A slight fissuration was observed in 2 females on day 2 and 3 p.a. and was still
apparent in one female until day 7 p.a. No treatment-related macroscopic pathological changes
were noted at necropsy.
Conclusion : The dermal LD50 value of Menno-Florades was greater than 2000 mg/kg bw
(limit dose) for male and female rats. In accordance with current EC guidelines, no classification is required.
B.6.11.3 Acute inhalation toxicity
A study was not conducted. It is considered not nessecary on the basis of the available
information about the active substance, the preparation and the intended uses.
22 November 2000
B.6.11.4 Skin Irritation - Rabbit
Report:
Bien, E. (1994): Acute Dermal Irritation / Corrosion Test of
”MENNO-Florades” in Rabbits, IBR Forschungs GmbH, 29664
Walsrode, Germany, Project No.: 10-03-0862/00-94, May 1994; experimental period: April 19, 1994 to May 9, 1994.
Yes.
Guidelines:
Deviations:
GLP:
Acceptance:
Material and methods: 0.5 ml of Menno-Florades (Batch No.: 9401; 9.0% a.i.) was applied
in the original state (pH value 2.73) to a 6 cm2 skin area of the clipped dorsum of 3 New
Zealand White rabbits (Kaninchenhof Südstedt), an adjacent area of untreated skin serving as
control. Each skin area was covered with a semi-occlusive dressing for a 4-hour exposure
period. According to the scheme of Draize, the test sites were examined for dermal irritation
at approximately 60 minutes, and at 24, 48, and 72 hours after patch removal and thereafter
once daily up to reversibility of the findings at day 6 after application.
Findings :
There were no mortalities or clinical signs of toxicity observed during the
observation period. At the one-hour observation, all three test animals exhibited slight
erythema. In one animal no skin reactions were seen at the following days. In two animals a
slight to moderate redness and in one of these animals a slight swelling were observed within
5 days after patch removal (Table B.6.11-2).
Table B.6.11-2:
Animal
No.
1
2
3
Individual and mean skin irritation scores (erythema/oedema) according to the Draize scheme
1h
24 h
48 h
72 h
4d
5d
6d
1/0
1/0
1/0
0/0
2/0
2/1
0/0
1/0
2/1
0/0
0/0
2/1
2/0
1/0
0/0
mean:
24 / 48 / 72 h
0/0
1/0
2/1
Conclusion : For the three animals, the erythema and oedema scores were 0/1/2 and 0/0/1,
respectively (mean from the 24-, 48-, and 72-hour observations). In accordance with current
EC guidelines, Menno-Florades is regarded as non-irritating to rabbit skin.
B.6.11.5 Eye Irritation - Rabbit
Report:
Guidelines:
Deviations:
GLP:
Acceptance:
Bien, E. (1994): Acute Eye Irritation / Corrosion Test of ”MENNOFlorades” in Rabbits, IBR Forschungs GmbH, 29664 Walsrode, Germany, Project No.: 10-03-0861/00-94, June 1994; experimental period: May 5, 1994 to June 9, 1994.
Yes.
22 November 2000
Material and methods: 0.1 g Menno-Florades (Batch No.: 9401; 9.0% a.i.; density:
1.01 g/ml) was applied in the original state (pH value 2.73) into the conjunctival sac of the left
eye of each of 3 New Zealand White rabbits (Kaninchenhof Südstedt). The right eye served as
the untreated control. The eyes were examined pretreatment (the day prior to test substance
administration) and at 1, 24, 48, and 72 hours following dosing and thereafter once daily up to
day 21 after application.
Findings :
Menno-Florades caused ocular damages in varying severity inclusively
moderate to extreme corneal opacy, hyperemia of the iris and ruptured small blood vessels
within the eyeball (Table B.6.11-3). Therefore, an evaluation of each effect was not possible
at each time point. In 2 of 3 animals, the observed findings were not reversible within 21 days
after treatment. There were no mortalities or clinical signs of toxicity observed during the
observation period.
Table B.6.11-3:
Time after
treatment
1h
24 h
48 h
72 h
4d
5d
6d
7d
8d
9d
10 d
11 d
12 d
13 d
14 d
15 d
16 d
17 d
18 d
19 d
20 d
21 d
*
**
1
2
2
**
**
3
3
2
2
2
2
2
2
3
3
3
2
1
0
Eye irritation scores according to the Draize scheme
Cornea
animal:
2
3
3
4
4
4
4
3
3
3
2
2
2
2
2
2
1
1
1
1*
1*
**
**
+
+
2
2
3
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
+
+
+
0
0
0
Iris
animal:
2
+
+
+
+
+
+
+
+
+
1*
1*
1*
0
0
0
0
0
0
0
0
0
0
hyperemia
no observations due to adhesion of eyelids
3
1*
1*
1*
1*
1*
1*
1*
1*
1*
1*
1*
0
0
0
xx
xx
xx
xx
xx
xx
xx
xx
+
x
xx
Conj.: redness
animal:
1
2
3
2
2
2
3
3
3
**
3
3
**
3
3
3
3
3
1
3
3
1
3
3
1
3
3
Conj.: chemosis
animal:
1
2
3
4
4
4
3
3
4
**
4x
3x
**
4x
3x
3
3x
3x
2
3x
3x
1
3x
3x
1
3x
3x
1
1
1
1
1
0
0
0
0
0
3
2
1
2x
2x
3
2
1
2
2x
3
2
1
2
2
2
3
1
2
3
1
2
1x
1
2
0
1
1
0
1
0
0
1
0
0
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
evaluation was not possible
ocular secretion
ruptured small blood vessels within the eyeball
Conclusion : The test article caused moderate to severe ocular reactions. In 2 of 3 animals
the observed findings were not reversible within 21 days after treatment. In accordance with
current EC guidelines, Menno-Florades should be classified as corrosive (Xi: irritant; R 41:
risk of serious damage to eyes).
22 November 2000
B.6.11.6 Skin sensitization
No test was performed. As stated by the notifier, it is considered not necessary on the basis of
the available information about the active substance, the preparation/co-formulants and the
intended uses.
Benzoic acid was non sensitizing in various animal studies including the tests according to
Buehler and Magnusson/Kligman (B.6.2) and in one sensitization test in man (B.6.9.5).
Nevertheless, it should be noted that benzoic acid is known to cause pseudoallergic reactions
which are considered to be non-immune immediate contact reactions including non-immune
contact urticaria. There are estimations that up to 0.15% of the population are supersensitive
against food additives inclusive of benzoic acid (B.6.9.5).
B.6.12 Dermal absorption (Annex IIIA 7.3)
With regard to the available information about the active substance, the preparation and the
intended uses, the dermal absorption of Menno-Florades was not investigated experimentally.
In various studies, the low oral and dermal toxicity of bezoic acid and Menno-Florades has
been shown (B.6.2; B.6.11). Nevertheless, the oral absorption for bezoic acid is nearly complete and the results for the dermal absorption investigated under different conditions and on
different species varied considerably. The dermal absorption amounted up to 89±19% in
rhesus monkeys. For human dermal absorption rates up to 42.6±16.5% were found. In another
study, a comparison of absorption rates for human and rhesus monkeys revealed similar results for both species (B.6.1). Summarizing for practical reasons, a dermal absorption rate of
100% can be assumed.
B.6.13 Toxicological data on non active substances (Annex IIIA 7.4 and
point 4 of the introduction)
Besides its active ingredient benzoic acid (9%), the formulation Menno-Florades contains
<5% formic acid (C, R 35) to reduce the pH value to maintain existence of free benzoic acid
as well as solubilizing and surface active agents. Material Safety Data Sheets (MSDS) for the
co-formulants are available. The toxicological properties of the co-formulants are covered by
the toxicological studies with the preparation submitted.
B.6.14 Exposure data (Annex IIIA 7.2)
Menno-Florades (9% or 90 g/l a.i.) is intended for disinfection in horticulture in glass houses
(incl. culture and storage rooms). 1% to 4% solutions are prepared (0.9 - 3.6 g/l a.i.). Equipment and material are dipped into the solution. Work benches are flooded. Dependent on the
species/type of bacteria, virus, viroid or fungi, for watering and soaking a period of up to 16
hours (e.g. over night) and for dipping 3 minutes are proposed and for wetting sand beds and
fleece mats 2 l/m2 application solution, for ebb/flood-systems 0.2 l/m2 are recommended.
Taking into account the intended uses of Menno-Florades as disinfectant and the world wide
uses of benzoic acid in food stuffs, cosmetics etc., the notifier stated that even if protective
clothing is not used no undue risk is expected. The exposure would be negligible and the proposed limit (ADI = 5 mg/kg bw) will not be exceeded.
22 November 2000
Nevertheless, the current human daily intake (via medicine, food and industrial preservative,
cosmetics etc. and the natural distribution of the substance) is expected to be several hundred
mg. Estimates of the mean intakes of benzoates with food performed for consumers in China,
Japan and USA were in a range of 0.18 mg/kg bw/d to 14 mg/kg bw/d (12.6 to 980 mg per 70
kg body weight) (IPCS, 1999). Also in this range is the average value of 312 mg benzoic acid
(sum of acid and salts) for the human daily intake per capita in USA (quoted by the notifier).
Comparing this value with the proposed ADI/systemic AOEL of 5 mg/kg bw/d it can be seen
that already the intake from nonpesticide sources is in the range of the tolerated reference
dose. Therefore, the rapporteur regarded it necessary to quantify the possible additional exposures for the operator, worker and bystander as a result of the use of Menno-Florades.
Since there is no specific model available to assess the recommended uses, some considerations have been made by the rapporteur, to have an idea concerning the possible exposures.
For that, parts of the ”German model” (Uniform Principles for Safeguarding the Health of
Applicators of Plant Protection Products; Uniform Principles for Operator Protections;
Mitteilungen aus der Biologischen Bundesanstalt für Land- und Forstwirtschaft, BerlinDahlem, n° 277) have been taken and in addition to that the predictive workplace exposure
assessment model ”EASE” from the TGD (Estimation and Assessment of Substance Exposure; Technical Guidance Documents in Support of the Commission Directive 93/67/EEC on
Risk Assessment for New Notified Substances and the Commission Regulation (EC) 1488/94
on Risk Assessment for Existing Substances; pre-print version, 1996) have been used. The
results of these assessments support the notifiers view that the handling of the diluted formulation is not of concern. However, when handling the undiluted product, the recommended
PPE (gloves and goggles) should be worn with regard to the possible local effects as well as
for reducing the systemic exposure.
In summary, no detrimental effects on human health from the use of benzoic acid as a plant
protection product to disinfect equipment is expected.
B.6.14.1 Operator exposure
Depending on the country and type of food where benzoic acid is used as a preservative, the
highest tolerated concentrations in food range from 1 to 12 g/kg (0.1 – 1.2%, quoted by the
notifier). Thus the benzoic acid concentration in the application solution of Menno-Florades
(0.9 - 3.6 g/l) is in the range that can be found in food for human consumption. To get an impression of the amounts involved, the tolerable values (ADI; systemic AOEL) of 5 mg/kg
bw/d (i.e. ca. 350 mg/person/d) can be compared with the amount of benzoic acid (max.
