6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-propionaldehyde

Endpoint summary

Description of key information

Under the conditions of the test (OECD 422, GLP), the systemic NOAEL was determined to be at least 120 mg/kg bw/day.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

120 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

Introduction and method: The substance was tested in a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD 422) following GLP. The dose levels in this study were selected to be 0, 30, 60, 120 mg/kg/day, based on the results of the dose range finder in which mortality was observed at 450 mg/kg/day but no severe effects were recorded at 90 mg/kg/day. The test item and vehicle (water) were administered once daily by oral gavage 7 days a week for a minimum of 29 days. Males were treated for 29 days, up to and including the day before scheduled necropsy. This included a minimum of 14 days prior to mating and during the mating period. Females that delivered were treated for 50 to 57 days, i.e. 14 days prior to mating (with the objective to cover at least two complete estrous cycles), the variable time to conception, the duration of pregnancy and at least 13 days after delivery, up to and including the day before scheduled necropsy.

Parameters measured: Mortality/moribundity, clinical signs, functional observations, body weight and food consumption, estrous cycle determination, clinical pathology, measurement of thyroid hormone T4 (F0-males), gross necropsy findings, organ weights and histopathologic examinations. In addition, the following reproduction/developmental parameters were determined: mating and fertility indices, precoital time, number of implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights, sex, anogenital distance, areola/nipple retention and macroscopy, measurement of thyroid hormone T4 (PND 14-16 pups)).

Results: Mortality: One female (No. 52) at 30 mg/kg/day was found dead on Day 7 post-coitum. No clinical signs were observed that were associated with its death. At necropsy beginning autolysis, a soft urinary bladder wall (probably a result of autolysis) and many dark red foci on the thymus were recorded. There were no microscopic observations indicating the cause of death. At the isolated incidence observed and with the absence of a dose-related trend, this death was considered an incidental occurrence rather than related to treatment with the test item.

Clinical signs: No toxicologically significant changes were noted.

Functional observation tests: No toxicologically significant changes were noted.

Body weight: No toxicologically significant changes were noted.

Food consumption: No toxicologically significant changes were noted.

Haematology and clotting parameters: No effects observed.

Clinical chemistry: Decreased total protein concentrations in males starting at 60 mg/kg/day were considered non-adverse in the absence of corroborating findings.

Hormone levels: Male T4 thyroid hormone levels were not affected.

Organ weights and histopathology: Relationships were suspected between enlarged liver, increased liver weight and hepatocellular hypertrophy. The (mainly periportal) hepatocellular hypertrophy in females at 60 and 120 mg/kg/day and males at 120 mg/kg/day was considered non-adverse at the current severities (minimal to slight) and in the absence of any degenerative findings. Therefore, the higher liver weights (up to 19%) in males and females were considered non-adverse.

Conclusion: In conclusion, based on the results of this combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test, the parental NOAEL is at least 120 mg/kg/day.

Justification for classification or non-classification

Based on the results of the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD 422) the substance does not have to be classified for repeated dose toxicity according to EU CLP (EC 1272/2008 and its amendments).