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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

294.6 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

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

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

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 Guideline No 422 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 up to 64 consecutive days (including a three week maturation phase, pairing, gestation and early lactation for females), 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).

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 treatment-related effects were detected in mating performance, fertility and gestation lengths:

- all animals mated within the first five days of pairing;

- there were no differences in conception rates for treated animals;

- the distribution of gestation lenghts for treated females was comparable to controls. The majority of females showed a gestation lenghts between 21 1/2 and 23 days.

Under the test condition, the NOAEL of terpinolene monoconstituent for systemic toxicity for females and males was 2500 and 5000 ppm, respectively (equivalent to 161.5 and 294.6 mg/kg bw/day, respectively). A combined NOAEL for males and females was determined as 154.6 mg/kg bw/day.

The NOAEL for reproductive toxicity was considered to be 5000 ppm (294.6 mg/kg bw/day).

No signs of toxicity to reproduction were identified in this study. Therefore, no further testing is deemed necessary.

Short description of key information:
A combined repeated dose toxicity study 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.
The NOAEL for reproductive toxicity was determined to be 5000 ppm (equivalent to 294.6 mg/kg bw/day, highest dose tested).

Justification for selection of Effect on fertility via oral route:
Only one study available for this endpoint

Effects on developmental toxicity

Description of key information

A developmental toxicity screening test combined with a repeated dose toxicity study 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.
The NOAEL for developmental toxicity was determined to be 2500 ppm (equivalent to 356 mg/kg bw/day) based on reduced bodyweight gain (maternal toxicity).  

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

154.6 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

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

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via dermal route

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 Guideline No 422 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 up to 64 consecutive days (including a three week maturation phase, pairing, gestation and early lactation for females), 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).

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 treatment-related effects were detected in mating performance, fertility and gestation lengths.

No significant effects were noted on offspring litter size, sex ratio, viability, growth and development:

- no significant differences were detected for implantation losses, litter size or litter viability for treated animals when compared to controls;

- there were no interfroup differences in sex ratio (percentage male offspring) for litters from treated groups compared to controls;

- reduced litter weights were evident from females treated with 5000 ppm on Day 7post partumwhen compared to controls. Mean offspring weights were reduced from these litters on Day 7post partumresulting in a reduction in body weight gain between Days 4 and 7post partum. In the absence of any effect in litter size or litter viability the intergroup differences detected in offspring development were considered to be related to the decline in heath of the adult female rather than a direct toxic effect on the offspring.

Under the conditions of the test, the NOAEL of terpinolene monoconstituent 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. The NOAEL for developmental toxicity was determined to be 2500 ppm (equivalent to 356 mg/kg bw/day).

No signs of toxicity to development were identified in this study. Therefore, no further testing is deemed necessary.

Justification for selection of Effect on developmental toxicity: via oral route:
One reproduction / developmental screening study showing no adverse effect on development up to maternal toxic dose is available (Iuclid section 7.8.1). A waiver is therefore submitted for this endpoint.

Justification for classification or non-classification

In a recent GLP combined repeated dose toxicity and reproduction / developmental toxicity screening test conducted according to OECD Guideline No 422, no signs of toxicity to reproduction that could be attributable to the test item were identified in male and female rats. No effects were identified on offspring of female rats exposed by diet from 2 weeks before mating until day 7 of lactation up to maternal toxic dose.

Therefore, terpinolene monoconstituent is not classified for reproduction and developmental toxicity according to Directive 67/548/EEC and CLP Regulation (EC) No 1272/2008.