2-methylcyclohexanone

Endpoint summary

Description of key information

In order to predict the repeated dose toxicity for 2-methylcyclohexanone, a read across study was performed using the source substance as Cyclohexanone.

It is concluded that a highly similarity exists between the target and the source compound since the identified structural difference, i.e. methyl group, is not expected to significantly impact the toxicity of the two chemicals. The mechanistic profile comparison leads to the conclusion that the target 2-methylcyclohexanone and the source cyclohexanone show very similar mechanistic profiles. The analysis highlights that the target 2-methylcyclohexanone and the source cyclohexanone show overall
similar physicochemical profiles. The analysis of the reactivity properties highlights that the target 2-methylcyclohexanone and the source cyclohexanone show very similar reactivity profiles.

The results for oral repeated-dose toxicity test of cyclohexanone exhibit qualitative and quantitative consistency. The combined oral NOEL in male and female rats of 508 mg/kg/day can be employed to estimate the repeated dose toxicity of the target compound - 2-methylcyclohexanone.
Therefore, the study can be used for predicting repeated dose toxicity of the target 2-methylcyclohexanone.

According to CLP Regulation (EU CLP, 2008), classification is not warranted since no significant toxic effects are expected at doses <100 mg/kg/day after repeated oral exposures.
The prediction is associated with an overall low uncertainty coming from a similarity justification and high-tier complex endpoint (repeated dose toxicity).

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral, other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1984-1986

Reliability:

2 (reliable with restrictions)

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

The animals received a solution of cyclohexanone in tap water acidified with HCl to pH 2.5 ad libitum, (for bacterial growth suppression). The solutions were dispensed into bottles with sipper tubes and prepared every 2 weeks and stored at 5 degrees C. Bottles were changed three times a week. Control animals received only acidified water and were kept in the same room. All animals were 7-8 weeks old at the beginning of the treatment The weighing of animals occurred once a week and at the end of the study. The weight of the male rats was 162 g (139-180 g); female rats - 126 g (107-143); male mice - 23 g (20-26 g); and female mice - 20 g (17-23 g). For the subchronic study, rats were housed 5 to a cage and mice were housed 10 to a cage. In the chronic study, rats and mice were housed 4 to a cage. The study with both species was conducted in a single animal holding room at 22-24°C in which there was frequent change of air (15 times per h). The animals were raised and housed behind a barrier, in a facility with clean-unclean corridors, the air pressure within the room being arranged so that air from the room would flow to the unclean side. Mice were monitored for murine virus antibodies. The animals were fed Wayne Sterilizable Lab Meal ad libitum. Animals were sacrificed and dissected, organs and tissues were fixed in Formalin, slides were prepared for histopathological examination.

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: drinking water

Details on route of administration:

The drinking water: solution of cyclohexanone in tap water acidified with HCl to pH 2.5 ad libitum, (for bacterial growth suppression). The solutions were dispensed into bottles with sipper tubes and prepared every 2 weeks and stored at 5 degrees C. Bottles were changed three times a week.

Vehicle:

water

Duration of treatment / exposure:

25 weeks

Frequency of treatment:

Daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Remarks:

equiv. 6500 ppm

Dose / conc.:

723 mg/kg bw/day (nominal)

Remarks:

equiv. 4700 ppm

Dose / conc.:

508 mg/kg bw/day (nominal)

Remarks:

equiv. 3300 ppm

Dose / conc.:

246 mg/kg bw/day (nominal)

Remarks:

equiv. 1600 ppm

Dose / conc.:

122 mg/kg bw/day (nominal)

Remarks:

equiv. 800 ppm

Dose / conc.:

61 mg/kg bw/day (nominal)

Remarks:

equiv. 400 ppm

Dose / conc.:

29 mg/kg bw/day (nominal)

Remarks:

equiv. 190 ppm

No. of animals per sex per dose:

5

Control animals:

yes

Observations and examinations performed and frequency:

The weighing of animals occurred once a week and at the end of the study. Animals were sacrificed and dissected, organs and tissues were fixed in Formalin, slides were prepared for histopathological examination.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

In both male and female rats receiving 6,500 ppm cyclohexanone, there was a depression of weight gain, which approximated 10% less than the weight gain of the controls during the 25-week treatment, however no significant histopathological findings were observed.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not examined

Endocrine findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Dose descriptor:

NOAEL

Effect level:

723 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

body weight and weight gain

Key result

Dose descriptor:

NOEL

Effect level:

508 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

body weight and weight gain

Key result

Critical effects observed:

no

Lowest effective dose / conc.:

1 000 mg/kg bw/day (nominal)

System:

other: depression in weight gain

Other than mentioned above, the only pathological change observed was a mild degenerative change in the thyroid gland of 2 male rats given 4,700 ppm cyclohexanone, not seen in other animals.

Conclusions:

The oral 25-week repeated-dose assay in rats provided a NOEL value (508 mg/kg/day) and a NOAEL (No Observed Adverse Effect Level) value (723 mg/kg/day).

Executive summary:

A 25-week repeated-dose study was conducted in F344 rats by administering a solution of cyclohexanone in drinking water. All trested animals survived by the end of the treatment. A NOEL value (508 mg/kg/day - equiv. 3300 ppm) and a NOAEL (No Observed Adverse Effect Level) value (723 mg/kg/day - equiv 4700 ppm) was established. A 10 % depression in weight gain was observed at 1000 mg/kg/day (equiv. 6500 ppm). The only pathological change observed was a mild degenerative change in the thyroid gland of 2 male rats given 4,700 ppm cyclohexanone, not seen in other animals.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

508 mg/kg bw/day

Study duration:

chronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

According to CLP Regulation (EU CLP, 2008), classification is not warranted since no significant toxic effects are expected at doses <100 mg/kg/day after repeated oral exposures. As the prediction did not presented any possible significant toxic effects arising from repeated exposure, the 2-methylcyclohexanone does not meet the criteria for classification for STOT RE (specific target organ toxicity, repeat exposure) according to Regulation (EC) No 1272/2008, Annex I section 3.9.