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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
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:
1960
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

Constituent 1
Reference substance name:
Benzoic acid
EC Number:
200-618-2
EC Name:
Benzoic acid
Cas Number:
65-85-0
IUPAC Name:
benzoic acid
Details on test material:
- Name of test material (as cited in study report): Benzoesäure

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 oral 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
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
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
- Section schedule rationale (if not random): no data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

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

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (3rd generation)
HISTOPATHOLOGY: Yes (3rd generation)

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
liver weight increase in females caused by weight increase during lactation and variation in litter size (3rd generation)
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
no data

BODY WEIGHT AND WEIGHT GAIN
no effects

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
no effects

FOOD EFFICIENCY
no data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
no data

OPHTHALMOSCOPIC EXAMINATION
no data

HAEMATOLOGY
no data

CLINICAL CHEMISTRY
no data

URINALYSIS
no data

NEUROBEHAVIOUR
no data

ORGAN WEIGHTS
liver weight increase in females caused by weight increase during lactation and variation in liter size (3rd generation)

GROSS PATHOLOGY
no effects

HISTOPATHOLOGY: NON-NEOPLASTIC
no effects

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
no data

HISTORICAL CONTROL DATA (if applicable)
no data

Effect levels

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

Target system / organ toxicity

Critical 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

-

Applicant's summary and conclusion

Conclusions:
No effects were noted after chronic dietary exposure of rats 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 was exposed for 16 weeks and the 4th generation was exposed 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 and interpreted as weight increase during lactation and due to variation in litter size. No effects after histopathological examinations were detected in the treated animals of the 3rd generation. Causes of death in this chronic study were not investigated. Based on the data of this study, the NOEL for chronic exposure to benzoic acid in the diet is 1% (corresponding to 500 mg/kg bw/day benzoic acid and 557 mg/kg bw/day methyl benzoate).

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