3,3,5-trimethylcyclohexan-1-one

Endpoint summary

Description of key information

Acute toxicity: oral

LD50 was estimated to be 2412.14 mg/kg bw when rats were orally exposed with test substance 3,3,5-trimethylcyclohexan-1-one.

Acute toxicity: inhalation

LC50 was estimated to be 10.293 mg/l ( 10293 mg/m3) when rats were exposed via inhalation with test substance 3,3,5-trimethylcyclohexan-1-one.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 412.14 mg/kg bw

Quality of whole database:

Data is predicted using OECD QSAR toolbox version 3.3

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

10 293 mg/m³ air

Quality of whole database:

Data is predicted using OECD QSAR toolbox version 3.3

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute toxicity oral:

In different studies, 3,3,5-trimethylcyclohexan-1-one has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in mice and rats. Study from one of the RA substance (CAS No. 78-59-1) was also used. The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

For target chemical, In a prediction done by SSS (2017) using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor, the acute oral toxicity was estimated for 3,3,5-trimethylcyclohexan-1-one. LD50 was estimated to be 2412.14 mg/kg bw when rats were orally exposed with test substance 3,3,5-trimethylcyclohexan-1-one. Thus based on this prediction it can be concluded that the substance 3,3,5-trimethylcyclohexan-1-one is not classified in acute oral category as per the criteria of CLP regulation.

Further supported experimental study given by abstract of a publication, the acute oral LD50 value for the chemical 3,3,5-trimethylcyclohexan-1-one was tested in rats. LD50 value was determined to be 3800 mg/Kg with clinical symptoms similar to those of narcotics. Thus based on this value it can be concluded that the substance 3,3,5-trimethylcyclohexan-1-one is not classified in acute oral category as per the criteria of CLP regulation.

Also further supported by study from same abstract, the acute oral LD50 value for the chemical 3,3,5-trimethylcyclohexan-1-one was tested in mice. LD50 value was determined to be 3372 mg/Kg with clinical symptoms similar to those of narcotics. Thus based on this value it can be concluded that the substance 3,3,5-trimethylcyclohexan-1-one is not classified in acute oral category as per the criteria of CLP regulation.

Another study is from NTIS study report for the target chemical where acute oral LD50 test was conducted for the test substance 3,3,5-trimethylcyclohexan-1-one in rats for 8 days. Rats were exposed to gradually increasing concentration of the test substance. Death in four animals were observed within 24 hours at the 5000 mg/kg level and all animals at the highest level. Immediate observations were excessive masticatory movements and salivation at all levels, also depression and labored respiration at three higher levels. There was complete recovery in one hour at the three lower levels. Other clinical signs included marked depression, slow labored respiration, and marked ataxia, sprawling of limbs, depressed reflexes, and coma. Prior to death, two survivors at two highest levels were also comatose; However survivor at the 5000 mg/kg level completely were recovered by the fifth day. There was death in four animals within 24 hours at the 5000 mg/kg level and all animals at the highest level. Major necropsy findings were congestion of the lung, kidneys, adrenals, and pancreas and gastrointestinal inflammation.  Thus based on the study results the acute oral LD50 value of test chemical 3,3,5- rimethylcyclohexan-1-one was determined to be 3450 mg/Kg in rats when tested for 8 days. Thus based on this value it can be concluded that the substance 3,3,5-trimethylcyclohexan-1-one is not classified in acute oral category as per the criteria of CLP regulation.

Further supported by RA study (CAS No. 78-59-1) from Environmental Health Criteria Monographs (EHCs) where the acute oral LD50 value for the chemical 3,5,5-trimethylcyclohex-2-enone was tested in mice. LD50 value was determined to be 2200 mg/Kg with signs of toxicity were similar to those of solvents and narcotics, prostration being followed rapidly by coma. Also, degenerative changes in the liver were reported in animals that died. Thus based on this value it can be concluded that the substance 3,5,5-trimethylcyclohex-2-enone is not classified in acute oral category as per the criteria of CLP regulation.

Based on the overall reported results for target chemical 3,3,5-trimethylcyclohexan-1-one and for its read across substance 3,5,5-trimethylcyclohex-2-enone

, it can be concluded that the test substance 3,3,5-trimethylcyclohexan-1-one is non-toxic to animals and hence not classify in acute oral category as per the criteria.

Acute toxicity inhalation:

Various studies for the 3,3,5-trimethylcyclohexan-1-one (873-94-9) and its read across (CAS 78-59-1) were reviewed to summarize the following information:

For target chemical, In a prediction done by SSS (2017) using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor, the acute inhalative toxicity was estimated for 3,3,5-trimethylcyclohexan-1-one. LC50 was estimated to be 10.293 mg/l when rats were exposed via inhalation with test substance 3,3,5-trimethylcyclohexan-1-one. Based on the estimated result, test chemical 3,3,5-trimethylcyclohexan-1-one can be considered to be classified under the category “Category 4”as per CLP regulation.

