Reaction mass of 3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-inden-5-yl isobutyrate and 3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-inden-6-yl isobutyrate

Endpoint summary

Description of key information

Acute oral toxicity (equivalent to OECD TG 401): LD50 mice > 10000 mg/kg bw;

Acute dermal toxicity is > 2000 mg/kg bw, because the acute oral toxicity is > 10000 mg/kg bw.

Acute inhalation toxicity (using route to route calculation, ECHA CLP guidance 2017: 3.1.3.3.5): LD50 > 26000 mg/m3

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

This information is based on the acute oral toxicity of Cyclabute and the supporting information of acute dermal toxicity of Cyclobutanate.

Additional information

Acute toxicity via oral route

A standard OECD TG 401 is not available. There is a study available in mice which can be considered similar to OECD TG 401. An acute oral range-finding toxicity test was performed with oral intubation in 4-5 week old white mice in a protocol which is equivalent to OECD TG 401. Three doses were tested: 2.0 ml/kg (1 male/ 1 female) 5.0 ml/kg (3 male/ 3 female) and 10.0 ml/kg (1 male/ 1 female), corresponding to 1945, 4867, and 9733 mg/kg bw. Animals were observed for 7 days after intubation.

The mice dosed at 5.0 ml/kg and 10.0 ml/kg were hypothermic and showing signs of stress within 30 minutes after treatment. After 18 hours all mice except for the male mouse dosed at 10.0 ml/kg had recovered, and this animal recovered within 42 hours. The mice dosed at 2.0 ml/kg appeared unaffected by the treatment. All mice gained weight during the 7 day observation period. No animals died during observation period. All survivors were killed and examined post mortem after 1 week, at autopsy pale intestines, mottled livers, kidneys and spleens were observed. An approximate acute LD50 value of >10.0 ml/kg bw corresponding to >9733 mg/kg, was identified. Based on these results, Cyclabute is not considered to be acute toxic via the oral route, under the conditions of this test.

In addition, a very similar substance Cyclobutanate also shows an LD50 of > 2000 mg/kg bw in rat. This substance has a straight alkyl chain instead of a branched one attached to the ester and the communal backbone (see also the read across document in the repeated dose toxicity section for more details).

Acute toxicity via dermal route

Acute dermal toxicity of Cyclabute is not available and not anticipated because the acute oral toxicity in mice was > 10000 mg/kg bw and using the conservative oral and dermal absorption of 50%. This is supported with the information from Cyclobutanate. This analogue has a butanoic chain instead of an isobutanoic chain which is not anticipated to influence the acute dermal toxicity. A summary is presented below a full read across justification is not considered necessary based on the absence of acute toxicity at a dose of 10000 mg/kg bw in mice.

Cyclobutanate and its acute dermal toxicity used as supporting information for Cyclabute

An acute dermal toxicity test (limit test) was performed with analogue substance Cyclobutanate as testing material. This substance is very similar to Cyclabute: Cyclobutanate is a straight butyl ester while Cyclabute has a branched butyl ester. The backbones of both substances are the same. In view of this close similarity a separate read across document for acute dermal toxicity was thought not necessary. We refer to the repeated dose toxicity read across information where further chemical structure and toxicological details of both Cyclabute and Cyclobutanate are provided.

The acute dermal toxicity test with Cyclobutanate test was performed according to OECD guideline 402 (Acute dermal toxicity) in a group of 10 rats (5 males, 5 females). The rats were dermally exposed to the substance at 2000 mg/kg bw for 24 hours. The substance was applied to a shorn skin (approximately 10% of body surface) using a graduated syringe. A piece of surgical gauze was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage. No mortality was observed in the 14 days period after exposure. No signs of systemic toxicity were observed during clinical observation. No signs of dermal irritation were noted in male animals. Very slight erythema was noted in all female animals one to three days after dosing. No abnormalities were noted at necropsy. Body weight of all animals increased during study. The acute dermal median lethal dose (LD50) of the test material in the Sprague-Dawley strain rat, was found to be >2000 mg/kg bw.

Acute toxicity via inhalation route

For inhalation, an LD50 of >10000 mg/kg bw can be roughly converted into > 26000 mg/m3 (ECHA CLP guidance 2017, section 3.1.3.3.5) =((acute oral toxicity in mg/kg bw / 2 (oral versus inhalation exposure)*0.0052)*1000

When the maximum saturated vapour pressure for Cyclabute is taken into account, a maximum concentration of 55 mg/m3 can be calculated (0.61 Pa (Vap Pr. Cyclabute) x 220 (MW)) / (8.3 (R, gas constant) x 293 (°K)). This means that Cyclabute cannot reach a concentration higher than 55 mg/m3.

Uncertainty: Though the ECHA CLP guidance uses rats instead of mice the 26000 versus 55 mg/m3 there is no anticipated acute inhalation toxicity. In addition, when using the oral acute toxicity of Cyclobutanate done with rats (LD50 > 2000 mg/kg bw) the inhalation value would be 5200 mg/m3 exceeding the saturated vapour pressure with a factor of almost 100. Overall, no acute inhalation toxicity is anticipated.

In the database of Research Institute for Fragrance Materials (RIFM) an acute inhalation study with Cyclabute is available, which results show than C&L for inhalation toxicity is not needed.

 

Justification for classification or non-classification

Based on the oral LD50 > 10000 mg/kg bw in mice, the anticipated dermal LD50 > 2000 mg/kg bw in rats and the calculated inhalation LC50 > 26000 mg/m3 classification for acute toxicity is not warranted in accordance with EU CLP (EC 1272/2008 and its updates).