360 mg) that is solved in 100 ml of application solution.
Usually when estimating exposures, the inhalation and dermal portions have to be taken into
account. However, the application solution is not sprayed or nebulized and does not produce
aerosols. Therefore the inhalation risk is negligible and only the dermal exposure should be
assessed.
For practical reasons on the basis of the available data, a dermal absorption rate of 100%
should be assumed (B.6.1; B.6.12). Taking into account the proposed use of Menno-Florades
which involves direct contact to the application solution, the rapporteur was trying to estimate
the possible dermal exposure, although there are no accepted calculation models for such a
kind of use of plant protection products.
The exposure estimation was conducted for mixing (handling the undiluted product)
according to the German model (high crop, hand held: mixing/loading) and for handling the
undiluted as well as the diluted product using the EASE model.
22 November 2000
It is to note that persons who react sensitive to pseudoallergic substances have to check for
benzoic acid/benzoates. If these are the causative substances in their individual case they
should avoid contact with them.
B.6.14.1.1 German model
In the German model, exposure estimations are based on data for use rate (kg a.i./ha) and
treated area per day (ha/d). Yet, for the use of Menno-Florades such data are not applicable.
Therefore as a rough assumption for the handled amounts, the need of mixing a 4%
application solution for 100 m2 is postulated.
2 l/m2 for wetting; i.e. 200 l dilution/100m2
4% dilution of the product contains 3.6 g a.i./l; i.e. 720 g a.i./200 l dilution (200 x 3.6).
That means 0.720 kg benzoic acid are handled when preparing the application solution. This
value was used for the calculation according to the German model (high crop, hand held;
liquid product; mixing/loading of the product):
- Estimated inhalation exposure:
Im
=
0.05 x 0.72 =
0.036 mg/person/d
- Estimated dermal exposure
Dm = 205 x 0.72 = 147.6
mg/person/d
Using this model and possibly overestimating the daily use rate, a dermal exposure of nearly
150 mg/person/d (i.e. ca. 2 mg/kg bw/d) can be derived. The inhalation exposure is also
negligible in this model calculation. Wearing gloves as recommended by the notifier due to
the local effects, the calculated dermal exposure would be reduced to ca 0.02 mg/kg bw/d.
Because of the assumed complete dermal absorption, no further reduction of the derived value
can be considered.
Without the use of PPE, the estimated exposure would be about 40% and wearing gloves it
would result in only 0.4% of the proposed systemic AOEL of 5.0 mg/kg bw/d.
B.6.14.1.2 EASE model
The EASE model (Estimation and Assessment of Substance Exposure; developed by UK HSE
for workplace assessment) has been used by the rapporteur for risk assessment for the
operator. This model is also in discussion for the risk assessment of biocides.
According to this TGD (TGD: chapter 2; appendix I; figure 1: ”Determination of exposure”)
the respective type of exposure (inhalation; dermal) have to be taken into account. Since the
inhalation exposure for Menno-Florades was considered to be negligible, only the dermal
exposure was assessed.
In the EASE model, the potential dermal exposure is estimated on an 8-hour full-shift basis.
All the default values as derived according to the TGD are given in Figure B.6.14-1.
22 November 2000
Figure B.6.14-1: Default values for dermal exposure expressed as mg/cm2 during a
working day (full shift) - according to the TGD
Determination of Dermal Exposure
(Physical state)
Gas or vapor
Liquid
Aerosol
(solid or liquid)
Solid
(Is the solid dusty)
Very low
Yes
No
(Pattern of use)
Very low
Closed system
Inclusion onto matrix
or nondispersive use
Wide dispersive use
(Pattern of control)
(Pattern of control)
Very low
Not direct handling
Direct handling
Not direct handling
Direct handling
Very low
(Contact level)
Very low
(Contact level)
None
Incidental
Intermittent
Extensive
Very low
[mg/cm2/d]
None
Incidental
Intermittent
Extensive
0.1 - 1
1-5
5 – 15
Very low
0 – 0.1
0.1 - 1
1-5
[Fig. 15 from "Technical Guidance Documents" in the support of Dir. 93/67/EEC and Reg. 1488/94/EEC:
TGD, pre-print version, 1996; Chapter 2; App. I; p 176]
On this basis, exposures up to 15 mg/cm2/d have to be taken into account. But, according to
the requirements of the EASE model, the exposure to Menno-Florades may be characterized
as follows:
- The physical state is liquid;
- The pattern of use is non dispersive;
- The pattern of control is direct handling;
- The contact level is intermittent.
Thus, 0.1–1 mg/cm2/d would be a reasonable value for risk assessment. As it is also proposed
in the TGD, an exposed body surface of 2000 cm2 (hands and forearms) should be assumed
for the model calculation. Further on, the following reduction factors should be taken into
consideration:
- It can be assumed that the total time for preparing the dilution and for application
procedures will amount to only 0.5-1.0 hours. Therefore, in the calculation one-tenth
of the shift was used;
- The bencoic acid content is 9% in Menno-Florades and 0.36% (i.e. 4% of MennoFlorades) in the application dilution in the highest concentration.
- The use of PPE (gloves) when handling the undiluted product will reduce the exposure. The calculation is conducted assuming 5% penetration (derived from the German
22 November 2000
model with 1% penetration for gloves, the UK POEM with 5% penetration for gloves
if aqueous based formulations are handled and the proposal of 5% penetration through
clothes and gloves in the worker re-entry risk assessment).
All the calculated numbers are listed in the Table B.6.14-1 and in the Table B.6.14-2 based on
the data from Figure B.6.14-1, for the undiluted and the diluted product.
Table B.6.14-1:
Estimation of exposure to the undiluted product
Default values from TGD
Nondispersive use
(full shift; maximum
Incidental
InterExtensive
values)
mittent
mg/cm2/d
0.1
1
5
Estimated exposure [mg/person/d]
Assumptions:
Exposed body
surface (hands 2000 cm2
200
2000
10000
and forearms)
Part of the
10%
20
200
1000
working day
PPE: gloves;
5%
1
10
50
penetration
Benzoic acid
conc.
9%
0.09
0.9
4.5
(undiluted
product)
Estimated exposure [mg/kg bw/d]
Body weight
70 kg
0.0013
0.0129
0.0643
Table B.6.14-2:
Dispersive use
Incidental
InterExtensive
mittent
1
5
15
2000
10000
30000
200
1000
3000
10
50
150
0.9
4.5
13.5
0.0129
0.0643
0.1929
Estimation of exposure to the diluted product
Default values from TGD
Nondispersive use
(full shift; maximum
Incidental
InterExtensive
values)
mittent
mg/cm2/d
0.1
1
5
Estimated exposure [mg/person/d]
Assumptions:
Exposed body
surface (hands 2000 cm2
200
2000
10000
and forearms)
Part of the
10%
20
200
1000
working day
PPE: none;
100%
20
200
1000
penetration
Benzoic acid
conc. (diluted
0.36%
0.072
0.72
3.6
product)
Estimated exposure [mg/kg bw/d]
Body weight
70 kg
0.0010
0.0103
0.0514
Incidental
1
Dispersive use
InterExtensive
mittent
5
15
2000
10000
30000
200
1000
3000
200
1000
3000
0.72
3.6
10.8
0.0103
0.0514
0.1543
On the basis of this model calculation and considering all the assumptions made, for a
nondispersive use with an intermittent contact, the estimated exposure would be 0.0129 mg/kg
bw/d during mixing (handling the undiluted product; with gloves) and 0.0103 mg/kg bw/d
when handling the dilution (without PPE). This values would be below 1% of the proposed
systemic AOEL of 5.0 mg/kg bw/d.
22 November 2000
The risk assessments using the German and EASE models have shown that the intended use
of Menno-Florades can be regarded as safe for operators. Under practical conditions, it is not
expected that the tolerated dose will be exceeded. Nevertheless, taking into account the relatively high intake from nonpesticide sources of benzoic acid and the high irritation potential
for the eyes and the slight skin irritation, protective gloves and goggles should be used when
handling the undiluted product, as recommended by the notifier.
B.6.14.2 Worker exposure
As for the operator, there is no inhalation risk. The dermal exposure is very low as estimated
for the operator (B.6.14.1) handling the dilution, even if protective clothing is not used. Eye
and slight skin irritation are possible, e.g. through splashes when handling the undiluted concentrate without protective gloves and goggles. This will happen only occasionally. This kind
of exposure is hardly predictable but it is not expected that the tolerated dose will be exceeded.
It is to note that persons who react sensitive to pseudoallergic substances have to check for
benzoic acid/benzoates. If these are the causative substances in their individual case they
should avoid contact with them.
B.6.14.3 Bystander exposure
As for the operator, there is no inhalation risk. The dermal exposure is very low as estimated
for the operator (B.6.14.1) handling the dilution, even if protective clothing is not used. It is
not expected that the tolerated dose will be exceeded.
Annex
point/
reference
number
Author(s)
AIIA-5
DFG (Deutsche
Forschungsgemeinschaft)
AIIA-5
FDA
Year Title
report no.
published or not
1995 Toxikologisch-arbeitsmedizinische Begründung
von maximalen Arbeitsplatzkonzentrationen
(MAK-Werte), Senatskommission der DFG,
Henschler, D. (ed.).
not GLP, published
VCH-Verlagsgesellschaft mbH, Weinheim,
Germany
TOX2000-277
1972 GRAS (Generally Recognized As Safe) food
ingredients: benzoic acid and sodium benzoate,
U.S. FDA Washington D.C.
not GLP, published
TOX2000-278
Data
Owner
protection
claimed
Y/N
N
-
N
-
Annex
point/
reference
number
Author(s)
AIIA-5
IPCS
AIIA-5
JECFA
Year Title
report no.
published or not
1999 Concise international chemical assessment document benzoic acid and sodium benzoate,
IPCS (International Programme on chemical
safety), 1. Draft, prepared by Wibbertmann, A.
November 1999.
TOX2000-272
series 37, Geneva.
not GLP, published
22 November 2000
Data
Owner
protection
claimed
Y/N
N
MEN
N
-
N
-
N
-
TOX2000-275
AIIA-5
JECFA
1983 27th report of the joint FAO/WHO expert committee on food additives WHO technical report
series no. 696, Geneva, cited in JECFA, 1996.
not GLP, published
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AIIA-5
JECFA
series 5 (technical report series no. 539), Geneva.
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Akira, K., Ta1993 Application of 13C-labeling and nuclear magnekagi, N., Takeo,
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AIIA-5.1
Altman, K.I.,
1954 Cited in JECFA, 1974.
Haberland, G.L.
not GLP, published
and Bruns, F.
