Registration Dossier

Administrative data

Description of key information

Based on read across to an appropriate source substance, the substance is not considered to be toxic after oral repeated dosing.

Rat:

Oral (OECD 422): NOAEL = 443.7 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Please consult section 13 for the RA justification document.
Reason / purpose:
read-across source
Limit test:
no
Key result
Dose descriptor:
NOAEL
Effect level:
443.7 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: Corrected for MW; No effects observed at highest tested dose.
Key result
Critical effects observed:
no
Conclusions:
Read-across was done from the appropriate source substance benzyl cinnamate. Based on the result, and on the structural, chemical and toxicological similarities between source and target substance, and taking into account the molecular weigth difference between the two substances, the NOAEL for systemic and reproductive toxicity in parental rats for the target substance was calculated to be 443.7 mg/kg bw/day.
Executive summary:

Read-across was done from an appropriate source substance. Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test in rats was performed to generate information concerning the effects of the source substance on male and female reproductive performance and possible health hazards likely to arise from repeated exposure over a relatively limited period of time. This study was conducted in accordance with OECD Guideline No. 422 for testing of chemicals, “Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test” adopted on March 22, 1996.

The source substance was administered orally at dose levels 65, 200 and 600 mg/kg bw/day corresponding to low, mid and high dose groups of male and female rats. A high dose recovery, concurrent control and a control recovery groups were also included in the study.

The males were dosed for a minimum of 4 weeks, up to and including the day before scheduled sacrifice, including minimum 2 weeks prior to mating, during the mating period and approximately 2 weeks post mating. Females were dosed throughout the treatment period, including 2 weeks prior to mating (with the objective of covering at least two complete oestrous cycles), the variable time to conception, the duration of pregnancy and at least 4 days after delivery, up to and including the day before scheduled sacrifice. Animals in the recovery groups were kept only for observations of reversibility, persistence or delayed occurrence of systemic toxic effects for 14 days post treatment and these animals were not mated and consequently not used for assessment of reproduction/developmental toxicity. The recovery period of the study was started from the day of sacrifice of the first littered animals.

All animals were observed for clinical signs, physical abnormalities and mortality. The body weight and food consumption were measured at periodic intervals. The functional observation battery was done shortly before sacrifice for randomly selected 5 males and 5 females from each group. For recovery groups, functional observation battery was done prior to sacrifice. Laboratory investigations such as haematology and clinical chemistry were performed in randomly selected 5 males and 5 females from each group at the end of the pre-mating period for main groups and at the end of recovery period from all animals of recovery groups. The animals were subjected to detailed necropsy at sacrifice after overnight fasting and study plan specified tissues were collected. Tissues collected from randomly selected 5 males and 5 females in the control and high dose groups were examined microscopically for histopathological changes. Histopathological examination of testes in the high dose group included a qualitative assessment of stages of spermatogenesis. All gross lesions were examined microscopically. The reproductive organs of infertile males and females across the groups were examined microscopically

No clinical signs or mortality were observed during the course of the study. No treatment-related neurological abnormalities/dysfunctions were observed at all doses tested. The body weights and food consumption were unaffected by the treatment at all doses tested. The maternal food consumption during gestation was not affected by the treatment at all doses. The maternal body weights and food consumption during lactation periods were unaffected at all doses tested. Treatment had no effect on pre-coital time and gestation length at all the tested doses. No treatment-related changes were observed in the fertility indices of sires and dams at all the doses tested. The survival index was not altered by the treatment at any dose. Administration of the source substance did not cause any treatment related changes in the hematology, coagulation and clinical chemistry parameters of both males and females. There were no test substance-related changes in the terminal body weights, organ weights and organs weight ratios in both males and females. There were no test substance-related changes observed at high dose group and therefore histopathological evaluation was not carried out for the lower and recovery dose groups. Gross examination of pups on lactation day 4 did not reveal any changes. There were no test substance-related gross and microscopic changes in both males and females.

The No Observed Adverse Effect Level (NOAEL) for systemic and reproductive toxicity in parental rats is considered to be 600 mg/kg bw/day for the source substance as there were no adverse effects observed in any parameters up to the highest dose tested.

Based on the result, and on the structural, chemical and toxicological similarities between the source and target substance, and taking into account the molecular weight differences between the two substances, the NOAEL for systemic and reproductive toxicity in parental rats for the target substance was calculated to be 443.7 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
443.7 mg/kg bw/day
Study duration:
subacute
Species:
rat

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

For this endpoint there is no data available on the substance itself. However, there is a reliable and good performed study available on the appropriate source substance benzyl cinnamate. The study uses the oral route as it is the most relevant route of administration for exposure in human.

The study on the source substance is a Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test in rats, performed to generate information concerning the possible effects of the source substance on male and female reproductive performance and possible health hazards likely to arise from repeated exposure over a relatively limited period of time. This study was performed according to OECD Guideline 422 and GLP.

The source substance was administered orally by gavage at dose levels of 65, 200 and 600 mg/kg bw/day and a high dose recovery, concurrent control and a control recovery groups were included in the study. Males were dosed 2 weeks pre-mating, during mating and 2 weeks post mating. Females were dosed throughout the treatment period, 2 weeks pre-mating, during mating, during pregnancy and at least 4 days after delivery. Animals in the recovery groups were kept only for observations of reversibility, persistence or delayed occurrence of systemic toxic effects for 14 days post treatment and these animals were not mated and consequently not used for assessment of reproduction/developmental toxicity. The recovery period of the study started from the day of sacrifice of the first littered animals.

All animals were observed for clinical signs, physical abnormalities, mortality, body weight and food consumption. Also functional observation battery and laboratory investigations such as haematology and clinical chemistry were performed. All animals were necropsied at sacrifice and tissues were collected. All gross lesions were examined microscopically.

No clinical signs or mortality was observed during the course of the study. No treatment-related neurological abnormalities/dysfunctions were observed at all doses tested. The body weights and food consumption were unaffected by the treatment. The source substance did not induce any treatment related changes in haematology, coagulation and clinical chemistry parameters of both males and females. There were no changes in the terminal body weights, organ weights and organs weight ratios in both males and females. There were no test substance-related gross and microscopic changes in both males and females. There were no test substance-related gross and microscopic changes in both males and females.

The NOAEL for systemic toxicity in parental rats for the source substance is considered to be 600 mg/kg bw/day as there were no adverse effects observed in any parameters up to the highest dose tested.

Based on the result, and on the structural, chemical and toxicological similarities between the source and target substance, and taking into account the difference in molecular weight between the two substances, the NOAEL for systemic toxicity in parental rats for the target substance was calculated to be 443.7 mg/kg bw/day.

Justification for classification or non-classification

Based on read-across the substance did not induce any adverse effects after repeated dosing. According to the criteria set out in the CLP Regulation No 1272/2008 in section 3.9 and specific values set out in Table 3.9.2 the substance does not need to be classified. The substance is therefore not toxic after repeated dosing.