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EC number: 202-259-7 | CAS number: 93-58-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- multi-generation reproductive toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: very concise study summary is available
Data source
Reference
- Reference Type:
- publication
- Title:
- Die Verträglichkeit der Benzoesäure in chronischen Fütterungsversuch
- Author:
- Kieckebusch W, Lang K
- Year:
- 1 960
- Bibliographic source:
- Arzneimittel Forschung 10, 1001-1003
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- 4-generation study
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- Benzoic acid
- EC Number:
- 200-618-2
- EC Name:
- Benzoic acid
- Cas Number:
- 65-85-0
- Molecular formula:
- C7H6O2
- IUPAC Name:
- Benzoic acid
- Details on test material:
- - Name of test material (as cited in study report): Benzoesäure
Constituent 1
Test animals
- Species:
- rat
- Strain:
- not specified
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Farbwerke Bayer (Elberfeld)
- Age at study initiation: no data
- Weight at study initiation: 40-50 g
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): first 8 weeks "paired feed" technique was applied and after ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: no data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): no data
- Mixing appropriate amounts with (Type of food): no data
- Storage temperature of food: no data - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: 14 days
- Proof of pregnancy: no data
- Further matings after two unsuccessful attempts: yes
- After successful mating each pregnant female was caged (how): no data
- Any other deviations from standard protocol: no data - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- every 6 weeks
- Duration of treatment / exposure:
- Generation 1 and 2: lifelong; generation 3: 16 weeks; generation 4: until breeding
- Frequency of treatment:
- in 8 first weeks a "paired feed" technique was applied and after ad libitum
- Details on study schedule:
- no data
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 0.5, 1 %
Basis:
nominal in diet
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: in the first 8 weeks body weight was measured weekly and later in four week interval
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data - Oestrous cyclicity (parental animals):
- no data
- Sperm parameters (parental animals):
- no data
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring: total number of offspring, % of survived offspring in litter
GROSS EXAMINATION OF DEAD PUPS:
no data - Postmortem examinations (parental animals):
- no data
- Postmortem examinations (offspring):
- no data
- Statistics:
- no data
- Reproductive indices:
- no data
- Offspring viability indices:
- no data
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- no effects observed
Details on results (P0)
no effects
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
no effects
TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
no effects
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
no data
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
no data
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
no data
ORGAN WEIGHTS (PARENTAL ANIMALS)
no effects: except in 3rd generation females liver weight increase caused by weight increase during lactation and variation in liter size
GROSS PATHOLOGY (PARENTAL ANIMALS)
no effects
HISTOPATHOLOGY (PARENTAL ANIMALS)
no effects
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOEL
- Effect level:
- 500 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: 1% of benzoic acid in food, assuming 150 mg (1%) of benzoic acid per day per rat and 300 g bw of rat
- Dose descriptor:
- NOEL
- Effect level:
- 557 mg/kg bw/day (nominal)
- Based on:
- other: methyl benzoate
- Sex:
- male/female
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Details on results (F1)
no effects
CLINICAL SIGNS (OFFSPRING)
no effects
BODY WEIGHT (OFFSPRING)
no effects
SEXUAL MATURATION (OFFSPRING)
no data
ORGAN WEIGHTS (OFFSPRING)
no effects
GROSS PATHOLOGY (OFFSPRING)
no effects
HISTOPATHOLOGY (OFFSPRING)
no effects
Effect levels (F1)
open allclose all
- Dose descriptor:
- NOEL
- Generation:
