Cinnamyl acetate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The “No Observed Adverse Effect Level" (NOAEL) for reproductive toxicity is considered to be 200 mg/kg bw/day.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfill the standard information requirements set out in Annex VIII, 8.6, of Regulation (EC) No 1907/2006.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

For this endpoint there is one recent key study available with data on toxicity after repeated dosing. This Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test in Wistar Rats was performed in accordance to OECD guideline 422 and in compliance with GLP regulations.

The test item was suspended in corn oil and administered orally at the dose levels of 65, 200 and 600 mg/kg bw/day as low, mid and high dose/ high dose recovery group rats, respectively. A concurrent control and a control recovery group of rats received vehicle (corn oil) alone. The dose volume administered was 5 mL/kg body weight. The main groups consisted of 10 male and 10 female rats per group and recovery groups consisted of 5 male and 5 female rats per group. The prepared dose formulations were administered once daily to specific group of rats prior to mating , during mating and post mating periods (for males), during pregnancy and up to lactation day 4 (for females). In the control and high dose recovery groups, the treatment period was followed by a 14-day no treatment (recovery) period. The recovery period of the study was started from the day of sacrifice of the first littered animals.

The stability and homogeneity of test item in the vehicle was tested. Based on the results, the test item was found to be stable for up to 24 hours at 1 and 200 mg/mL concentrations when stored at room temperature. The dose formulations were analysed for the test item concentration on Day 1 and during month 2 of the treatment period. The results indicated that the analysed concentrations were within ± 10 % of variations from the nominal concentrations.

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 the functional observation battery was performed 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 premating 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 (including reproductive organs) were examined microscopically for histopathological changes.

There were no test item-related changes observed at the high dose group; hence, histopathological evaluation was not carried out for lower (65 and 200 mg/kg bw/day) and recovery dose groups. Gross lesion was examined microscopically.The reproductive organs of infertile males and females across the groups were examined microscopically.

Under the experimental conditions, the following results were obtained:

- 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 65 and 200 mg/kg bw/day doses. At 600 mg/kg bw/day dose, the treatment resulted in significantly reduced male and female mating and fertility indices as compared to control group. The survival index was however not altered by the treatment at all the doses tested. There were no test item related gross and microscopic changes in both males and females.

No Observed Adverse Effect Level:

The “No Observed Adverse Effect Level (NOAEL)” for reproductive toxicity is considered to be 200 mg/kg bw/day.

Effects on developmental toxicity

Description of key information

The “No Observed Adverse Effect Level" (NOAEL) for developmental toxicity is considered to be > 600 mg/kg bw/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

600 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfill the standard information requirements set out in Annex VIII, 8.6, of Regulation (EC) No 1907/2006.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

The OECD 422 test does provide some limited information on developmental toxicity. At birth, all pups (dead and alive) in a litter from each dam were observed for any external deformities, the number of pups born, their sex and individual body weight was recorded. The litters were observed dailty to note the number of pups alive, dead and cannabalized. All the surviving pups were necropsied on lactation day 4 and findings were recorded. Dead and moribund pups were examined for possible defects and cause of death.

The mean number of male and female pups and the total number of pups per litter were not affected by the treatment at all doses. The mean body weight of male pups on day 4 was lower at the mid and high dose groups as compared to vehicle control. This was however considered incidental as the mean weight of the combined sexes was not altered. Gross examination of pups on lactation day 4 did not reveal any changes.

Justification for classification or non-classification

In section 3.7.2 of the EU regulation No. 1272/2008 on the Classification, Labelling and Packaging of Substances and Mixtures (CLP), the criteria are depicted for the classification of a substance for reproductive toxicity.

The reduced fertility indices observed in the available study at the highest dose level (600 mg/kg bw/d) are not accompanied by significant microscopic changes in the reproductive organs of the animals that failed to mate. As such, the effects observed on the fertility indices are not sufficient for classifying the substance as toxic to reproduction.

This assessment is supported by data from substances with similar chemical structures. No effects on fertility were observed in reproductive toxicity studies with two other cinnamate esters (benzyl and methyl cinnamate). Both cinnamate esters were investigated for reproductive toxicity in the Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test in rats according to OECD 422 and GLP regulations. In both studies the NOAEL for reproductive toxicity equaled the highest dose tested since no reproductive toxicity was observed.

Based on these findings, classification as a reproductive toxicant is not required for the test substance.