Biochem. Z., 326, 107
TOX2000-280
N
-
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reference
number
Author(s)
Year Title
Data
Owner
protection
report no.
claimed
published or not
Y/N
1969 Drug biotransformation interactions in man. II: A
N
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AIIA-5.1
Amsel, L.P.;
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AIIA-5.1
Andersen, K.E., 1980 The guinea-pig: an animal model for human skin
Maibach, H.I.
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-
AIIA-5.1
Armstrong,M.D.,Ch
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Wall, P.E.
1955 Endogenous formation of hippuric acid.
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N
-
AIIA-5.1
Baines, P.J.,
Bray, H.G.,
Hall, B.E. and
James, S.P.
1978 Metabolism of 14C-benzoic acid in the developing rat.
not GLP, published
IRCS Medical Science, 6, 221
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N
-
AIIA-5.1
Bernhard, K.,
Vuilleumier, J.
P. and Brubacher, G.
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N
-
AIIA-5.1
Bordas, Francois-Dainville,
Roussel
1925 L'elimination de l'acide benzoique et des benzoates dans l economie.
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-
AIIA-5.1
Bridges, J.W.,
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Williams, R.T.
1970 The fate of benzoic acid in various species.
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TOX1999-1414
N
-
Annex
point/
reference
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AIIA-5.1
Bronaugh, R.L.
and Stewart,
R.F.
AIIA-5.1
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published or not
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Owner
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claimed
Y/N
N
-
Carver, M.P.and 1989 Percutaneous absorption and excretion of xenoRiviere, J.E.
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AIIA-5.1
Feldmann,
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N
-
AIIA-5.1
Franz, T.J.
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Griffith,
1923 Studies in the synthesis of hippuric acid in the
W.H.and Lewis,
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reference
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Year Title
Data
Owner
protection
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claimed
published or not
Y/N
1980 Some pathways of xenobiotic metabolism in the
N
adult and neonatal marmoset (Callithrix jacchus).
not GLP, published
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AIIA-5.1
Hall, B.E.and
James, S.P.
AIIA-5.1
Hirom, P.C.,
Millburn, P.and
Smith, R.L.
1976 Bile and urine as complementary pathways for
the excretion of foreign organic compounds.
not GLP, published
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Högerle,
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M.L.and Winne,
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Huang, C.H.,
Kimura, R.,
Nassar, R.
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1985 Mechanism of nasal absorption of drugs. I: Physiochemical parameters influencing the rate of in
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Huckle, K.R.,
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Jones, A.R.
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Y/N
Kao, J., Jones,
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N
C.A., Fry,
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TOX2000-310
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AIIA-5.1
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I.and Wester,
R.C.
AIIA-5.1
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AIIA-5.1
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claimed
Y/N
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Moon, K.C.,
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Wester, R.C.and
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AIIA-5.1
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TOX2000-321
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reference
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Y/N
1979 Conjugation and urinary excretion of toluene and
N
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AIIA-5.1
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MEN
AIIA-5.1
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AIIA-5.1
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AIIA-5.1
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AIIA-5.1
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Grünbaum, A.
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AIIA-5.1
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AIIA-5.1
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AIIA-5.1;
AIIA-5.2;
AIIA-5.3;
AIIA-5.5;
AIIA-5.6
Anonym
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-
AIIA-5.1;
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.5;
AIIA-5.6
Anonym
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N
-
AIIA-5.1;
AIIA-5.9
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-
AIIA-5.1;
AIIA-5.9
Bignani, G.
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AIIA-5.1;
AIIA-5.3
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AIIA-5.1;
AIIA-5.9
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Y/N
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AIIA-5.2
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AIIA-5.2
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-
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AIIA-5.2
Fujitani, T.
AIIA-5.2
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claimed
Y/N
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Gerberick, G.F., 1992 Examination of the local lymph node assay for
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MEN
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AIIA-5.2
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N
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Year Title
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Owner
protection
claimed
Y/N
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TOX2000-373
AIIA-5.2
Opdyke, D.L.
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TOX2000-374
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AIIA-5.2
RCC Notox
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-
N
-
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-
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-
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AIIA-5.2
RCC Notox
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the rabbit (unpublished report). RCC Notox
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RCC Notox
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reference
number
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AIIA-5.2
Schulte, E.
AIIA-5.2
Stol, M., Cifkova, I. and Brynda, E.
AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.5;
AIIA-5.6
Year Title
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published or not
1999 Without given reference, cited in Ellinger, A.:
Aromatische Säuren in: Handbuch der experimentellen Pharmakologie, Heffter, A. (ed.).
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Owner
protection
claimed
Y/N
N
-
1988 Irritation effects of residual products derived
from poly (2-hydroxyethyl methacrylate) gels.
not GLP, published
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TOX2000-382
N
-
Anonym
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AIIA-5.2;
AIIA-5.3;
AIIA-5.4;
AIIA-5.6
Anonym
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Henschler, D. (Ed.)
TOX1999-1415
N
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AIIA-5.2;
AIIA-5.3
Bedford, B. and 1971 Suspected benzoic acid poisoning in the cat.
Clarke, M.A.
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TOX2000-358
N
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AIIA-5.2;
AIIA-5.3
Bedford, B. and 1972 Experimental benzoic acid poisoning in the cat.
Clarke, M.A.
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TOX2000-359
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-
AIIA-5.2;
AIIA-5.3
Bio-Fax
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-
N
-
in BUA, 1995.
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TOX2000-360
AIIA-5.2;
AIIA-5.3
Deuel, H.J.,
Alfin-Slater, R.,
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Smyth, H.F.
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reference
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Year Title
Data
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protection
report no.
claimed
published or not
Y/N
N
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TOX2000-369
AIIA-5.2;
AIIA-5.3;
AIIA-5.9
Ignatev, A.D.
AIIA-5.2;
AIIA-5.9
Lahti, A. and
Maibach, H. I.
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TOX2000-370
N
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AIIA-5.2;
AIIA-5.9
Lucas, D.R.
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AIIA-5.2;
AIIA-5.3
Rost, E., Franz,
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TOX2000-379
N
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AIIA-5.2;
AIIA-5.3
Smyth, H.F. and 1948 Further experience with the range finding test in
Carpenter, C.P.
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TOX2000-381
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AIIA-5.3
Corthay, J.,
Medilanski, P.
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1977 Induction of hepatic microsomal enzymes by
diuron, phenobenzuron, and metabolites in rats.
not GLP, published
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TOX2000-383
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AIIA-5.3
Fanelli, G.M.
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point/
reference
number
Author(s)
AIIA-5.3
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K.E.
AIIA-5.3
IRDC
Year Title
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1942 Report of a study on the toxicity of several food
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TOX2000-386
1981 Four-week subacute inhalation toxicity study of
benzoic acid in rats with amendment; Intl. Res.
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not GLP, published
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Data
Owner
protection
claimed
Y/N
N
-
N
-
N
-
TOX2000-387
AIIA-5.3
Kluge, H.
1933 Über den Einfluß von Konservierungsmitteln auf
die Wirkung von Fermenten.
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TOX2000-389
AIIA-5.3
Kowalewski, K. 1960 Abnormal pattern in tissue phospholipids and
potassium produced in rats by dietary sodium
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TOX2000-390
N
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AIIA-5.3
Kramer, M. und 1962 Die Wirkung von Konservierungsmitteln auf die
Tarjan, R.
Verwertung von Carotin.
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TOX2000-391
N
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AIIA-5.3
Kreis, H., Frese, 1967 Physiologische und morphologische VerändeK. und Wilmes,
rungen an Ratten nach peroraler Verabreichung
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TOX2000-392
N
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AIIA-5.3
Loncin, M.
N
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not GLP, published
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TOX2000-393
Annex
point/
reference
number
Author(s)
AIIA-5.3
Schafer, E.W.
and Bowles,
W.A.
AIIA-5.3
Shtenberg, A.J.
and Ignat ev,
A.D.
AIIA-5.3
Year Title
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published or not
1985 Acute oral toxicity and repellency of 933 chemicals to house and deer mice.
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Arch. Environ. Contam. Toxicol., 14, 111-129
TOX2000-394
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Data
Owner
protection
claimed
Y/N
N
-
1970 Toxicological evaluation of some combinations
of food preservatives.
not GLP, published
TOX2000-395
N
-
White, A.
1941 Growth-inhibition produced in rats by the oral
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not GLP, published
Yale J. Biol. Med., 13, 759-768
TOX2000-398
N
-
AIIA-5.3;
AIIA-5.5;
AIIA-5.6
Kieckebusch,
W. und Lang,
K.
not GLP, published
TOX2000-388
N
-
AIIA-5.3;
AIIA-5.5
Sodemoto, Y.
and Enomoto,
M.
not GLP, published
TOX2000-396
N
-
AIIA-5.3;
AIIA-5.5
Toth, B.
not GLP, published
TOX2000-397
N
-
AIIA-5.4
Abe, S. and
Sasaki, M.
1977 Chromosome aberrations and sister chromatid
exchanges in chinese hamster cells exposed to
various chemicals.
not GLP, published
J. Natl. Cancer Inst., 58, 6, 1635-1641
TOX2000-399
N
-
Annex
point/
reference
number
Author(s)
AIIA-5.4
Anderson, D.
and Styles, J.A.
AIIA-5.4
Anderson, D.
and Styles, J.A.
AIIA-5.4
Commoner, B.
Year Title
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published or not
1978 The bacterial mutation test; Appendix II to article of Purchase et al.
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Br. J. Cancer, 37, 924-930
TOX2000-400
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Data
Owner
protection
claimed
Y/N
N
-
1978 The bacterial mutation test.
not GLP, published
Br. J. Cancer, 37, 1978, 924-930
TOX1999-1421
N
-
1976 Report EPA-600/1-76-022; Office of Research
and Development; Us Environmental Protection
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1983.
not GLP, published
N
-
N
-
N
-
N
-
N
-
TOX2000-405
AIIA-5.4
Ishidate, Jr., M.
and Odashima,
S.
AIIA-5.4
Ishidate, Jr., M., 1984 Primary mutagenicity screening of food additives
Sofuni, T., Yoscurrently used in Japan.
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Hayashi, M.,
Fd. Chem. Toxic., 22, 8, 1984, 623-636
Nohmi, T.,
TOX1999-1422
Sawada, M. and
Matsuoka, A.
Ishidate, M.
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not GLP, published
Mutat. Res., 195, 151-213
TOX2000-410
AIIA-5.4
AIIA-5.4
1977 Chromosome tests with 134 compounds on Chinese hamster cells in vitro - A screening for
chemical carcinogens.
not GLP, published
Mutation Research, 48, 1977, 337-354
TOX1999-1423
Ishidate, M. and 1977 Chromosome tests with 134 compounds on chiOdashima,S.
nese hamster cells in vitro - a screening for chemical carcinogens.
not GLP, published
TOX2000-407
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Annex
point/
reference
number
Author(s)
Year Title
Data
Owner
protection
report no.
claimed
published or not
Y/N
1980 Chromosome aberration tests with chinese
N
hamster cells in vitro with and without metabolic
activation a comparative study on mutagens
and carcinogens.
not GLP, published
Arch. Toxicol. suppl., 4, 41-44
TOX2000-408
AIIA-5.4
Ishidate, M.,
Sofuni, T. and
Yoshikawa K.
