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Description of key information

NOAEL for systemic toxicity = 7500 ppm (equivalent to mean achieved dosage of 435.8 mg/kg bw /day), highest dose tested.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
435.8 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Recent GLP study conducted according to OECD Guideline 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 the Reproduction / Developmental Toxicity Screening Test conducted according to OECD Guideline 422 and in compliance with GLP, three groups of Sprague-Dawley Crl: CD®BR strain rats, each comprising of ten male and ten females for the main phase (except for control and top dose: 5 males/dose), five females for the toxicity phase and 5 male and 5 females/dose (control and top dose) for the recovery phase received Terpinolene multiconstituent at doses of 800, 2000 and 7500 ppm by dietary admixture (initially mixed with 2% corn oil). Main phase males were dosed daily during premating and mating periods and up to 42 days and females were dosed up to 56 consecutive days (including a three week maturation phase, pairing, gestation and early lactation for females). Toxicity phase females were dosed daily up to 42 consecutive days. Recovery phase animals were treated with the high dose 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 clinical condition, performance under detailed physical and arena examination, sensory reactivity, grip strength, motor activity, bodyweight, food consumption, water consumption, haematology, blood chemistry, oestrous cycle, mating performance, fertility and gestation length. Organ weight, macroscopic and microscopic pathology investigations were undertaken in the adults. The clinical condition of offspring, litter size and survival, sex ratio and offspring bodyweight were assessed and macroscopic pathology investigations were undertaken.

No mortality and no clinical signs related to treatment were observed. There were no treatment related effects detected in behavioural assessments, functional performance parameters and sensory reactivity assessments.At 7500 ppm, treatment was associated with lower food consumption during the first week of treatment with a concomitant reduction in mean body weight gain, or mean body weight loss in all animals. The lower food intake had been anticipated and was considered to be due to an initial reluctance to eat the low palatable treated diet. Although lower body weight gain was apparent for females during the second week of treatment, in general subsequent food intake and body weight were not adversely affected by treatment. There was no effect of treatment on body weight gain, food consumption and food utilisation at 800 and 2000 ppm throughout the study. Water consumption was considered to have been unaffected by treatment. No adverse effects of treatment were detected in the haematological and blood chemistry parameters examined. No treatment related effects were detected in mating performance, fertility and length of gestation between control and treated groups. At all dietary levels, main phase males showed a slight increase in absolute and body weight relative liver weights, compared to controls. At the lower dietary levels of 800 and 2000 ppm there was no dosage relationship and all individual body weight relative values were within the historical control range. This increase in liver weights was associated with adaptive liver changes during histopathological examination at all dose levels therefore it was considered as an adaptive response to the treatment. No macroscopic findings considered to be related to test item toxicity was observed. Centrilobular hepatocellular hypertrophy was observed in males with an incidence and/or severity proportional to the dose administered at all dietary inclusion levels. Liver of females receiving 7500 ppm also showed minimal centrilobular hypertrophy. After fourteen days of recovery, liver morphology was considered to have returned to normal. The hepatocellular hypertrophy observed was considered as an adaptive metabolic response of the liver to the presence of a xenobiotic. In thyroid, a higher incidence of hypertrophy of the follicular epithelium was observed in males at 7500 ppm and it was considered secondary to the liver hypertrophy. One female at 7500 ppm also showed minimal hypertrophy of the epithelium. After fourteen days of recovery, thyroid morphology was considered to have returned to normal. In kidneys, treatment-related lesions characterized by tubular degeneration and regeneration, granular casts, interstitial fibrosis and mixed cell infiltration, mainly of the proximal portion of the nephrons, were observed in males receiving 7500 ppm. These kidney findings were partially reversible in recovery males at 7500 ppm following the fourteen days treatment-free period, although three males still showed minimal or slight tubular degeneration, regeneration, interstitial fibrosis and mixed cell infiltration. The lesions were suggestive of alpha 2 μ-globulin nephropathy. It is assumed that this effect has no toxicological relevance for humans although it is considered adverse for the male rats. In spleen, increased hemopoiesis was observed in two males receiving 7500 ppm and minimally in one male at 2000 ppm. Reversibility was apparent after fourteen days of recovery, with only one male at 7500 showing minimal increased hemopoiesis. Because of the minimal magnitude of this finding, it was not considered an adverse effect.

Based on the findings in this study, the No-Observed-Adverse–Effect-Level (NOAEL) of Terpinolene multiconstituent for systemic toxicity for both males and females was 7500 ppm (excluding the male rat-specific effects related to alpha2μ-globulin nephropathy), equivalent to mean achieved dosage of 435.8 mg/kg bw/day.


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

Justification for classification or non-classification

No adverse toxic effects relevant to humans were reported in a repeated dose toxicity study up to the highest dose tested (7500 ppm equivalent to a mean achieved dosage of 435.8 mg/kg bw/day) therefore Terpinolene multiconstituent does not need to be classified according to the annex VI of the Directive 67/548/EEC and the CLP Regulation (EC) No. 1272-2008.