Potassium benzoate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Study period:

Up to life-long (first and second generation), 16 weeks (third generation), 3 - 5 weeks fourth generation (until mating)

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 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. Benzoic acid is considered to be a suitable test material for the assessment of benzoates.

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

Test material

Test material information

Constituent 1

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

Specific details on test material used for the study:

Not specified

Test animals

Species:

rat

Strain:

not specified

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

Not specified
Starting weight for dosing 40 - 50 g

Administration / exposure

Route of administration:

oral: feed

Details on route of administration:

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 oral exposure:

Administered in food

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 in food

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

375 mg/kg diet

Doses / concentrations 2

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).

Positive control:

No

Examinations

Observations and examinations performed and frequency:

Growth (weight, weight gain, food efficiency) and organ weights
Lactation examined as appropriate
The third generation animals were sacrificed and examine histopathologically

Sacrifice and pathology:

It appears males

Other examinations:

It is implied that the brains, heart, liver, kidney, testis and spleen were examined.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

No effects reported. In view of reproductive success and life-span, then assumed no critical clinical effects

Mortality:

no mortality observed

Description (incidence):

Not specified, but survival rates no affected by treatment

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:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 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

Key result

Critical 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 gwenerations 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.