AIIA-5.4
Ishidate, M.,
Sofuni, T., Yoscurrently used in Japan.
hikawa K.,
not GLP, published
Hayashi, M. and
Fd Chem Toxic, 22, 8, 623-636
Nohmi, T.
TOX2000-409
N
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AIIA-5.4
Ishizaki, M. and 1989 The DNA-damaging activity of natural and synUeno, S.
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TOX2000-411
N
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AIIA-5.4
Jansson, T.,
Curvall, M.,
Hedin, A. and
Enzell, C.R.
N
-
AIIA-5.4
Kawachi, T.,
1980 Results of recent studies on the relevance of
Komatsu, T.,
various short-term screening tests in Japan; In:
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bei Überempfindlichkeit gegen Natriumbenzoat.
not GLP, published
Allergo J., 3, 1994, 307-312
TOX1999-1446
Annex
point/
reference
number
AIIA-5.9
Author(s)
Year Title
report no.
published or not
Green, T.P.,
1983 Disposition of sodium benzoate in newborn
Marchessault,
infants with hyperammonemia.
R.P. and Freese,
not GLP, published
D.K.
The Journal of Pediatrics, 102, 785-790
TOX2000-503
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
AIIA-5.9
Hjorth, N.
1961 Reactions to single components in balsam of
Peru; in: Eczematous allergy to balsams.
not GLP, published
Acta Dermato-Venereologica, 46, 43-48
TOX2000-504
N
-
AIIA-5.9
Juhlin, L., Michaelsson, G.
and Zetterström
O.
1972 Urticaria and asthma induced by food-and-drug
additives in patients with aspirin hypersensitivity.
not GLP, published
J. Allergy Clin. Immunol., 50, 2, 92-98
TOX2000-505
N
-
AIIA-5.9
Kemp, A.S. and 1985 An elimination diet for chronic urticaria of
Schembri, G.
childhood.
not GLP, published
The Medical Journal of Australia., 143, 1985,
234-235
TOX1999-1447
N
-
AIIA-5.9
Kinsey, R.E.
and Wright,
D.O.
1944 Reaction following ingestion of sodium benzoate
in a patient with severe liver damage.
not GLP, published
J. Lab. Clin. Med., 29, 188-196
TOX2000-507
N
-
AIIA-5.9
Kligman, A.M.
1966 The identification of contact allergens by human
assay.
not GLP, published
393-409
TOX2000-508
N
-
AIIA-5.9
Lahti, A.
1978 Skin reactions to some antimicrobial agents.
not GLP, published
Contact Dermatol., 4, 302-303
TOX2000-509
N
-
Annex
point/
reference
number
Author(s)
AIIA-5.9
Lahti, A.
AIIA-5.9
Larmi, E.
AIIA-5.9
Year Title
report no.
published or not
1980 Non-immunologic contact urticaria.
not GLP, published
Acta Derm Venereol, 60, 91, 49 pages
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Data
Owner
protection
claimed
Y/N
N
-
N
-
Larmi, E., Lahti, 1989 Effects of infra-red and neodymium yttrium
A. and Hannukaluminium garnet laser irradiation on nonsela, M.
immunologic immediate contact reactions to
not GLP, published
Dermatosen, 37, 6, 210-214
TOX2000-512
N
-
AIIA-5.9
Larmi, E., Lahti, 1989 Immediate contact reactions to benzoic acid and
A. and Hannukthe sodium salt of pyrrolidone carboxylic acid.
sela, M.
not GLP, published
TOX2000-513
N
-
AIIA-5.9
Lewis, M.A.O.,
Forsyth, A. and
Gall, J.
N
-
AIIA-5.9
Leyden, J.J. and 1977 Contact sensitization to benzoyl peroxide.
Kligman, A.M.
not GLP, published
TOX2000-515
N
-
AIIA-5.9
Malanin, G. and 1989 The results of skin testing with food additives
Kalimo, K.
and the effect of an elimination diet in chronic
and recurrent urticaria and recurrent angioedema.
not GLP, published
Clinical and Experimental Allergy, 19, 539-543
TOX2000-516
N
-
1989 Systemic effect of ultraviolet irradiation on nonimmunologic immediate contact reactions to
not GLP, published
Acta Derm Venereol, 69, 296-301
TOX2000-511
1989 Recurrent erythema multiforme: A possible role
of foodstuffs.
not GLP, published
Br. Dent. J., 166, 371-373
TOX2000-514
Annex
point/
reference
number
AIIA-5.9
Author(s)
Year Title
report no.
published or not
Michaelsson, G. 1973 Urticaria induced by preservatives and dye addiand Juhlin, L.
tives in food and drugs.
not GLP, published
TOX2000-517
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Data
Owner
protection
claimed
Y/N
N
-
AIIA-5.9
Michaelsson,
1974 Purpura caused by food and drug additives.
G., Pettersson,
not GLP, published
L. and Juhlin, L.
Arch. Dermatol, 109, 49-52
TOX2000-518
N
-
AIIA-5.9
Michils, A.,
Vandermoten,
G., Duchateau,
J. and Yernault,
J.-C.
1991 Anaphylaxis with sodium benzoate.
not GLP, published
The Lancet, 337, 1424-1425
TOX2000-519
N
-
AIIA-5.9
MoneretVautrin, D.A.
1986 Food antigens and additives.
not GLP, published
J.Allergy Clin. Immunol., 78, 1039-1046
TOX2000-520
N
-
AIIA-5.9
Nethercott, J.R., 1984 Airborne contact urticaria due to sodium benzoLawrence, M.J.,
ate in a pharmaceutical manufacturing plan.
Roy, A. and
not GLP, published
Gibson, B.L.
J. Occup. Med., 26, 734-736
TOX2000-521
N
-
AIIA-5.9
Ortolani, C.,
Pastorello, E.,
Fontana, A.,
Rotondo, F.,
Gerosa, S. and
Zanussi, C.
1986 Oral double blind placebo controlled additive
provocations and acetyl salicylic acid (ASA)
intolerance in intrinsic asthma.
not GLP, published
TOX2000-522
N
-
AIIA-5.9
Pachor, M.L.,
Urbani, G.,
Cortina, P.,
Lunardi, C.,
Nicolis, F.,
Peroli, P., Corrocher, R. and
Gotte, P.
1989 Is the Melkersson-Rosenthal syndrome related to
the exposure to food additives?.
not GLP, published
Oral Surg Oral Med Oral Pathol, 67, 393-395
TOX2000-523
N
-
Annex
point/
reference
number
Author(s)
AIIA-5.9
Pevny, I., Rauscher, E., Lechner, W. and
Metz, J.
AIIA-5.9
Rademaker M.
and Forsyth, A.
AIIA-5.9
Year Title
report no.
published or not
1981 Exzessive Allergie gegen Benzoesäure mit anaphylaktischem Schock nach Expositionstest.
not GLP, published
Dermatosen, 29, 5, 123-130
TOX2000-524
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
1989 Contact dermatitis in children.
not GLP, published
TOX2000-525
N
-
Ros, A., Juhlin,
L. and Michaelsson, G.
1976 A follow-up study of patients with recurrent
urticaria and hypersensitivity to aspirin, benzoates and azo dyes.
not GLP, published
TOX2000-526
N
-
AIIA-5.9
Rosenhall, L.
and Zetterström
O.
1975 Asthmatic patients with hypersensitivity to aspirin, benzoic acid and tartrazine.
not GLP, published
Tubercle, 56, 168
TOX2000-527
N
-
AIIA-5.9
Schaubschläger, 1991 Release of mediators from human gastric mucosa
W.W., Becker,
and blood in adverse reactions to benzoate.
W.-M., Schade,
not GLP, published
U., Zabel, P.
Int. Arch. Allergy Appl. Immunol., 96, 1991, 97and Schlaak, M.
101
TOX1999-1449
N
-
AIIA-5.9
Senator, H.
1879 Über die Wirkung der Benzoesäure bei der
rheumatischen Polyarthritis.
not GLP, published
Zeitschr. f. klin. Medicin, 1, 2, 243-264
TOX2000-529
N
-
AIIA-5.9
Swanson,
W.W.;
1925 The effect of sodium benzoate ingestion upon the
composition of the blood and urine with especial
reference to the possible synthesis of glycine in
the body.
not GLP, published
J. Biol.Chem., 62, 565-673
TOX2000-530
N
-
Annex
point/
reference
number
Author(s)
AIIA-5.9
Takeda, E.,
Kuroda, Y.,
Toshima, K.,
Watanabe, T.,
Naito, E. and
Miyao, M.
AIIA-5.9
Tarlo, S.M. and
Broder, I.
AIIA-5.9
Year Title
report no.
published or not
1983 Effect of long-term administration of sodium
benzoate to a patient with partial ornithine carbamoyl transferase deficiency.
not GLP, published
Clinical Pediatrics, 22, 3, 1983, 206-208
TOX1999-1450
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
1980 Tartrazine/benzoate challenge and dietary avoidance in troublesome asthma.
not GLP, published
TOX2000-532
N
-
Thune, P. and
Granholt, A.
1975 Provocation tests with antiphlogistica and food
additives in recurrent urticaria.
not GLP, published
TOX2000-533
N
-
AIIA-5.9
Van Bever,
H.P., Docx, M.
and Stevens,
W.J.
1989 Food and food additives in severe atopic dermatitis.
not GLP, published
Allergy, 44, 588-594
TOX2000-534
N
-
AIIA-5.9
Vieluf, D.,
Przybilla, B.,
Tränker, I. and
Ring, J.
1990 Provocation of atopic eczema by oral challenge
tests with food additives.
not GLP, published
Arch Dermatol Res, 281, 544
TOX2000-535
N
-
AIIA-5.9
Vogt; T.
1999 Sodium benzoate-induced acute leucocytoplastic
vasculitis with unusual clinical appearance.
not GLP, published
Arch Dermatol, 135, 726-727
TOX2000-536
N
-
AIIA-5.9
Waldo, J.F.,
Masson, J.M.,
Lu, W. and
Tollstrup, J.
1948 The effect of benzoic acid and caronamide on
blood penicillin levels and on renal function.
not GLP, published
Amer. J. Med. Sci., 117, 563-568
TOX2000-537
N
-
AIIA-5.9
Warin, R.P. and 1976 Challenge test battery in chronic urticaria.
Smith, R.J.
not GLP, published
TOX2000-538
N
-
Annex
point/
reference
number
AIIA-5.9
AIIA-5.9
Author(s)
Year Title
report no.
published or not
Warin, R.P. and 1982 Chronic urticaria investigations with patch and
Smith, R.J.
challenge tests.
not GLP, published
TOX2000-539
Wiley, H.M.
and Bigelow,
W.D.
