Butanoic acid, 3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-indenyl ester

Endpoint summary

Description of key information

NOAEL Cyclobutanate >= 1000 mg/kg bw (OECD TG 407)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Species:

rat

Quality of whole database:

Three repeated dose toxicity studies are available. One for the substance as such and two of a close analogue (90-day study and Reproscreen). The latter information is used to support the reproductive read across.

Additional information

The key study present for Cyclobutanate is a 28-day repeated dose toxicity study. For a closely related analogue, Cyclacet, a 90 days subchronic repeated dose toxicity study is available, which is used to support the read across to Cyclobutanate from Cyclacet for the reproductive toxicity endpoint, where a full read across justification is presented. After the summary of the Cyclobutanate 28-day study a summary will be presented on the repeated dose toxicity of Cyclacet (OECD TG 408) and the systemic toxicity of Cyclacet in the Reproscreen study (OECD TG 421).

Cyclobutanate 28 -day study

This oral repeated dose toxicity study conducted according to OECD guideline 407, which was performed to determine the toxicity of Cyclobutanate in rats after repeated exposure. Male and female rats were exposed to 0, 15, 150 or 1000 mg/kg bw/day of Cyclobutanate for 28-days. Also two satellite groups were included that were allowed to recover for 14 days. Mortality, clinical signs, body weight, food consumption and organ weights were recorded. Hematology, clinical chemistry and urinanalysis, gross pathology and histopathology were performed.

An increase in salivation from day 6 onwards was observed in the high-dose group animals, recovery was apparent in the 14 day period after treatment. This effect is usually considered attributable to an unpleasant tasting or locally irritant formulation rather than an indication of systemic toxicity. In the mid-dose group females a significant reduction of body weight was observed in the last week of treatment. As no dose-relationship was observed, this finding was not considered of toxicological importance. A higher incidence of globular accumulations of eosinophilic material in the tubular epithelium was observed in male rats of the high and mid-dose group (hydrocarbon nephropathy). Regression of this condition was seen in the 14 days of recovery. All remaining morphological changes were commonly observed in laboratory rats and therefore not considered to be of toxicological importance.

Results: Under the conditions of this study, no adverse effects were observed in female and male rats up to the highest dose group. For males, non-adverse hydrocarbon nephropathy was observed histopathologically in the 150 and 1000 mg/kg bw/day dose groups, which is an effect not relevant for humans. Therefore, a NOAEL of >=1000 mg/kg bw/day was set for risk assessment.

Cyclacet - 90 -day study

In a sub-chronic repeated dose toxicity study performed according to OECD 408 and under GLP conditions, rats were orally exposed to Cyclacet for 90 days via the food. The dose levels were 0, 200, 2000, 6000, and 20000 ppm, corresponding to 0, 15.3, 154.9, 464.1, and 1504.6 mg/kg bw/day, respectively. Clinical signs, functional observations, body weight change, dietary intake, and water consumption were monitored during the study. During week 7 and at the end of the study, haematology, blood chemistry and urinalysis were evaluated. Furthermore, oestrus cycle assessment was performed on female animals between week 6 and 7 and week 12 and 13. Opthalmoscopic examination was performed at the start and end of the study in control and high-dose animals. At the end of the study, all animals were subjected to gross necropsy examination and histopathological examination of tissues was performed on animals from control and high-dose. Furthermore, sperm assessment was performed on males at necropsy.

Results: Reduced overall body weight was observed in male and female animals in the highest dose group, correlated with reduced food consumption and adverse effects on food efficiency, indicating decreased food palatability. At the highest dose level, reduced chloride concentration, sodium concentration, aspartate aminotransferase levels, alanine aminotransferase levels, bile acid levels, and increased cholesterol levels were observed in male animals. The observed changes in aminotransferases, bile acid and cholesterol can be explained by the reduced food consumption. Changes in chloride and sodium concentrations may be explained by the observed kidney effects in males. Increased kidney weights were also observed in males, as well as hyalin droplet nephropathy, which is a rat-specific effect that is not relevant for humans. In females, no toxicologically significant effects were observed in clinical chemistry, organ weights or histopathology. Therefore the NOAEL could be established as the highest dose tested, 20000 ppm or 1500 mg/kg bw/day, under the conditions of this test.

Cyclacet systemic effects in the ReproScreen test (OECD TG 421)

In addition to this key study absence of systemic effects was confirmed in the oral gavage reproductive toxicity screening study (OECD TG 421) of the structurally related substance Cyclacet.

 

Based on these results, the NOAEL for Cyclobutanate for humans is established to be ≥1500 mg/kg bw/day based on the subchronic information from Cyclacet and sub-acute information from Cyclobutanate.

Justification for classification or non-classification

Based on the NOAEL of >=1000 mg/kg bw/day (highest dose tested) observed in a 28 day study of Cyclobutanate, therefore the substance does not need to be classified for (oral) repeated dose toxicity according to EU CLP (EC 1272/2008 and its amendments).