- F1
- Effect level:
- 500 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Dose descriptor:
- NOEL
- Generation:
- F1
- Effect level:
- 557 mg/kg bw/day (nominal)
- Based on:
- other: methyl benzoate
- Sex:
- male/female
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 1. Body weight gain in g (mean ± deviation)
|
Control |
0.5% Benzoic acid |
1% benzoic acid |
|||
|
Male |
Female |
Male |
Female |
Male |
Female |
I Generation |
|
|
|
|
|
|
Week 4 |
70 ± 5.0 |
67 ± 4.1 |
69 ± 2.7 |
64 ± 2.4 |
75 ± 1.4 |
61 ± 2.2 |
Week 8 |
159 ± 6.6 |
124 ± 5.2 |
160 ± 5.0 |
135 ± 5.4 |
147 ± 2.8 |
133 ± 2.4 |
Week 12 |
219 ± 6.3 |
- |
221 ± 5.6 |
- |
237 ± 6.0 |
- |
|
|
|
|
|
|
|
II Generation |
|
|
|
|
|
|
Week 4 |
69 ± 2.3 |
57 ± 3.3 |
71 ± 2.2 |
60 ± 6.7 |
73 ± 3.3 |
70 ± 2.4 |
Week 8 |
167 ± 2.0 |
122 ± 3.6 |
161 ± 2.6 |
131 ± 3.5 |
158 ± 4.6 |
123 ± 5.3 |
Week 12 |
243 ± 5.5 |
- |
238 ± 3.3 |
- |
231 ± 5.6 |
- |
|
|
|
|
|
|
|
III Generation |
|
|
|
|
|
|
Week 4 |
73 ± 3.0 |
60 ± 3.5 |
68 ± 3.8 |
71 ± 2.4 |
72 ± 3.5 |
67 ± 3.7 |
Week 8 |
157 ± 4.5 |
134 ± 4.1 |
158 ± 5.3 |
137 ± 3.9 |
168 ± 2.0 |
136 ± 4.5 |
Week 12 |
240 ± 4.6 |
- |
226 ± 5.8 |
- |
233 ± 3.8 |
- |
|
|
|
|
|
|
|
IV Generation |
|
|
|
|
|
|
Week 4 |
93 ± 1.7 |
76 ± 4.8 |
84 ± 2.9 |
70 ± 3.1 |
73 ± 5.3 |
72 ± 3.5 |
Week 8 |
189 ± 5.3 |
137 ± 4.3 |
168 ± 3.7 |
143 ± 2.4 |
159 ± 6.2 |
134 ± 4.5 |
Week 12 |
255 ± 4.6 |
- |
245 ± 4.4 |
- |
240 ± 4.4 |
- |
Table 2. The organ weights of animals of the 3rd generation (% of bodyweight)
|
Control |
0.5% Benzoic acid |
1% Benzoic acid |
|||
|
Male |
Female |
Male |
Female |
Male |
Female |
Bodyweight, g |
326 ± 5 |
262 ± 5 |
329 ± 5 |
276 ± 5 |
316 ± 3 |
248 ± 6 |
Brain |
0.57 ± 0.01 |
0.69 ± 0.02 |
0.58 ± 0.01 |
0.68 ± 0.01 |
0.61 ± 0.00 |
0.75 ± 0.02 |
Heart |
0.34 ± 0.02 |
0.35 ± 0.01 |
0.32 ± 0.01 |
0.39 ± 0.01 |
0.33 ± 0.01 |
0.35 ± 0.01 |
Liver |
3.49 ± 0.1 |
5.32 ± 0.3 |
3.34 ± 0.1 |
5.19 ± 0.2 |
3.49 ± 0.1 |
5.40 ± 0.2 |
Spleen |
0.21 ± 0.00 |
0.25 ± 0.01 |
0.21 ± 0.04 |
0.23 ± 0.01 |
0.22 ± 0.01 |
0.25 ± 0.01 |
Rein |
0.72 ± 0.02 |
0.8 ± 0.03 |
0.70 ± 0.04 |
0.79 ± 0.01 |
0.74 ± 0.02 |
0.78 ± 0.02 |
Testes |
0.85 ± 0.03 |
- |
0.83 ± 0.04 |
- |
0.92 ± 0.01 |
- |
Table 3. Reproduction in rats in chronic benzoic acid feeding throughout 4 generations
|
Benzoic acid in food, % |
||
|
0 |
0.5 |
1.0 |
Total number of pregnant females |
80 |
78 |
80 |
Sterile females, % |
14 |
10 |
4 |
Females with delayed sexual maturity |
7.5 |
17 |
9 |
Litter per generation |
9.0 ± 0.33 |
9.5 ± 0.26 |
9.6 ± 0.29 |
Total number of offspring |
625 |
688 |
741 |
% of survived offspring in litter |
74 |
66 |
65 |
Old pairing (2nd generation) the number of pregnant females |
37 |
38 |
38 |
Litter per generation |
6.8 |
7.7 |
7.5 |
Total number of offspring |
173 |
139 |
171 |
% of survived offspring in litter |
72 |
61 |
73 |
Applicant's summary and conclusion
- Conclusions:
- No effects were noted after chronic dietary exposure of rats (parents and offspring) to 1% benzoic acid (equivalent to 500 mg/kg bw/day). The NOEL for benzoic acid can be converted to a NOEL for methyl benzoate of 557 mg/kg bw/day.
- Executive summary:
In a life long chronic multi-generation study 2 experimental groups of 20 male and 20 female rats were treated with 0.5 and 1% of benzoic acid in food. The control group received untreated food and consisted also of 20 male and 20 female rats. The first and the second generations were treated lifelong, the 3rd generation for 16 weeks and the 4th generation until breeding. No effects on body weight and food intake were detected in all 4 generations. Liver weight increase in females of the 3rd generation was considered as not treatment related effect but may be caused by weight increase during lactation and due to variation in litter size. Otherwise no effects after histopathological examinations were detected in the treated animals of the 3rd generation. No effects were detected on reproduction and offspring raise in both dosing groups. Causes of death in this chronic study were not investigated. Based on the data of this study, the NOEL is 1% (500 mg/kg bw/day of benzoic acid and 557 mg/kg bw/day of methyl benzoate).
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