1908 Influence of benzoic acid and benzoates on digestion and health. Bulletin 84, Pt. IV, Bureau of
Chemistry, U. S. Department of Agriculture,
cited in FDA, 1972.
not GLP, published
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
N
-
TOX2000-540
AIIA-5.9
Ylipieti, S. and
Lahti, A.
1989 Effect of the vehicle on non-immunologic immediate contact reactions.
not GLP, published
TOX2000-541
N
-
AIIA-5.9
Young, E.,
1987 The prevalence of reaction to food additives in a
Patel, S., Stonesurvey population.
ham, M., Rona,
not GLP, published
R. and WilkinJournal of the Royal College of Physicians of
son, J.D.
London, 21, 4, 241-247
TOX2000-542
N
-
AIIIA-7.1.1
Bien, E.
1994 Acute oral toxicity test of "Menno Florades" in
rats.
PROJECT NO.: 10-04-0859/00-94
GLP, unpublished
TOX98-51130
Y
MEN
AIIIA-7.1.2
Bien, E.
1994 Acute dermal toxicity test of "Menno Florades"
in rats.
PROJECT NO.: 10-04-0860/00-94
GLP, unpublished
TOX98-51131
Y
MEN
AIIIA-7.1.4
Bien, E.
1994 Acute dermal irritation / corrosion test of "Menno Florades" in rabbits.
PROJECT NO.: 10-03-0862/00-94
GLP, unpublished
TOX98-51132
Y
MEN
Annex
point/
reference
number
Author(s)
AIIIA-7.1.5
Bien, E.
AIIIA-7.4
Anonym
Year Title
report no.
published or not
1994 Acute eye irritation / corrosion test of "Menno
Florades" in rabbits.
PROJECT NO.: 10-03-0861/00-94
GLP, unpublished
TOX98-51133
1996 Safety Data Sheet Menno Florades.
not GLP, published
TOX2000-543
Codes of owner
MEN:
22 November 2000
Data
Owner
protection
claimed
Y/N
Y
MEN
N
-
Annex B
Benzoic acid
B-7: Residue data
- 149 Benzoic acid – Annex B.7: Residue data
22 November 2000
B.7 Residue data
B.7.1 Metabolism, distribution and expression of residues in plants
(Annex IIA 6.1; Annex IIIA 8.1)
Application fields for benzoic acid are disinfection of deposit areas (fleece mats, ebb/flood
benches), culture vessels, knives, and gardening equipment by watering and dipping. Neither
plants nor soil will be treated with the compound. Consequently, no studies on distribution
and expression of residues in plants are necessary.
B.7.2 Metabolism, distribution and expression of residues in livestock
Since no residues of benzoic acid will occur in plants (cf. B.7.1), no studies on metabolism,
distribution and expression of residues in livestock are necessary.
B.7.3 Definition of the residue (Annex IIA 6.7; Annex IIIA 8.6)
No residue definition has to be set, because benzoic acid is not applied to plants or soil.
Therefore, respective residues will not occur (cf. B.7.1).
B.7.4 Use pattern
Benzoic acid is used for disinfection of deposit areas (fleece mats, ebb/flood benches), culture
vessels, knives, and gardening equipment. It is effective against virus, bacteria, and fungi.
Deposit areas are watered with a 1 or 4 % solution of benzoic acid in water, whereas
gardening tools are dipped into a 1 to 3 % solution of the compound. No actual contact
between the plant protection product and plants or soil is intended.
B.7.5 Identification of critical GAPs
The one existing GAP as referred to in B.7.4 comprises uses only in horticulture and
floriculture where benzoic acid is applied to deposit areas and gardening tools, but not on
plants or soil. As regards residues in plants, no critical GAP exists.
B.7.6 Residues resulting from supervised trials (Annex IIA 6.3; Annex
IIIA 8.2)
As pointed out in B.7.1, no residues will occur in plants, because neither plants nor soil will
be treated with the compound. Supervised field trials are thus not necessary.
22 November 2000
B.7.7 Effects of industrial processing and/or household preparation
Disinfection of deposit areas or gardening tools with benzoic acid will not result in residues in
plants (cf. B.7.1). Therefore, no processing studies are necessary.
B.7.8 Livestock feeding studies (Annex IIA 6.4; Annex IIIA 8.3)
As mentioned before, livestock metabolism studies are not necessary due to the absence of
benzoic acid residues in plants (cf. B.7.1 and B.7.2). Consequently, no livestock feeding
studies are necessary.
B.7.9 Residues in succeeding or rotational crops (Annex IIA 6.6; Annex
IIIA 8.5)
Since benzoic acid is applied neither to soil nor to plants, rotational or succeding crops will
not be affected by its application.
B.7.10 Proposed pre-harvest intervals for envisaged uses, or withholding
periods, in the case of post-harvest uses (Annex IIA 6.8; Annex IIIA
8.7)
Benzoic acid is used for disinfection of deposit areas and gardening tools and is therefore
applied independently of plant growth stages. No residues in plants will occur (cf. B.7.1) and
no pre-harvest intervals are necessary.
B.7.11 Community MRLs and MRLs in EU Member States (Annex IIIA
12.2)
No MRLs have been set in other EU member states so far, because benzoic acid is a new active ingredient.
B.7.12 Proposed EU MRLs and justification for the acceptability of those
residues (Annex IIA 6.7; Annex IIIA 8.6)
Benzoic acid is used for disinfection of deposit areas and gardening tools and is not applied to
soil or plants, so no residues will occur in plants (cf. B.7.1). As the compound is used in horticulture and floriculture, the respective crops are not used as food or feedingstuffs. Above that,
benzoic acid is approved and extensively used as a preservative for food. Therefore, setting of
MRLs is not necessary for this compound.
B.7.13 Proposed EU Import tolerances
acceptability of those residues
22 November 2000
and
justification
for
the
There are no EU Import tolerances applied for by the notifier.
B.7.14 Basis for differences, if any, in conclusion reached having regard to
established or proposed Codex MRLs
No Codex MRLs are set for benzoic acid.
B.7.15 Estimates of potential and actual dietary exposure through diet and
other means (Annex IIA 6.9; Annex IIIA 8.8)
Application of benzoic acid to deposit areas or gardening tools for disinfection purposes will
not result in residues in plants (cf. B.7.1). This also applies for products of animal origin (cf.
B.7.2). Therefore, no numerical estimation of dietary exposure through diet and other means
is necessary.
B.7.16 Summary and evaluation of residue behaviour (Annex IIA 6.10;
Annex IIIA 8.9)
The application of benzoic acid according to the GAP does not constitute a risk of residue
formation in neither plants nor livestock. The product is used for disinfection of deposit areas
and gardening tools by watering and dipping. Neither plants nor soil will be treated with the
compound, so no residues will occur.
Moreover, the intended uses in horticulture and floriculture exclude any occurrence of residues in food or feedingstuffs. Above that, benzoic acid is approved and extensively used as a
preservative for food.
Against this background, studies on metabolism in plants and livestock, supervised residue
trials, processing studies, feeding studies, and residue studies for succeeding or rotational
crops are not necessary. No MRLs or pre-harvest periods have to be set.
Annex B
Benzoic acid
B-8: Environmental fate and behaviour
- 155 Benzoic acid – Annex B.8: Environmental fate and behaviour
22 November 2000
B.8 Environmental fate and behaviour
B.8.1 Route and rate of degradation in soil (Annex IIA 7.1.1; Annex IIIA
9.1.1)
The active substance is a natural component in soils, especially acidic soils. Besides other
aromatic acids like hydroxy benzoic acids, methoxy benzoic acid and vanillic acid, in a Calluna dominated heathland soil between March and December concentrations of benzoic acid
in the range of 1.29 – 5.86 mg/kg dry weight soil (Oh horizon) and 0.32 – 7.54 mg/kg (Ah
horizon) were found. Findings in a spruce dominated heathland soil were in the range of 0.9 –
10.8 mg/kg (Oh horizon) and 0.14 – 6.92 mg/kg, respectively (Jalal and Read, 1982). Benzoic
acid was determined in sand soil of quackgrass rhizosphere and in loam soil containing decomposing quackgrass residues at concentrations ranging from 3.9 –4.6 mg/kg and 8.6 –
10.6 mg/kg dry soil, respectively (only water soluble fraction; Baziramakenga et al., 1995).
Benzoic acid can be metabolised by micro-organisms via pyrocatechol or 3,4-dihydroxy benzoic acid (Schlegel, 1992). In soil under aerobic conditions rapid degradation was reported:
100 % degradation in not adapted loam (25 mg/kg) or loamy sand (16 mg/kg) within 1 day;
40 % degradation in not adapted sandy soil from depth of 18 m (0.05 mg/kg) within 15 days;
63 % mineralization in alkaline parabrown soil (20 mg/kg, micro-organisms isolated on phydroxybenzoic acid) (Anonym, 1993).
Taking into account the kind of application the contamination of soil following use as a disinfectant according to the GAP is not expected. With regard to toxicity to human beings and
ecotoxicology there are no specific concerns arising from the fate and behaviour of benzoic
acid in soil following application according to the GAP. It is therefore deemed acceptable that
studies addressing route and rate of degradation in soil were not submitted and further data
requirements with regard to fate and behaviour of the active substance in soil are waived.
B.8.2 Adsorption, desorption and mobility in soil (Annex IIA 7.1.2, 7.1.3;
Annex IIIA 9.1.2)
Benzoic acid is reported to show only low degree of adsorption. Investigating two different
sandy soils and one clayey subsoil at 6 °C, in one case (77.9 % sand, 0.1 % organic matter, pH
4.7) a Freundlich adsorption constant of 0.23 could be determined. In the two other soils no
adsorption could be observed (Lokke, 1983). In a publication dealing with kinetics of
adsorption and degradation of benzoic acid using a silt loam (0.84 % organic carbon, pH 5.4),
Dao and Lavy (1987) reported instantaneous adsorption when the limitations of diffusion were
minimized.
Benzoic acid has to be regarded as mobile in soil. Taking into account the kind of application
the contamination of soil following use as a disinfectant of equipment (watering of surfaces
on which plants in pots or other culture vessels stand, soaking of culture vessels, dipping of
tools like knives etc.) is not expected. Since the active substance is a natural component of
soils which is readily degraded a risk of ground water contamination resulting from application of benzoic acid according to the GAP is not expected.
It is therefore deemed acceptable that studies addressing mobility in soil were not submitted
and further data requirements with regard to fate and behaviour of the active substance in soil
are waived.
22 November 2000
B.8.3 Predicted environmental concentrations in soil (Annex IIIA 9.1.3)
dipping of tools like knives etc.). Taking into account the kind of application the contamination of soil following use as a disinfectant according to the GAP is not expected. The estimation of predicted environmental concentrations in soil is therefore deemed to be not necessary.
