Reaction mass of cis-1-methyl-1-(4-methylcyclohexyl) ethyl acetate and trans-1-methyl-1-(4-methylcyclohexyl) ethyl acetate and cis- 4-isopropyl-1-methylcyclohexyl acetate and trans-4-isopropyl-1-methylcyclohexyl acetate

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

298.8 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP study conducted according to OECD Guideline 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 the Reproduction / Developmental Toxicity Screening Test conducted according to OECD Guideline 422 and in compliance with GLP, Menthanyl acetate multiconstituent was administered by dietary admixture (initially mixed with 2 % corn oil to avoid evaporation) to three groups of Sprague-Dawley Crl: CD® BR strain rats, for up to 63 consecutive days (including a three week maturation phase, pairing, gestation and early lactation for females), at dietary concentrations of 0, 800, 1500 and 5000 ppm (equivalent to a mean achieved dosage of 0, 50.7, 93.7 and 298.8 mg/kg bw/day respectively). Each dose group was subdivided into two phases: main phase (at 800 and 1500 ppm: 10 rats/sex/dose; at 0 and 5000 ppm: 5 males and 10 females/dose) and toxicity phase (5 female/dose). A control group was treated with basal laboratory diet (with 2% corn oil). Two recovery groups (5 rats/sex/dose) were treated with 5000 ppm or basal laboratory diet alone for 42 consecutive days and then maintained without treatment for a further 14 days. During the study, data was recorded on mortality, clinical signs, behavioural assessments, body weight change, food and water consumption, haematology, blood chemistry, mating performance, fertility and gestation length. All animals were subjected to a gross necropsy examination, selected organs were weighed and histopathological evaluation of selected tissues was performed. The clinical condition of offspring, litter size and survival, sex ratio and offspring bodyweight were assessed and macroscopic pathology investigations were undertaken.

No unscheduled deaths or treatment-related clinical signs were noted. No treatment-related effects were noted on behavioural, sensory reactivity and functional performance parameters. A significant reduction (-65 %) in body weight gain was evident in females treated with 5000 ppm during the first week of treatment. Food consumption and food efficiency were also adversely affected in these females during this period. The reduced food consumption was considered to reflect an initial reluctance to eat the diet admixture due to its low palatability. Recovery was evident thereafter. No treatment-related significant changes were detected after haematology and blood chemistry investigations. No treatment-related effects were detected in mating performance, fertility and gestation lengths. Main phase males from all treatment groups showed an increase in kidney and liver weight both absolute and relative to terminal body weight. A true dose related response however was not evident. Recovery males treated with 5000 ppm also showed an increase in absolute and relative liver weight. Toxicity phase females treated with 5000 ppm showed an increase in liver weight both absolute and relative to terminal body weight. Post mortem examinations did not reveal any treatment-related macroscopic findings for interim death or terminal kill offspring. Histopathology revealed microscopic abnormalities in liver (minimal to slight diffuse hepatocellular hypertrophy in main phase males and toxicity phase females at 1500 and 3000 ppm) and thyroid (minimal diffuse follicular cell hypertrophy in main phase males and toxicity phase females at 5000 ppm). These findings were fully reversible in recovery animals and considered either to be adaptive in nature or incidental and therefore not to represent an adverse effect of treatment. At 5000 ppm, microscopic changes in kidney (slight focal and unilateral tubular degeneration/regeneration, and minimal focal to multifocal and unilateral to bilateral corticomedullary mineralization) were observed in in main phase males, toxicity phase females and recovery animals (partly reversible). These findings were considered to be reflecting a minimal variant of alpha 2u-globulin nephropathy (males only) or premature stages of chronic progressive nephropathy which are not indicative of a hazard to human health. No treatment-related significant effects were noted on offspring litter size, sex ratio, viability, growth and development.

Under the test condition, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity when effects relevant to man are taken into account can be established at 5000 ppm (298.8 mg/kg bw/day).The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 5000 ppm (298.8 mg/kg bw/day).