Supporting the above prediction in an experimental study from NTIS report, the LC50 in male wistar rats was determined for the test substance 3,3,5-trimethylcyclohexanone by standard acute inhalation test. Groups of 10 male rats were exposed continuously for four hours to graded Concentrations (11.5, 15 and 18 mg/l) of test material in air. Observation for mortality and signs of toxicity were made at half-hour intervals during the actual exposure and daily during a 14-day post-exposure observation period. Signs of increased activity leading to prostration and coma were seen at each concentration during the exposure followed by central nervous system depression, decreased activity, ruffled fur and loss of body weight. Thus based on the study, the LC50 value of test substance 3,3,5-trimethylcyclohexanone after exposure by inhalation in male rats for 4 hrs was determined to be 14.2 mg/l. Based on the result, test chemical 3,3,5-trimethylcyclohexan-1-one can be considered to be classified under the category “Category 4”as per CLP regulation.

Also, for target chemical, Sensory irritation threshold in humans was determined for the test substance 3,3,5-trimethylcyclohexanone by exposing (air)at gradually increasing concentration levels to six adult volunteer subjects. Air containing the chosen concentration of the test substance was diverted from a manifold through a full-face mask. Each subject was provided with a signaling device to indicate the presence (or disappearance) of odor and eye, nose or throat irritation. Exposures to each concentration were for seven minutes and four to nine concentrations of a given substance were used at each session. A second series of test runs two weeks later was used for confirmatory purposes. In these sessions two or three concentration levels of each substance were used. During the initial series of exposures to test substance, four of the six subjects were able to detect odor; but only one subject experienced sensory irritation (eye) at 15 ppm after four previous exposures to concentrations of 20, 37, 69, and 96 ppm, in that order. Yet, during the challenge series, the same six Subjects were exposed to a concentration of 12 ppm, and all detected odor (five out of six within five seconds); eye, nasal, and throat irritation were also recorded. The sensory irritation threshold of test substance 3,3,5-trimethylcyclohexanone after exposure by inhalation in human volunteers was determined to be 0.12 mg/l. Thus, based on the above study, it can be concluded that the test substance 3,3,5-trimethylcyclohexanone causes sensory irritation in human through inhalation and hence can be classified under “Category 3” of Specific target organ toxicity-single exposure (STOT SE-3) as per CLP regulation.

The above classification is supported by study from its RA (CAS No. 78-59-1) wherein also the sensory irritation threshold was determined for the substance 3,5,5-trimethylcyclohex-2-enone. For this a short inhalation experiment was performed on mice by exposing the substance for 5 min. The sensory irritation was estimated as the concentration of chemical causing a 50% decrease in respiratory rate (measured using individual plethysmographs) in mice (RD50). The RD50 for test substance 3,5,5-trimethylcyclohex-2-enon (isophorone) was determined to be 0.1587 mg/l (158.7 mg/m3 or 27.8 ppm) for a 5-min exposure. For comparison, the RD50 values for toluene diisocyanate and acetone were 0.24 and 23.480 ppm, respectively. Thus, based on the above study, it can be concluded that the substance 3,5,5-trimethylcyclohex-2-enone causes sensory irritation in mice through inhalation and hence can be classified under "Category 3" of Specific target organ toxicity-single exposure (STOT SE-3) as per CLP regulation.

Based on the reported results for target chemical 3,3,5-trimethylcyclohexan-1-one (873-94-9), it can be concluded that the test substance 3,3,5-trimethylcyclohexan-1-one is toxic to animals via inhalation route and hence can be considered to be classified under the category “Category 4” of acute toxicity inhalation as per the criteria. Also, as per the available data for the target substance 3,3,5-trimethylcyclohexan-1-one (873-94-9) and its read across 3,5,5-trimethylcyclohex-2-enone (78-59-1), it is observed that it causes sensory irritation when inhaled and hence can be classified under "Category 3" of Specific target organ toxicity-single exposure (STOT SE-3) as per CLP regulation.

Justification for classification or non-classification

Based on the above studies and predictions on 3,3,5-trimethylcyclohexan-1-one, it can be concluded that 3,3,5-trimethylcyclohexan-1-one can be considered as not classified  for acute oral toxicity and classified under “Category 4” for acute Inhalation toxicity and also classified under "Category 3" of Specific target organ toxicity-single exposure (STOT SE-3) as per CLP regulation.