B.8.4 Fate and behaviour in water (Annex IIA 7.2.1; Annex IIIA 9.2. 1,
9.2.3)
The active substance is a compound naturally occurring in soil and plants. Apart from its natural occurrence findings of benzoic acid in the environment may be due to industrial and other
anthropogenic emissions. For instance, emissions from production and processing of benzoic
acid and phthalic acid anhydride into receiving streams at four locations in Germany were
estimated to be < 10 t/a (Anonym, 1993).
Taking account of the chemical structure (aromatic monocarbon acid) hydrolysis at pH 5 – 9
will not occur. Benzoic acid can be metabolised by micro-organisms via pyrocatechol or 3,4dihydroxy benzoic acid (Schlegel, 1992). Low concentrations of 14C-benzoic acid (0.059 µg/l
and 59 µg/l, resp.) were found to be mineralized to 94.5 – 98.6 % in water samples from two
lakes and 99.4 – 99.5 % in sewage within 7 days at 29 °C (Rubin et al., 1982). The active substance can be regarded as readily biodegradable: 85 % degradation within 14 d were observed
in the MITI test at a concentration of 100 mg benzoic acid/l (MITI list, Biodegradation and
Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan, 1992, p. 3-99). 84 %
degradation within 10 d were observed in the modified MITI test at a concentration of 100 mg
sodium benzoate/l (Anonym, 1993). Easy degradation is reported from several studies some of
them using special conditions like degradation under anaerobic conditions, degradation in sea
water or rain water (Anonym, 1993). Due to this property sodium benzoate can be used as
reference compound in order to check the activity of the inoculum for the investigation of
ready biodegradability of chemical substances according to OECD guideline 301. Using
adapted activated sludge at 20 °C with benzoic acid as sole carbon source, 99 % COD removal at 88.5 mg COD/g dry inoculum/h is reported (Verschueren, 1977). Testing the inherent biological degradability through the batch method using non-adapted activated sludge (1 g
dry matter/l) benzoic acid (COD 1000 mg/l) was found to be degraded to > 90 % within
2 days based on COD measurement (Zahn and Wellens, 1980).
Taking account of the kind of application and the ready biodegradability of the active substance it can be assumed that the use of the plant protection product Menno Florades according to the GAP will not lead to an additional relevant load of benzoic acid in the aquatic environment. With regard to toxicity to human beings and ecotoxicology there are no specific concerns arising from the fate and behaviour of benzoic acid in water following application according to the GAP. It is therefore deemed acceptable that studies addressing route and rate of
degradation in aquatic systems were not submitted and that the data requirements with regard
to fate and behaviour of the active substance in water are waived.
22 November 2000
B.8.5 Impact on water treatment procedures (Annex IIIA 9.2.2)
Specific data adressing the impact on water treatment procedures were not submitted. Due to
the ready biodegradability of the active substance relevant residues in ground or surface water
following application as disinfectant for horticultural equipment according to the GAP are not
expected (cf. Point B.8.6).
B.8.6 Predicted environmental concentrations in surface water and in
ground water (Annex IIIA 9.2.1, 9.2.3)
B.8.6.1
Surface water
As the plant protection product is applied as a disinfectant of horticulture equipment (watering
dipping of tools like knives etc.) a direct contamination of surface water via spray drift or runoff can be excluded. Thus, the only possible entry route into water bodies is via disposal into
waste water.
Application is made using an 1 – 4 % solution of the plant protection product which corresponds to concentrations of 0.9 – 3.6 g a.s./l. Disposal into waste water will result in considerable dilution followed by biological degradation of the active substance during waste water
treatment. Further dilution of possibly remaining active substance in the effluent of waste
water treatment plant will occur in the receiving waterbody. It can be anticipated that these
factors will lead to a decline of the concentration of benzoic acid by several orders of magnitude. Accounting for the three mentioned factors by rough estimates (pre-treatment dilution
1/1000, 95 % degradation, post-treatment dilution 1/10, no adsorption to sediment) the environmental concentration expected in aquatic ecosystems (river receiving effluent from waste
water treatment) will be 18 µg/l which will add to benzoic acid due to natural or nonagricultural anthropogenic sources. Therefore, it is concluded that the use of the plant protection product Menno Florades according to the GAP will not lead to an additional relevant load
of benzoic acid in the aquatic environment.
B.8.6.2
Ground water
Benzoic acid has to be regarded as mobile in soil. Taking into account the kind of application
the contamination of soil following use as a disinfectant of equipment (watering of surfaces
on which plants in pots or other culture vessels stand, soaking of culture vessels, dipping of
tools like knives etc.) is not expected. Since the active substance is a natural component of
soils which is readily degraded a risk of ground water contamination resulting from application of benzoic acid according to the GAP is not expected.
B.8.7 Fate and behaviour in air (Annex IIA 7.2.2; Annex IIIA 9.3)
The vapour pressure of benzoic acid is reported to be 0.11 – 0.53 Pa (20 °C), Henry’s Law
constant was calculated to be 0.0046-0.022 Pa m3 mol-1 (Anonym, 1993).
of surfaces, soaking of culture vessels, dipping of tools like knives etc.). It is deemed
acceptable that further data requirements with regard to fate and behaviour of the active
substance in air are waived.
22 November 2000
B.8.8 Predicted environmental concentrations in air (Annex IIIA 9.3)
Taking into account the type of formulation and the kind of application the predicted environmental concentration in air following use as a disinfectant according to the GAP (watering
of surfaces, soaking of culture vessels, dipping of equipment) will be negligible.
B.8.9 Definition of the residue (Annex IIA 7.3)
As outlined in the chapters considering fate and behaviour in the environment the active
substance is naturally occurring in the environment. Contamination of soil following
application according to the GAP is not expectecd. Benzoic acid is readily biodegradable in
aquatic systems. Furthermore, it will not be possible to discriminate by residue analytical
means between the species applied as a plant protection product and those due to industrial
emissions (e.g. production/processing of benzoic acid and phthalic acid anhydride) or natural
occurence.
Annex
point/
reference
number
Author(s)
Year Title
report no.
published or not
1992 Allgemeine Mikrobiologie
7. Auflage.
not GLP, published
1992
BOD2000-543
Data
Owner
protection
claimed
Y/N
N
-
AIIA-7
Schlegel, H. G.
AIIA-7
Verschueren, K. 1977 Handbook of environmental data on organic
chemicals.
not GLP, published
1977, 120-121
BOD2000-542
N
-
AIIA-7.1
Baziramakenga, 1995 Determination of organic acids in soil extracts by
R.; Simrad, R.R.
ion chromatography.
and Leroux,
not GLP, published
G.D.
BOD2000-559
N
-
Annex
point/
reference
number
Author(s)
AIIA-7.1
Dao, T.H. and
Lavy, T.L.
AIIA-7.1
Jalal, M.A.F.
and Read, D.J.
AIIA-7.1.2
Year Title
report no.
published or not
1987 A Kinetic Study of Adsorption and Degradation
of Aniline, Benzoic Acid, Phenol, and Diuron in
Soil Suspensions.
not GLP, published
Soil Science , 143, 1, 1987, 66-72
BOD97-00592
22 November 2000
Data
Owner
protection
claimed
Y/N
N
-
fungitoxicity.
not GLP, published
Plant and Soil, 70, 1983, 273 - 286
BOD2000-558
N
-
Lokke, H.
1984 Leaching of Ethylene Glycol and Ethanol in
Subsoils.
not GLP, published
Water, Air, and Soil Pollution , 2, 1984, 373-387
BOD97-00593
N
-
AIIA-7.1;
AIIA-7.2
Anonym
not GLP, published
Relevance, 1993
BOD2000-562
N
-
AIIA-7.2.1.3
Rubin, H.E.,
Subba-Rao,
R.V. and Alexander, M.
1982 Rates of Mineralization of Trace Concentrations
of Aromatic Compounds in Lake Water and
Sewage Samples.
not GLP, published
Applied and Environmental Microbiology , 43,
5, 1982, 1133-1138
WAS97-00186
N
-
AIIA-7.2.1.3
Zahn, R. und
Wellens, H.
1980 Prüfung der biologischen Abbaubarkeit im
Standversuch - weitere Erfahrungen und neue
Einsatzmöglichkeiten.
not GLP, published
Z. Wasser Abwasser Forsch. , 13, 1, 1980, 1-7
WAS97-00187
N
-
Codes of owner
Annex B
Benzoic acid
B-9: Ecotoxicology
- 163 Benzoic acid – Annex B.9: Ecotoxicology
22 November 2000
B.9 Ecotoxicology
B.9.1 Effects on birds (Annex IIA 8.1; Annex IIIA 10.1)
B.9.1.1
Toxicity (Annex IIA 8.1, Annex IIIA 10.1)
No avian toxicity studies have been conducted either with benzoic acid or its formulations.
B.9.1.2
Risk assessment for birds
Therefore birds will normally not come into contact with the active substance. In exceptional
cases individual birds might perch on treated objects and thus are subject to dermal exposure.
However the ready-to-use fluid contains only 3.6 mg as/l and thus the magnitude of exposure
is low. Taking into account that benzoic acid as well as the preparation Menno-Florades is of
low toxicity to mammals (oral and dermal LD50 >2000 mg/kg bw in rats) there is no risk to
birds.
B.9.2 Effects on aquatic organisms (Annex IIA 8.2; Annex IIIA 10.2)
B.9.2.1
Acute toxicity to fish
Reference: Jonas, W., 1998, NA 98 9408/3, WAT98-50279
Test guideline: OECD 203 (1992)
GLP compliance: yes
Materials and methods: Acute effects of benzoic acid on unfed Oncorhynchus mykiss were
examined under semistatic conditions (daily renewal of the test solution). Seven animals
(initial length: 5.0 ± 1.0 cm) per test concentration were exposed for 96 h to 12, 26, 55 and
120 mg/l benzoic acid and a negative control. Test conditions were checked daily. Actual
concentrations of the test compound were determined via HPLC after 0, 24 and 48 h.
Findings: The test was considered to be valid. The overall average of measured concentrations
of the test substance in the test solutions was 101 % of nominal. No lethal nor sublethal
effects were observed during the test.
Assessment: NOEC (96 h): 120 mg/l
B.9.2.2
22 November 2000
Acute toxicity to aquatic invertebrates
Test guideline: OECD 202, part I (1984)
GLP compliance: yes
Materials and methods: Acute effects of benzoic acid on immobilisation of Daphnia magna
were examined under semistatic conditions (daily renewal of the test solution). Twenty
animals per test concentration (5 per replicate) were exposed to 12, 26, 55 and 120 mg/l
benzoic acid and a negative control. Immobilised daphnia were counted after 24 h and 48 h.
Test conditions were checked at the beginning and the end of the test. Actual concentrations
of the test compound were determined via HPLC after 0, 24 and 48 h.
of the test substance in the test solutions was 100 % of nominal. No immobilised animals
were observed after 24 h. After 48 h 25 % of animals exposed to the highest test concentration
of 120 mg/l were found immobilised.
Assessment: NOEC (48 h): 55 mg/l. An EC50-value could not be determined.
