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

Endpoint summary

Description of key information

NOAEL for systemic toxicity was established at 350mg/kg bw in an OECD 422 study.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

350 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

DISCUSSION

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.

Justification for classification or non-classification

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

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