p-mentha-1,4(8)-diene

Endpoint summary

Description of key information

An oral diet repeated dose toxicity study (combined with a reproduction/developmental toxicity screening test) was conducted with terpinolene monoconstituent according to OECD Guideline No 422 and in compliance with GLP.
The NOAEL (No Observed Adverse Effect Level) for systemic toxicity was determined to be 2500 ppm for females (equivalent to 161.5 mg/kg bw/day) and 5000 ppm for males (equivalent to 294.6 mg/kg bw/day). A combined NOAEL for males and females was determined as 154.6 mg/kg bw/day and was used for risk assessment.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

154.6 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Recent GLP study conducted according to OECD Guideline No 422 without any deviation (Klimisch score = 1).

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

Additional information

In a combined repeated dose toxicity study with a reproduction / developmental toxicity screening test conducted according to OECD 422 Guideline and in compliance with GLP, terpinolene monoconstituent was administered by dietary admixture (initially mixed with 2 % corn oil to avoid evaporation) to three groups of Sprague-Dawley rats, for 42 consecutive days, at dietary concentrations of 0, 800, 2500 and 5000 ppm (equivalent to a mean achieved dosage of 0, 54.1, 154.6 and 300.8 mg/kg bw/day, respectively). Animals allocated to the recovery phase assay were treated for 42 days and then given untreated diet (with 2% corn oil) for a further 14 days.

No unscheduled deaths or treatment-related clinical signs were noted. No treatment-related effects were noted on behavioural, sensory reactivity and functional performance parameters.

Reduced overall body weight gain was evident in animals of either sex treated with 5000 ppm (-24% in males, -50% in females). Males treated with 2500 ppm and females treated with 800 ppm showed a reduction in body weight gain during the first week of treatment (-22% and -28% respectively). No such effects were detected in males treated with 800 ppm.

Food consumption was adversely affected at 5000 ppm in animals of either sex and in toxicity and recovery phase females during the first week of treatment. It was considered to reflect a reluctance to eat the diet admixture due to its low palatability. Toxicity and recovery phase females also showed a reduction in dietary intake during the treatment period.

Water consumption was considered to have been unaffected by treatment.

Main phase males treated with 5000 ppm showed an increase in liver weight both absolute and relative to terminal body weight when compared to controls. Recovery 5000 ppm males continued to show an increase in absolute and relative liver weight following fourteen days without treatment. In liver, minimal to slight centrilobular hepatocellular hypertrophy was evident in main phase males treated with 2500 and 5000 ppm. The hepatocellular hypertrophy was partly reversible in severity following fourteen days without treatment however it was still at a minimal severity in all recovery males treated with 5000 ppm. Hepatocyte enlargement is commonly observed in the rodent liver following the administration of xenobiotics and in the absence of associated inflammatory or degenerative changes, is generally considered to be adaptive in nature and does not represent an adverse health effect.

Microscopic examination also revealed effects in the kidneys of males from all treatment groups. Minimal to marked multifocal tubular degeneration/regeneration was present in males from all treated groups. These tubular findings were also accompanied by the presence of slight to marked hyaline droplets in the proximal convoluted tubules and minimal to moderate granular casts in the tubules of the inner cortex. Recovery 5000 ppm males showed minimal to slight multifocal tubular degeneration/regeneration in the renal cortical tubules and minimal to slight hyaline droplets were present in the proximal convoluted tubules. Minimal to moderate granular casts were also present in the tubules of the inner cortex. This finding is commonly observed in male rats following treatment with some xenobiotics and is not predictive of any adverse effect in humans.

No toxicologically significant effects were detected in any treated toxicity phase female or in main phase males treated with 800 or 2500 ppm.

No treatment-related significant changes were detected after haematology and blood chemistry investigations.

No toxicologically significant macroscopic abnormalities were detected in animals of either sex treated with 5000, 2500 or 800 ppm.

Under the test conditions, the No-Observed-Adverse-Effect-Level (NOAEL) of terpinolene monoconstituent for systemic toxicity for females and males was 2500 and 5000 ppm, respectively (equivalent to 161.5 mg/kg bw/day and 294.6 mg/kg bw/day respectively).

As no specific target organ toxicity relevant to humans was identified, it is not deemed necessary to perform a 90-day toxicity study.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Only one study available

Justification for classification or non-classification

No toxic effects were observed in the repeated dose toxicity study below 300.8 mg/kg bw/day (dose level >300 mg/kg bw/day). The major toxic effect observed at this dose level was a reduction in bodyweight gain, no target organ was identified. Therefore terpinolene monoconstituent is not classified for repeated dose toxicity according to Directive 67/548/EEC and CLP Regulation (EC) No 1272 /2008.