B.9.2.3
Effects on algal growth
Test guideline: OECD 201 (1984)
GLP compliance: yes
Materials and methods: Effects of benzoic acid on growth inhibition of Pseudokirchneriella
subcapitata were examined according to OECD guideline 201. Algae were exposed to 3.75,
7.5, 15, 30, 60 and 120 mg/l benzoic acid and a negative control. Algal concentrations were
measured turbidimetrically after 24, 48 and 72 h of incubation. Test conditions and actual
concentrations of the test compound were checked at the beginning and the end of the test.
of the test substance in the test solutions was 98 % of nominal. The buffering capacity of the
test medium was surpassed in the test concentrations of 60 and 120 mg/l. Effects therefore
might also be attributed to the low pH-value observed at these concentrations.
Assessment: NOEC (72 h): 7.5 mg/l; EbC50 (72 h): 33 mg/l; ErC50 (24-72 h): 72 mg/l.
B.9.2.4
22 November 2000
Risk assessment for aquatic organisms
According to the intended uses the formulated product Menno-Florades (9 % benzoic acid)
will be used exclusively in glass houses. A contamination of surface water therefore is
unlikely to occur. The test results with fish, daphnia and algae indicate a low toxicity.
Furthermore, benzoic acid is a natural compound of the environment. No adverse effects have
been reported so far in the literature. The overall risk to aquatic organisms is considered to be
low.
B.9.3 Effects on other terrestrial vertebrates (Annex IIIA 10.3)
B.9.3.1
Toxicity to wild mammals (Annex IIIA 10.3)
Benzoic acid as well as the preparation Menno-Florades are of low toxicity to mammals. The
acute oral and dermal LD50 for rats is >2000 mg/kg (see section B.06, Toxicology).
B.9.3.2
Risk assessment for wild mammals
Therefore wild mammals will normally not come into contact with the active substance. In
exceptional cases individuals may traverse treated areas and thus are subject to dermal
exposure. However the ready-to-use fluid contains only 3.6 g as/l and thus the magnitude of
exposure is low. Taking into account the low toxicity there is no risk to mammals.
B.9.4 Effects on bees (Annex IIA 8.3.1; Annex IIIA 10.4)
Because of the application of the product Menno Florades (disinfection of mats, vessels, and
gardening equipment) an exposure of bees to the active substance benzoic can be excluded.
B.9.5 Effects on other arthropod species (Annex IIA 8.3.2; Annex IIIA
10.5)
The intended uses for formulated benzoic acid cover disinfection of culture vessels and
equipment on deposit areas, only. Therefore the exposure of non-target arthropods to the
active substance is not likely and consequently unacceptable risks to non-target arthropods are
most unlikely to occur. No data are required.
B.9.6 Effects on earthworms (Annex IIA 8.4; Annex IIIA 10.6.1)
Therefore earthworms will normally not come into contact with the active substance.
22 November 2000
B.9.7 Effects on other soil non-target macro-organisms (Annex IIIA
10.6.2)
Therefore other soil non-target macro-organisms will normally not come into contact with the
active substance.
B.9.8 Effects on soil non-target micro-organisms (Annex IIA 8.5; Annex
IIIA 10.7)
Because of the intended uses of benzoic acid soil microorganisms will normally not come into
contact with the active substance. Therefore, no studies on effects on activities of soil
microorganisms are required.
B.9.9 Effects on other non-target organisms (flora and fauna) believed to
be at risk (Annex IIA 8.6)
Therefore non-target terrestrial plants will normally not come into contact with the active
substance.
B.9.10 Effects on biological methods of sewage treatment (Annex IIA 8.7)
A study has not been provided. However, it can be assumed from published literature, that
benzoic acid serves as substrate to the microflora. Data available from the national
authorisation procedure indicate a 3h-EC50 > 1000 mg/l (pH 7.5).
Annex
point/
reference
number
AIIA-8.2.1
Author(s)
Jonas, W.
Year Title
report no.
published or not
1998 Acute toxicity test on the rainbow trout (Oncorhynchus mykiss) Semistatic test procedure
Testsubstance: Benzoic Acid.
NA 98 9408/3
GLP, unpublished
WAT98-50279
Data
Owner
protection
claimed
Y/N
Y
MEN
Annex
point/
reference
number
Author(s)
AIIA-8.2.4
Jonas, W.
AIIA-8.2.6
Jonas, W.
Year Title
report no.
published or not
1998 Acute immobilisation test on Daphnia magna
(semistatic test procedure) Testsubstance: Benzoic Acid.
NA 98 9408/2
GLP, unpublished
WAT98-50278
1998 Determination of the growth inhibition on Pseudokirchneriella subcapitata (former name: Ankistrodesmus bibraianus) Testsubstance: Benzoic
Acid.
NA 98 9408/1
GLP, unpublished
WAT98-50277
Codes of owner
MEN:
22 November 2000
Data
Owner
protection
claimed
Y/N
Y
MEN
Y
MEN
Appendix 1
Benzoic acid
Standard Terms and Abbreviations
- 171 Benzoic acid – Annex B.10: Appendices
22 November 2000
B.10 Appendices
B.10.1 Appendix I: Standard terms and abbreviations
Part 1 Technical Terms
A
ACH
AChE
ADI
ADP
AE
AFID
A/G
ai
ALD50
ALT
AMD
ANOVA
AOEL
AP
approx
ARC
ARfD
as
AST
ASV
ATP
BCF
bfa
BOD
bp
BSAF
BSE
BSP
Bt
Bti
Btk
Btt
BUN
bw
c
°C
CA
CAD
CADDY
cd
CDA
ampere
acetylcholine
acetylcholinesterase
acceptable daily intake
adenosin diphosphate
acid equivalent
alkali flame-ionization detector or detection
albumin/globulin ratio
active ingredient
approximate median lethal dose, 50 %
alanine amitrotransferase (SGPT)
automatic multiple development
analysis of variance
acceptable operator exposure level
alkaline phosphatase
approximate
anticipated residue contribution
acute reference dose
active substance
aspartate aminotransferase (SGOT)
air saturation value
adenosine triphosphate
bioconcentration factor
body fluid assay
biological oxygen demand
boiling point
biota-sediment accumulation factor
bovine spongiform encephalopathie
bromosulfophthalein
bacillus thuringiensis
bacillus thuringiensis israelensis
bacillus thuringiensis kurstaki
bacillus thuringiensis tenebrionis
blood urea nitrogen
body weight
centi- (x 10-2)
degree celsius (centigrade)
controlled atmosphere
computer aided design
computer aided dossier and data supply (an electronic dossier
interchange and archiving format)
candela
controlled drop(let) application
cDNA
CEC
cf
CFU
ChE
CI
CL
cm
CNS
COD
CPK
cv
Cv
CXL
d
DES
DFR
DMSO
DNA
dna
DO
DOC
dpi
DRES
DT50
DT90
dw
DWQG
ε
EC50
ECD
ECU
ED50
EDI
ELISA
e-mail
EMDI
EPMA
ERC
ERL
F
F0
F1
F2
FIA
FID
FOB
fp
FPD
22 November 2000
complementary DNA
cation exchange capacity
confer, compare to
colony forming units
cholinesterase
confidence interval
confidence limits
centimetre
central nervous system
chemical oxygen demand
creatinine phosphatase
coeficient of variation
ceiling value
Codex Maximum Residue Limit (Codex MRL)
day
diethylstilboestrol
dislodgeable foliar residue
dimethylsulfoxide
deoxyribonucleic acid
designated national authority
dissolved oxygen
dissolved organic carbon
days pot inoculation
dietary risk evaluation system
dry weight
drinking water quality guidelines
decadic molar extinction coefficient
effective concentration
electron capture detector
European currency unit
median effective dose
estimated daily intake
enzyme linked immunosorbent assay
electronic mail
estimated maximum daily intake
electron probe micro analysis
environmentally relevant concentration
extraneous residue limit
field
parental generation
filial generation, first
filial generation, second
fluorescence immuno assay
flame ionization detector
functional observation battery
freezing point
flame photometric detector
FPLC
g
G
GAP
GC
GC-EC
GC-FID
GC-MS
GC-MSD
GEP
GFP
GGT
GI
GIT
GL
GLC
GLP
GM
GMO
GMM
GPC
GPPP
GPS
GSH
GV
h
H
ha
Hb
HCG
Hct
HDT
hL
HEED
HID
HPAEC
HPLC
HPLC-MS
HPPLC
HPTLC
HRGC
Hs
Ht
I
I50
IC50
ICM
ID
22 November 2000
fast protein liquid chromatography
gram
glasshouse
good agricultural practice
gas chromatography
gas chromatography with electron capture detector
gas chromatography with flame ionization detector
gas chromatography-mass spectrometry
gas chromatography with mass-selective detection
good experimental practice
good field practice
gamma glutamyl transferase
gastro-intestinal
gastro-intestinal tract
guideline level
gas liquid chromatography
good laboratory practice
geometric mean
genetically modified organism
genetically modified micro-organism
gel-permeation chromatography
good plant protection practice
global positioning system
glutathion
granulosevirus
hour(s)
Henry`s Law constant (calculated as a unitless value) (see also K)
hectare
haemoglobin
human chorionic gonadotropin
haematocrit
highest dose tested
hectolitre
high energy electron diffraction
helium ionization detector
high performance anion exchange chromatography
high pressure liquid chromatography or high performance liquid
chromatography
high pressure liquid chromatography – mass spectrometry
high pressure planar liquid chromatography
high performance thin layer chromatography
high resolution gaschromatography
Shannon-Weaver index
haematocrit
indoor
inhibitory dose, 50 %
median immobilization concentration
integrated crop management
ionization detector
IEDI
IGR
im
inh
ip
IPM
IR
ISBN
ISSN
iv
IVF
k
K
Kads
Kdes
Koc
Kom
kg
L
LAN
LASER
LBC
LC
LC-MS
LC50
LCA
LCLo
LC-MS-MS
LD50
LDLo
LDH
LOAEC
LOAEL
LOD
LOEC
LOEL
LOQ
LPLC
LSC
LSD
LSS
LT
m
M
µm
MC
MCH
MCHC
22 November 2000
international estimated daily intake
insect growth regulator
intramuscular
inhalation
intraperitoneal
integrated pest management
infrared
international standard book number
international standard serial number
intravenous
in vitro fertilization
kilo
Kelvin or Henry`s Law constant (in athmospheres per cubic meter per
mole) (see also H)13
adsorption constant
apparent desorption coefficient
organic carbon adsortion coefficient
organis matter adsorption coefficient
kilogram
litre
local area network
light amplification by stimulated emission
loosely bound capacity
liquid chromatography
liquid chromatography-mass spectrometry
lethal concentration, median
life cycle analysis
lethal concentration low
liquid chromatography with tandem mass spectrometry
lethal dose, median; dosis letalis media
lethal dose low
lactate dehydrogenase
lowest observable adverse effect concentration
lowest observable adverse effect level
limit of determination
lowest observable effect concentration
lowest observable effect level
limit of quantification (determination)
