3,4-dihydroxy-1-[(Z)-octadec-9-enyl]pyrrolidine-2,5-dione

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

500 mg/kg bw/day

Additional information

The study was designed to investigate the systemic toxicity and potential adverse effects of the test material on reproduction and complies with the recommendations of the OECD Guidelines No. 422.

The oral administration of the test substance to rats for a period of up to forty two days at dose levels of 50, 350 and 1000 mg/kg/day (reduced to 750 mg/kg/day on Day 8 and then 500 mg/kg/day on Day 15), resulted in treatment-related effects in animals of either sex treated at the high dose level and at 350 mg/kg/day.

Clinically observable signs developed in high dose animals throughout the treatment period. Increased salivation around the time of dosing was evident at the high dose level from the first week of treatment onwards together with staining around the mouth/snout/ano-genital region and incidents of noisy respiration, diuresis, tiptoe gait and hunched posture. Bodyweight development was also adversely effected at the high dose level. Significant actual bodyweight losses were evident in the majority of animals during the first week of treatment and in males during the second week of treatment.

Subsequently the cumulative bodyweight gains for males were significantly reduced throughout the treatment period. As a result of this adverse bodyweight effect the high dose level was reduced to 750 mg/kg/day on Day 8 and then to, and for the remainder of the study, 500 mg/kg/day on Day 15. Food consumption and food efficiency was also adversely affected at the high dose level during the first week of treatment for animals of either sex and during Week two for males. No haematological parameters were affected however blood chemical assessments revealed an increase in albumin/globulin ratio and a reduction in total protein for high dose males at the Day 14, 42 and 56 (total protein only) assessments.

Microscopic changes were identified in the bone marrow and thymus. A greater incidence of higher grades of adipose infiltration of the marrow, indicative of marrow hypoplasia, was seen for males only treated at the high dose level. This was however probably associated with the decline in animal health. Lymphoid atrophy in the thymus was seen in relation to treatment for four females and two males treated at the high dose level.

There was no evidence of regression of the condition seen in the bone marrow among recovery high dose males following an additional fourteen days without treatment however atrophy of the thymus had fully regressed after completion of the recovery period.

Effects detected at 350 mg/kg/day were confined to increased salivation and/or fur loss/generalised fur staining, a slight reduction in bodyweight development in males and lymphoid atrophy in the thymus for three females. In the absence of any associated changes or any effect on reproduction (the parameters examined for the parental generation including pre-coital interval, fertility indices, gestation length, parturition index, etc), these effects were considered not to represent an adverse health effect.

The oral administration of the test substance to rats by gavage, at dose levels of 50, 350 and1000 mg/kg/day (reduced to 750 mg/kg/day on Day 8 and then 500 mg/kg/day on Day 15), no treatment-related effects were detected in the reproductive parameters measured. In view of the longer administration period the ‘No Observed Effect Level’ (NOEL) for reproductive toxicity was considered to be 500 mg/kg/day.

Short description of key information:
NOAEL of 500 mg/kg/day was obtained for reproductiontoxicity when the test substance was administered orally by gavage to rats (OECD422)

Effects on developmental toxicity

Description of key information

NOAEL of 150 mg/kg/day was obtained for maternal toxicity and prenatal development when the test substance was administered orally by gavage to pregnant New Zealand White rabbits (OECD 414)

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

150 mg/kg bw/day

Additional information

Two studies conducted on two different species are available for development endpoints.

• Study I:

The test substance in the vehicle, 0.5% carboxymethylcellulose (CMC), was administered orally by gavage to 3 groups of 25 time-mated female New Zealand White rabbits once daily from gestation days 7 through 28. Dosage levels were 50, 150, and 400 mg/kg/day administered at a dosage volume of 5 mL/kg. A concurrent control group of 25 time-mated females received the vehicle (0.5% CMC) on a comparable regimen. Maternal toxicity evidenced by morbidity and mortality and excreta-related clinical findings, mean body weight losses, lower mean body weight gains, and reduced food consumption in the 400 mg/kg/day group. In addition, reduced mean fetal weights were observed at 400 mg/kg/day. Therefore, a dosage level of 150 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity and prenatal development when the test substance was administered orally by gavage to pregnant New Zealand White rabbits.

• Study II:

The study was designed to investigate the systemic toxicity and potential adverse effects of the test material on reproduction and complies with the recommendations of the OECD Guidelines No. 422.

The oral administration of the test substance to rats for a period of up to forty two days at dose levels of 50, 350 and 1000 mg/kg/day (reduced to 750 mg/kg/day on Day 8 and then 500 mg/kg/day on Day 15), resulted in treatment-related effects in animals of either sex treated at the high dose level and at 350 mg/kg/day.

Clinically observable signs developed in high dose animals throughout the treatment period. Increased salivation around the time of dosing was evident at the high dose level from the first week of treatment onwards together with staining around the mouth/snout/ano-genital region and incidents of noisy respiration, diuresis, tiptoe gait and hunched posture. Bodyweight development was also adversely effected at the high dose level. Significant actual bodyweight losses were evident in the majority of animals during the first week of treatment and in males during the second week of treatment.

Subsequently the cumulative bodyweight gains for males were significantly reduced throughout the treatment period. As a result of this adverse bodyweight effect the high dose level was reduced to 750 mg/kg/day on Day 8 and then to, and for the remainder of the study, 500 mg/kg/day on Day 15. Food consumption and food efficiency was also adversely affected at the high dose level during the first week of treatment for animals of either sex and during Week two for males. No haematological parameters were affected however blood chemical assessments revealed an increase in albumin/globulin ratio and a reduction in total protein for high dose males at the Day 14, 42 and 56 (total protein only) assessments.

Microscopic changes were identified in the bone marrow and thymus. A greater incidence of higher grades of adipose infiltration of the marrow, indicative of marrow hypoplasia, was seen for males only treated at the high dose level. This was however probably associated with the decline in animal health. Lymphoid atrophy in the thymus was seen in relation to treatment for four females and two males treated at the high dose level.

There was no evidence of regression of the condition seen in the bone marrow among recovery high dose males following an additional fourteen days without treatment however atrophy of the thymus had fully regressed after completion of the recovery period.

Effects detected at 350 mg/kg/day were confined to increased salivation and/or fur loss/generalised fur staining, a slight reduction in bodyweight development in males and lymphoid atrophy in the thymus for three females. In the absence of any associated changes or any effect on reproduction these effects were considered not to represent an adverse health effect.

Regarding embryotoxic/teratogenic effects, of the litters born, litter size at birth and subsequently on Day 1 and 4 post partum were comparable to controls. Offspring bodyweight gain and litter weights at birth and subsequently on Day 1 and 4 post partum were comparable to controls.

Litter observations. No clinically observable signs of toxicity were detected for offspring from all treatment groups.

In view of the longer administration period the ‘No Observed Effect Level’ (NOEL) for reproductive (developmental) toxicity was considered to be 500 mg/kg/day in rat.

Justification for classification or non-classification

There are conclusive and sufficient data for classification of the test substance with regard to reproduction toxicity.

The test substance is not classified for this endpoint in accordance to the CLP Regulation (EC) No 1272/2008.