Isopropyl benzoate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Study period:

1960-2000

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data reviewed by an expert panel of the OECD HPV Programme and considered "valid with restrictions." "Meets generally accepted scientific standards, well documented and acceptable for assessment. Flagged as a critical study for SIDS endpoint."

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Die Vertraglichkeit der Benzoesaure im chronischen Futterungsversuch

Author:

Kieckebush W and Lang K

Year:

1960

Bibliographic source:

Arzneimittel-Forschung 10, 1001- 1003

Reference 2

Reference Type:

review article or handbook

Title:

SIDS Initial Assessment Report for the 13th SIAM: Benzoates

Author:

OECD HPV Programme

Year:

2001

Bibliographic source:

http://www.inchem.org/documents/sids/sids/BENZOATES.pdf

Report date:

2001

Reference 3

Reference Type:

publication

Title:

Unnamed

Year:

1983

Reference 4

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2002

Report date:

2002

Reference 5

Reference Type:

review article or handbook

Title:

Benzoic Acid and Sodium Benzoate

Author:

World Health Organization

Year:

2000

Bibliographic source:

International Chemical Assessment Document 26: 1-48. http://www.inchem.org/documents/cicads/cicads/cicad26.pdf

Reference 6

Reference Type:

review article or handbook

Title:

Safety assessment of alkyl benzoates as used in cosmetics

Author:

Becker LC, Bergfeld WF, Belsito DV, et al.

Year:

2012

Bibliographic source:

Int. J. Toxicol. 31:342S-72S

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD 416 Two-Generation Reproduction Toxicity

Deviations:

yes

Remarks:

Two doses (plus control) only, extends to 4 generations

GLP compliance:

not specified

Limit test:

yes

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

IUPAC Name:

benzoic acid

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): Benzoic acid
- Physical state: Powder
- Analytical purity: No data

Test animals

Species:

rat

Administration / exposure

Route of administration:

oral: feed

Details on exposure:

First 8 weeks: paired feed technique; afterwards, ad libitum.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No details provided. The mean compound consumption was calculated according to Lehman AJ, Food Drug Official Q. Bull., 66 (1954).

Duration of treatment / exposure:

Generations 1 & 2: lifelong.
Generation 3: 16 weeks
Generation 4: until breeding.

Frequency of treatment:

continuously in diet

Duration of test:

4 generations (48 weeks)

No. of animals per sex per dose:

20 per sex per dose group. Initial body weight: 40-50 g.

Control animals:

yes

Details on study design:

Group I was dosed with 375 mg/kg.
Group II was dosed with 750 mg/kg;
An additional control group was used.

Examinations

Maternal examinations:

DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation after 21 days 3rd generation
- Organs examined: Live fetuses were removed, examined for gross malformations, weighed, and prepared for histological examination. Skeletal examination was carried out under low magnification.

Fetal examinations:

- External examinations: Yes:
- Head examinations: No data

Statistics:

No abnormalities survivors rates as comparable to the control animals.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
In all 4 generations, no influence on growth (weight, weight gain and food efficiency (measured by protein efficiency)) and organ weights was found. In all 4 generations, no effects on fertility and lactation were found. No remarkable histopathological findings were found in the 3rd generation animals. In the paper no information is given on the organs investigated, however the robustness of the total study, the reputation of the investigators, as well as the reputation of the Professor who did the histopathologic investigation, a high quality has to be assumed. In addition after 48 weeks, there was no influence on start of menopause. Feeding of 375 mg/kg bw/d led to prolongation of survival compared to controls.
NOAEL (Parental) > 750 mg/kg/day

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

>= 500 - 750 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

500 - 750 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
NOAEL (F1 Offspring) > 750 mg/kg/day
NOAEL (F2 Offspring) > 750 mg/kg/day

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

> 750 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No fetal effects observed.

Remarks on result:

not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

There are differing estimates of the dose as expressed in mg/kg bw/d, which range from 500 to 750. See discussion in Kieckebush and Lang, 1960, endpoint study record under Repeated Dose Toxicity.

Applicant's summary and conclusion

Conclusions:

In a 4-generation study (48 weeks) reproductive toxicity study of 0.5 and 1% benzoic acid in rats by the dietary route, there were no observed adverse effects in growth, body weight, organ weights, reproductive parameters or developmental effects. The Parental and offspring NOAELs were greater than 500-750 mg/kg bw/d. This study is informative for evaluation of the toxicity of members of the Alkyl Benzoates category, and is adequate for filling the data requirement for the registration of this substance. It is valid for hazard classification and risk assessment.