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Diss Factsheets

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
multi-generation reproductive toxicity
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
4 Generation
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Study cited in CICAD review of benzoic acid as key for repeated dose toxicity and reproduction.
Although some details not available, it is noted in the review that there is sufficient evidence to draw the necessary conclusions demonstrating low toxicity of benzoates.
Benzoate salts dissociate under biological systems, so data considered valid for Na, K or Li salts.

Data source

Reference
Reference Type:
publication
Title:
4 Generation reproduction
Author:
Kieckebusch, W. & Lang, K.
Year:
1960
Bibliographic source:
Kieckebusch, W. & Lang, K., Arzneim.-Forsch. 10: 1001-1003 (1960)

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
4-generation study with 20 rats/sex/group with dosing continuously in the diet at levels of 375 or 750 mg/
kg/day benzoic acid.
In all generations the weight, weight gain and food efficiency (measured by protein efficiency) were
assessed and organ weights examined.
The animals of the 3rd generation were killed and examined histopathologically after 16 weeks dosing
(after lactation of the pups).
GLP compliance:
no
Remarks:
Pre-dates GLP
Limit test:
no
Justification for study design:
Accepted scientific principles

Test material

Constituent 1
Chemical structure
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

Test animals

Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
Starting weight for dosing 40 - 50 g

Administration / exposure

Route of administration:
oral: feed
Details on exposure:
0.5% or 1% in diet (note that earlier work at 5% in diet caused death of animals)
Administered in feed and doses estimated as mg/kg based on dietary uptake of groups and known animal
weights.
Details on mating procedure:
Not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Parental animals of each of three generations taken to mating dosed up to 16 weeks to end of lactation
(females), but male dosing would be 3 - 5 weeks from maturity to mating
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
375 mg/kg diet
Dose / conc.:
750 mg/kg diet
No. of animals per sex per dose:
20
Control animals:
yes, plain diet
Details on study design:
4-generation study with 20 rats/sex/group with dosing continuously in the diet at levels of 375 or 750 mg/
kg/day benzoic acid.
In all generations the weight, weight gain and food efficiency (measured by protein efficiency) were
assessed and organ weights examined.
The animals of the 3rd generation were killed and examined histopathologically after 16 weeks dosing
(after lactation of the pups).

Examinations

Parental animals: Observations and examinations:
Growth (weight, weight gain, food efficiency) and organ weights
Lactation examined as appropriate
The third generation animals were sacrificed and examine histopathologically
Oestrous cyclicity (parental animals):
Not specified, but implied
Sperm parameters (parental animals):
Not specified
Litter observations:
Yes
Postmortem examinations (parental animals):
Not specified
Postmortem examinations (offspring):
Not specified
Statistics:
Not specified
Reproductive indices:
Yes
Offspring viability indices:
Yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
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
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
> 750 mg/kg diet
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
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):
no effects observed
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Effect levels (P1)

Key result
Dose descriptor:
NOAEL
Effect level:
> 750 mg/kg diet
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (P1)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
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
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 750 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Results: F2 generation

General toxicity (F2)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
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
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Other effects:
not specified

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not specified

Effect levels (F2)

Key result
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
> 750 mg/kg diet
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F2)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
Concluded in UN Review that this study met 'generally accepted scientific standards'.
Despite lack of detailed examinations of organs and blood chemistry, the survival and vigour of 4 gwener
ations implies no adverse effects.
The first tweo generations were dosed fo up to 48 weeks and no impact on vigour noted. In fact, the
report suggests greater survival than control animals, but this is not statistically demonstrated.
Executive summary:

No adverse effects observed at up to 750 mg/kg/day

Note that other work on benzoic acid suggests 5 % in diet (3750 mg/kg/day in diet) caused death, but details

not found as to cause of death.