Phenethyl acetate

Carcinogenicity

Description of key information

PEA was included in this pulmonary tumour assay as a GRAS food additive on the basis of structural similarity to known carcinogens (e.g. presence of keto groups, double bonds, methoxy groups on a benzene ring etc).  The bioassay was specifically for lung tumour induction in mice and the paper concludes that several of the food additives with carcinogenic activity in other bioassays were found to be negative in this one.  PEA did not increase frequency of lung tumours in this assay

supplementary data are available from four carcinogenicity investigations with benzyl acetate,  a read across candidate for phenylethyl acetate based on structural similarities.  The studies were conducted using rats and mice as the test species, specifically, male and female Fischer 344 rats and male and female B6C3F1 mice.  Benzyl acetate  was administered orally, either by gavage or in the feed.  There was no indication that the study was conducted according to GLP or any relevant guidelines.

Based on the results of the key study, NOAEL of 300 mg/kg bw/day, benzyl acetate does not require classification according to Directive 67/548/EEC or Regulation EC No. 1272/2008.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

A range of studies providing supporting data based on read across to benzyl acetate resulted in a reliable NOAEL of 300 mg/kg bw/day in rats. A supplementary LOAEL was also determined in mice, despite some confounding vehicle issues that affected mortality rather than carcinogenesis, but the lower NOAEL was more appropriate for use in the risk assessment.

Phenylethyl acetate was administered in tricaprylin to mice. No evidence of carcinogenesis was observed for phenylethyl acetate.
17 of the 20 mice dosed at 6000 mg/kg with phenylethyl acetate survived to week 20. No pulmonary tumours were evident.
13 of the 20 mice dosed at 1200 mg/kg with phenylethyl acetate survived to week 20. A single pulmonary tumour was recorded in one mouse.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the results for phenylethyl acetate and read across to benzyl acetate, no classification for carcinogenicity is required

Additional information

In a mouse pulmonary tumour incidence assay, groups of 20 mice were intraperitoneally injected with 24 doses of phenylethyl acetate in tricaprylin 2097. The dose levels were the MTD, 6000 mg/kg and one-fifth MTD, 1200 mg/kg. Neither resulted in an increased incidence of pulmonary tumours in comparison with vehicle and untreated controls

In a read across benzyl acetate study conducted by Abdo (1986), groups of 50 rats of each sex were administered 0,250, or 500 mg/ kg benzyl acetate in corn oil by gavage, 5 days per week for 103 weeks. Additional groups of 50 rats of each sex were included at the start of the two-year studies to serve as untreated controls. These controls were sacrificed early in the study (weeks 42-44 for rats) as a result of a program wide decision that vehicle controls are more appropriate than untreated controls for interpreting the results of gavage studies.Under the conditions of these studies, benzyl acetate increased the incidence of acinar-cell adenomas of the exocrine pancreas in male F344/ N rats; the gavage vehicle may have been a contributing factor. No evidence of carcinogenicity was found for female F344/N rats. The carcinogenic potential of Benzyl Acetate is inconclusive based on the results of this study.

In a study conducted by Abdo (1986), groups of 50 mice of each sex received 0,500, or 1,000 mg/ kg benzyl acetate in corn oil by gavage, 5 days per week for 103 weeks. Additional groups of 50 mice of each sex were included at the start of the two-year studies to serve as untreated controls. These controls were sacrificed early in the study (weeks 53-55 for mice) as a result of a program wide decision that vehicle controls are more appropriate than untreated controls for interpreting the results of gavage studies.Under the conditions of these studies, for male and female B6C3F1 mice there was some evidence of carcinogenicity in that benzyl acetate caused increased incidences of hepatocellular adenomas and squamous cell neoplasms of the forestomach.The carcinogenic potential of Benzyl Acetate is inconclusive based on the results of this study.

In the study conducted by Abdoet al(1993), the test substance, Benzyl Acetate, was investigated for its carcinogenic potential in groups of 60 male and female F344/N rats. The rats were fed the test substance in feed containing 0, 300, 600 or 1200mg/kg bw/day benzyl acetate daily over a two year period.

Survival of exposed rats was comparable to that of the controls. The mean body weights of the 1200mg/kg bw/day males and exposed females were approximately 5% lower than those of the controls throughout most of the study. The feed consumption by 1200mg/kg bw/day fed males was slightly lower than that of the controls. No biologically significant changes in haematology or clinical chemistry parameters were found that could be attributed to benzyl acetate administration. No compound related increased incidences of neoplasms or nonneoplastic lesions occurred in male or female F344/N rats teceiving benzyl acetate for two years.

Under the conditions of this study, there was no evidence of carcinogenic activity of benzyl acetate in male or female F344/N rats following oral administration of the test substance at 300mg/kg bw/day, 600mg/kg bw/day or 1200mg/kg bw/day over 2 years. As a result of this, the test substance does not require classification according to Regulation EC No. 1272/2008 or Directive 67/548/EEC.

In the study conducted by Abdoet al(1993), the test substance, Benzyl Acetate, was investigated for its carcinogenic potential in groups of 60 male and female B6C3F1 mice. The mice were fed the test substance in feed containing 0, 33, 100 or 300mg/kg bw/day benzyl acetate daily over a two year period.

Survival of all exposed mice, except the 300mg/kg bw/day females was similar to that of the control groups. Survival of 300mg/kg bw/day females was significantly higher than that of the control group. Throughout the 2 -year study, the mean body weights of 100 and 300mg/kg bw/day males and females were 2 to 14% lower than those of the control groups. No biologically significant changes in haematology or clinical chemistry parameters were observed in mice receiving 33, 100 or 300mg/kg bw/day benzyl acetate.

Under the conditions of this study, there was no evidence of carcinogenic activity of benzyl acetate in male or female B6C3F1 mice following oral administration of the test substance at 33, 100 and 300mg/kg bw/day over 2 years. As a result of this, the test substance does not require classification according to Regulation EC No. 1272/2008 or Directive 67/548/EEC.

The key study was determined to be the study conducted by Abdo in 1993 conducted in mice and rats as it primarily focuses on carcinogenesis following dietary adminstration of the test substance. While the other Abdo study from 1986 covers carcinogenicity, it is not as specific and therefore, cannot be considered to be the key study.

Justification for selection of carcinogenicity via oral route endpoint:

The read across candidate was investigated in a series of preliminary and full carcinogenesis determinations using rats and mice as the test models.  The rat chronic exposure study provided a systemic NOAEL of 300 mg/kg bw/day that was considered suitable as a starting point for the risk assessment

Carcinogenicity: via oral route (target organ): respiratory: lung