Isopropyl benzoate

Endpoint summary

Description of key information

The NOAEL in repeated dose toxicity studies in rats is 500 mg/kg bw/d or higher.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

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

Adequacy of study:

key study

Study period:

1960

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study predates current guidelines. This older study meets generally accepted scientific standards. The data is published in German and has been accepted as valid by panels of toxicologists including those at JECFA, EFS and WHO.

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD Guideline: 416

Principles of method if other than guideline:

This is a 4-generation repeated dose toxicity study of benzoic acid.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

other: Bayer-Elberfeid

Sex:

male/female

Route of administration:

oral: feed

Details on oral exposure:

In a 4-generation study, 20 rats/sex/group were dosed continuously with 0.5 and 1% in the diet, equivalent to 250 or 500 mg/kg/day, of benzoic acid.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

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

Frequency of treatment:

Daily (continuous) in the diet

Remarks:

Doses / Concentrations:
0.5 and 1% in the diet (estimated as 250-500 mg/kg bw/d, 275- 500 mg/kg bw/d, or 375-750 mg/kg bw/day by different expert groups)
Basis:
nominal in diet

No. of animals per sex per dose:

20 per sex per group.

Control animals:

yes, plain diet

Details on study design:

Chronic repeated dose toxicity study, in which animals were allowed to mate through 4 generations. The animals of the 3rd generation were killed and examined histopathologically after 16 weeks (after lactation of the pups).

Positive control:

No data

Observations and examinations performed and frequency:

Animals were examined for weight, weight gain and food efficiency (measured by protein efficiency)) and organ weights.

Sacrifice and pathology:

HISTOPATHOLOGY:Yes
The animals of the 3rd generation were killed and examined histopathologically after 16 weeks (after lactation of the pups).

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:

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

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

No adverse effects were observed in 4 generations of rats at doses of 1% benzoic acid in the feed. There was slightly increased survival at the dose of 0.5%. No signficant findings were noted in the post-mortem examination. The NOAEL is 1% (approximately equivalent to 500-750 mg/kg bw/d).

Dose descriptor:

NOAEL

Effect level:

500 - 750 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: as 1% in the diet

Critical effects observed:

not specified

Conclusions:

Rats were administered 0, 0.5 and 1% benzoic acid in the diet for 4 generations. No harmful effects were observed on growth, fertility, development, lactation and lifespan. The no effect dietary level was 1%, approximately equivalent to 500-750 mg/kg bw/d. This study is informative for evaluation of the toxicity and environmental fate 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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

adequate

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There are several chronic repeated dose toxicity studies of benzoic acid (Kieckebush and Lang, 1960, Shtenberg et al., 1970) and sodium benzoate (Deuel, et al., 1954) which indicate that dietary intake of these substances does not result in substantial toxicity to rats and mice. The studies were completed prior to the establishment of OECD guideline methods or GLP requirements, but nevertheless have been evaluated as valid and supportive of benzoic acid and salts as food additives (JECFA, beginning in 1961; U.S. FDA 1970). The NOAEL of Kieckebush and Lang, 1960, of 1% benzoic acid in the diet (equivalent to approximately 500-750 mg/kg bw/d) is established as the point of departure for calculation of an acceptable daily intake (ADI) of 5 mg/kg bw/d for humans.

Isopropyl benzoate is part of a category of chemicals, the Alkyl Benzoates, which utilize this data on benzoic acid and sodium benzoate for safety evaluation. The establishment of a benzoates category has been accepted by numerous expert toxicology groups, including the Joint Expert Committee for Food Additives (JECFA), the Scientific Committee on Food (SCF), the European Food Safety Organization (EFSA), the U.S. Food and Drug Administration (FDA), the World Health Organization (WHO), and the OECD High Production Volume Chemicals Programme (OECD HPV). The basis of the large category for all these organizations (EFSA now has a category of 41 substances qualifying as Benzyl Derivative flavours) is a common breakdown product, benzoic acid, which forms rapidly by acidic hydrolysis as well as due to the action of esterase enzymes. Genetic and reproductive toxicity studies are also negative. In addition to this category, the U.S. Cosmetic Ingredient Review (CIR) Expert Panel evaluated the safety of 17 alkyl benzoate esters as a category (2012) based on a common functional group (benzoic acid ester) which are metabolized to benzoic acid.

When isopropyl benzoate is metabolized to benzoic acid, isopropyl alcohol is also formedin situ. Lifetime repeated dose (inhalation) toxicity data on isopropanol is available, in which the NOAEL in rats is 1230 mg/m³(500 ppm, 6 h per day, 5 days per week), with higher concentrations resulting in a male rat-specific condition of renal hyaline droplet formation. Genetic and reproductive toxicity studies are also negative, with an oral reproductive toxicity NOAEL of approximately 5400 mg/kg bw/d (Beyer, et al. 1993). These data support the NOAEL used by JECFA of 500 mg/kg bw/d.

Justification for classification or non-classification

Benzoic acid and substances metabolised to benzoic acid, including isopropyl benzoate, have not displayed repeated dose toxicity in experimental studies. The substance does not meet the criteria of Regulation EC No. 1272/2008 for repeated dose toxicity.