Short description of key information:
NOAEL for systemic toxicity = 5000 ppm (equivalent to mean achieved dosage of 298.8 mg/kg bw/day, highest dose tested).
NOAEL for reproduction toxicity = 5000 ppm (equivalent to mean achieved dosage of 298.8 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

NOAEL for systemic toxicity = 5000 ppm (equivalent to  mean achieved dosage of 298.8 mg/kg bw/day, highest dose tested).
NOAEL for developmental toxicity = 5000 ppm (equivalent to  mean achieved dosage of 298.8 mg/kg bw/day, highest dose tested).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

298.8 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP study conducted according to OECD Guideline 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 the Reproduction / Developmental Toxicity Screening Test conducted according to OECD Guideline 422 and in compliance with GLP, Menthanyl acetate multiconstituent was administered by dietary admixture (initially mixed with 2 % corn oil to avoid evaporation) to three groups of Sprague-Dawley Crl: CD® BR strain rats, for up to 63 consecutive days (including a three week maturation phase, pairing, gestation and early lactation for females), at dietary concentrations of 0, 800, 1500 and 5000 ppm (equivalent to a mean achieved dosage of 0, 50.7, 93.7 and 298.8 mg/kg bw/day respectively). Each dose group was subdivided into two phases: main phase (at 800 and 1500 ppm: 10 rats/sex/dose; at 0 and 5000 ppm: 5 males and 10 females/dose) and toxicity phase (5 female/dose). A control group was treated with basal laboratory diet (with 2% corn oil). Two recovery groups (5 rats/sex/dose) were treated with 5000 ppm or basal laboratory diet alone for 42 consecutive days and then maintained without treatment for a further 14 days. During the study, data was recorded on mortality, clinical signs, behavioural assessments, body weight change, food and water consumption, haematology, blood chemistry, mating performance, fertility and gestation length. All animals were subjected to a gross necropsy examination, selected organs were weighed and histopathological evaluation of selected tissues was performed. The clinical condition of offspring, litter size and survival, sex ratio and offspring bodyweight were assessed and macroscopic pathology investigations were undertaken.

No unscheduled deaths or treatment-related clinical signs were noted. No treatment-related effects were noted on behavioural, sensory reactivity and functional performance parameters. A significant reduction (-65 %) in body weight gain was evident in females treated with 5000 ppm during the first week of treatment. Food consumption and food efficiency were also adversely affected in these females during this period. The reduced food consumption was considered to reflect an initial reluctance to eat the diet admixture due to its low palatability. Recovery was evident thereafter. No treatment-related significant changes were detected after haematology and blood chemistry investigations. No treatment-related effects were detected in mating performance, fertility and gestation lengths. Main phase males from all treatment groups showed an increase in kidney and liver weight both absolute and relative to terminal body weight. A true dose related response however was not evident. Recovery males treated with 5000 ppm also showed an increase in absolute and relative liver weight. Toxicity phase females treated with 5000 ppm showed an increase in liver weight both absolute and relative to terminal body weight. Post mortem examinations did not reveal any treatment-related macroscopic findings for interim death or terminal kill offspring. Histopathology revealed microscopic abnormalities in liver (minimal to slight diffuse hepatocellular hypertrophy in main phase males and toxicity phase females at 1500 and 3000 ppm) and thyroid (minimal diffuse follicular cell hypertrophy in main phase males and toxicity phase females at 5000 ppm). These findings were fully reversible in recovery animals and considered either to be adaptive in nature or incidental and therefore not to represent an adverse effect of treatment. At 5000 ppm, microscopic changes in kidney (slight focal and unilateral tubular degeneration/regeneration, and minimal focal to multifocal and unilateral to bilateral corticomedullary mineralization) were observed in in main phase males, toxicity phase females and recovery animals (partly reversible). These findings were considered to be reflecting a minimal variant of alpha 2u-globulin nephropathy (males only) or premature stages of chronic progressive nephropathy which are not indicative of a hazard to human health. No treatment-related significant effects were noted on offspring litter size, sex ratio, viability, growth and development.

Under the test condition, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity when effects relevant to man are taken into account can be established at 5000 ppm (298.8 mg/kg bw/day).The ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 5000 ppm (298.8 mg/kg bw/day).

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 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 the highest dose tested.

Therefore, Menthanyl acetate multiconstituent is not classified for reproduction and developmental toxicity according to the annex VI of the Directive 67/548/EEC and the CLP Regulation (EC) No. 1272-2008.