low pressure liquid chromatography
liquid scintillation counting or counter
least squared denominator multiple range test
liquid scintillation spectrometry
lethal threshold
metre
molar
micrometer (micron)
moisture content
mean corpuscular haemoglobin
mean corpuscular haemoglobin concentratin
MCV
MDL
MFO
µg
mg
MHC
min
mL
MLT
MLD
mm
mo
mol
MOS
mp
MRE
MRL
mRNA
MS
MSDS
MTD
n
NAEL
nd
NEDI
NEL
NERL
ng
nm
NMR
no
NOAEC
NOAEL
NOEC
NOED
NOEL
NOIS
NPD
NPV
NR
NTE
OC
OCR
ODP
ODS
OM
op
Pa
PAD
mean corpuscular volume
method detection limit
mixed function oxidase
microgram
milligram
moisture holding capacity
minute(s)
millilitre
median lethal time
minimum lethal dose
millimetre
month(s)
Mol
margin of safety
melting point
maximum residue expected
maximum residue limit or level
messenger ribonucleic acid
mass spectrometry
material safety data sheet
maximum tolerated dose
normal (defining isomeric configuration)
no adverse effect level
not detected
no effect daily intake (mg/kg body wt/day)
no effect level
no effect residue level
nanogram
nanometer
nuclear magnetic resonance
number
no observed adverse effect concentration
no observed adverse effect level
no observed effect concentration
no observed effect dose
no observed effect level
notice of intend to suspend
nitrogen-phosphorus detector or detection
nuclear polyhedrosis virus
not reported
neurotoxic target esterase
organic carbon content
optical character recognition
ozone-depleting potential
ozone-depleting substances
organic matter content
organophosphorus pesticide
pascal
pulsed amperometric detection
22 November 2000
2-PAM
pc
PC
PCV
PEC
PECA
PECS
PECSW
PECGW
PED
pH
PHED
PHI
PIC
pic
PIXE
pKa
PNEC
po
Pow
POP
ppb
PPE
ppm
ppp
ppq
ppt
PSP
PrT
PRL
PT
PTDI
PTT
QSAR
r
r2
RBC
REI
Rf
RfD
RH
RL50
RNA
RP
rpm
rRNA
RRT
RSD
s
22 November 2000
2-pralidoxime
paper chromatography
personal computer
haematocrit (packed corpuscular volume)
predicted environmental concentration
predicted environmental concentration in air
predicted environmental concentration in soil
predicted environmental concentration in surface water
predicted environmental concentration in ground water
plasma-emissions-detektor
pH-value
pesticide handler`s exposure data
pre-harvest interval
prior informed consent
phage inhibition capacity
proton inducted X-ray emission
negative logarithm (to the base 10) of the dissociation constant)
predicted no effect concentration
by mouth (per os)
partition coefficient between n-octanol and water
persistent organic pollutants
parts per billion (10-9)
personal protective equipment
parts per million (10-6)
plant protection product
parts per quadrillion (10-24)
parts per trillion (10-12)
phenolsulfophthalein
prothrombin time
practical residue limit
prothrombin time
provisional tolerable daily intake
partial thromboplastin time
quantitative structure-activity relationship
correlation coefficient
coefficient of determination
red blood cell
restricted entry interval
ratio of fronts
reference dose
relative humidity
residual lifetime
ribonucleic acid
reversed phase
reversed phase material
ribosomal ribonucleic acic
relative retention time
relative standard deviation
second
SAC
SAP
SAR
SBLC
sc
sce
SD
SE
SEM
SEP
SF
SFC
SFE
SIMS
SOP
sp
SPE
SPF
spp
sq
SSD
SSMS
STEL
STMR
t
t1/2
T3
T4
TADI
TBC
TCD
TCLo
TID
TDLo
TDR
TER
TERI
TERST
TERLT
tert
TEP
TGGE
TIFF
TLC
Tlm
TLV
TMDI
TMRC
TMRL
strong adsorption capacity
serum alkaline phosphatase
structure/activity relationship
shallow bed liquid chromatography
subcutaneous
sister chromatid exchange
standard deviation
standard error
standard error of the mean
standard evaluation procedure
safety factor
supercritical fluid chromatography
supercritical fluid extraction
secondary ion mass spectroscopy
standard operating procedures
species (only after a generic name)
solid phase extraction
specific pathogene free
subspecies
square
sulfur specific detector
spark source mass spectrometry
short term exposure limit
supervised trials median residue
tonne (metric ton)
half-life (define method of estimination)
tri-iodothyroxine
thyroxine
temporary acceptable daily tntake
tightly bound capacity
thermal conductivity detector
toxic concentration low
thermionic detector, alkali flame detector
toxic dose low
time domain reflectrometry
toxicity exposure ration
toxicity exposure ration for initial exposure
toxicity exposure ration following repeated exposure
toxicity exposure ration following chronic exposure
tertiary (in a chemical name)
typical end-use product
temperature gradient gel electrophoresis
tag image file format
thin layer chromatography
median tolerance limit
threshold limit value
theoretical maximum daily intake
theoretical maximum residue contribution
temporary maximum residue limit
22 November 2000
TOC
Tremcard
tRNA
TSH
TWA
UDS
UF
ULV
UV
v/v
WBC
wk
wt
w/v
w/w
XRFA
yr
<
≤
>
≥
22 November 2000
total organic chlorine
Transport emergency card
transfer riboncleic acid
thyroid stimulating hormone (thyrotropin)
time weighted average
unscheduled DNA synthesis
uncertainly factor (safety factor)
ultra low volume
ultraviolet
volume ratio (volume per volume)
white blood cell
week
weight
weight per volume
weight per weight
X-ray fluorescence analysis
year
less than
less than or equal to
greater than
greater than or equal to
Part 2 Organisations and Publications
ACPA
ACTM
BA
BART
CA
CAB
CAC
CAS
CCFAC
CCGP
CCPR
CCRVDF
CE
CIPAC
COREPER
EC
ECB
ECCA
ECDIN
ECDIS
ECE
ECETOC
American Crop Protection Association
American Society for Testing and Materials
Biological Abstracts (Philadelphia)
Beneficial Arthropod Registration Testing Group
Chemical Abstracts
Centre for Agriculture and Biosciences International
Codex Alimentarius Commission
Chemical Abstracts Service
Codex Committee on Food Additives and Contaminants
Codex Committee on General Principles
Codex Committee on Pesticide Residues
Codex Committee on Residues of Veterinary Drugs in Food
Council of Europe
Collaborative International Pesticides Analytical
Council Ltd
Comite des Representants Permanents
European Commission
European Chemical Bureau
European Crop Care Association
Environmental Chemicals Data and Information of the European
Communities
European Environmental Chemicals Data and Information System
Economic Commission for Europe
European Chemical Industry Ecology and Toxicology Centre
ECLO
ECMWF
ECPA
EDEXIM
EHC (number)
EHCD
EINECS
ELINCS
EMIC
EPA
EPO
EPPO
ESCORT
EU
EUPHIDS
EUROPOEM
FAO
FOCUS
FRAC
GATT
GAW
GCOS
GCPF
GEDD
GEMS
GIEWS
GIFAP
GRIN
HRAC
IARC
IATS
IBT
ICBB
ICBP
ICES
ICPBR
ILO
IMO
IOBC
IPCS
IRAC
IRC
ISCO
ISO
IUPAC
JECFA
JFCMP
22 November 2000
Emergency Centre for Locust Operations
European Centre for Medium Range Weather Forecasting
European Crop Protection Association
European Database on Export an Import of Dangerous Chemicals
Environment Health Criteria (number)
Environmental Health Criteria Document
European Inventory of Existing Commercial Chemical Substances
European List of New Chemical Substances
Environmental Mutagens Information Centre
Environmental Protection Agency
European Patent Office
European and Mediterranean Plant Protection Organization
European Standard Characteristics of Beneficials Regulatory Testing
European Union
European Pesticide Hazard Information and Decision Support System
European Predictive Operator Exposure Model
Food and Agriculture Organization of the UN
Forum for the Co-ordination of Pesticide Fate Models and their Use
Fungicide Resistance Action Committee
General Agreement on Tariffs and Trade
Global Atmosphere Watch
Global Climate Observing System
Global Crop Protection Federation (formerly known as GIFAP)
Global Environmental Data Directory
Global Environmental Monotoring System
Global Information and Early Warning System for Food and Agriculture
Groupement International des Association Nationales de Fabricants de
Produits Agrochimiques (now known as GCPF)
Germplasm Resources Information Network
Herbicide Resistance Action Committee
International Agency for Research on Cancer
International Academy of Toxicological Science
Industrial Bio-Test Laboratories
International Commissin of Bee Botany
International Council for Bird Preservation
International Council for the Exploration of the Seas
International Commissin for Plant-Bee Relationships
International Labour Organization
International Maritime Organisation
International Organization for Biological Control of noxious Animals
and Plants
International Programme on Chemical Safety
Insecticide Restistance Action Committee
International Rice Commission
International Soil Conservation Orginazation
International Organization for Standardization
International Union of Pure and Applied Chemistry
FAO/WHO Joint Expert Committee on Food Additives
Joint FAO/WHO Food and Animal Feed Contamination Monitoring
JMP
JMPR
NATO
NAFTA
NCI
NCTR
NGO
NTP
OECD
OLIS
PAN
RNN
RTECS
SCPH
SETAC
SI
SITC
TOXLINE
UN
UNEP
WCDP
WCP
WCRP
WFP
WHO
WTO
WWF
22 November 2000
Programme
Joint Meeting on Pesticdes (WHO/FAO)
Joint Meeting of the FAO Panel of Experts on Pesticide Residues in
Food and the Environment and the WHO Expert Group on Pesticide
Residues (Joint Meeting on Pesticide Residues)
North Atlantic Treaty Organisation
North American Free Trade Agreement
National Cancer Institute (USA)
National Center for Toxicological Research (USA)
non-governmental organization
National Toxicology Programme (USA)
Organization for Economic Cooperation and Development
On-line Information Service of OECD
Pesticides Action Network
Re-registration Notification Network
Registry of Toxic Effects of Chemical Substances (USA)
Standing Committee on Plant Health
Society of Environmental Toxicology and Chemistry
Systeme International d`Unites
Standard International Trade Classification
Toxicology Information On-line
United Nations
United Nations Environment Programme
World Climate Data Programmme
Workd Climate Programme
World Climate Research Programme
World Food Programme
World Health Organization
World Trade Organization
World Wide Fund for Nature
Appendix 2
Benzoic acid
Specific Terms and Abbreviations
B.10.2 Appendix II: Specific terms and abbreviations
BA
EbC50
ErC50
PAS
SB
TAS
benzoic acid
effective concentration (biomass)
effective concentration (growth rate)
pure active substance
sodium benzoate
technical active substance

Monograph

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