(3S,4aS,8aS)-N-tert-butyldecahydro-3-isoquinolinecarboxamide

Endpoint summary

Description of key information

A NOEL of 150 mg/kg bw/d is identified in a 28-day rat study based on mortality, signs of toxicity, changes in haematological and clinical chemistry parameters and liver pathology at the highest dose level of 600 mg/kg bw/d.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

A 28-day repeated oral administration study of sub-acute toxicity in the rat was conducted with PTH-decahydroamide. The main study dose levels were set using data from 5-day preliminary toxicity investigation. Range-finding results indicated suitable dose levels were 0, 30, 150 and 600 mg/kg bw/d. The study design was based on the test guidelines set out in EEC Directive 92/69/EEC, B.7 subacute toxicity - oral, 1992 and OECD Test Method No. 407, Repeated Dose Oral Toxicity - Rodent, 1981.

PTH-Decaydroamide was administered daily by oral gavage to groups of five male and five female Wistar rats for four weeks. Various parameters - clinical signs, bodyweights, food consumption, ophthalmoscopy, clinical pathology, haematology, organ weights, terminal necropsy and subsequent histopathology - were investigated in accordance with the test methods.

Formulations of PTH-decahydroamide were confirmed by analysis to be accurate, stable and homogeneous.

There were no teatment-related findings of any toxicological significance in the animals dosed at 30 or 150 mg/kg bw/d.

In the 600 mg/kg bw/d group, five of the rats died (on treatment days 6, 7 or 14) and the remaining five were terminated on welfare grounds on Day 18. The marked signs of toxicity, observed ante-mortem, included clinical signs of convulsive movements, abnormal posture, abnormal gait, recumbency and laboured respiration. Decreased red blood cell counts and reduced haemoglobin content were recorded in the males and females; decreased mean corpuscular haemoglobin concentration and an increased mean corpuscular volume were noted among the males only. Total protein and albumin levels were reduced for males and females and the inorganic phosphate levels were increased in both sexes. Increased liver enzyme activities were recorded for one male rat. Necropsy of the high dose rats revealed vacuolation or centrilobular necrosis in the liver of four males and one female.

Based on the results of the repeated administration of PTH-decahydroamide at 30, 150 or 600 mg/kg bw/d, the no observed effect level (NOEL) was 150 mg/kg bw/d.

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: other; digestive: liver

Justification for classification or non-classification

The marked effects observed at 600 mg/kg bw/day including mortality, functional disturbances and toxicologically significant effects (e.g. convulsions) indicate consideration of the risk phrase R48 "Danger of serious damage to health by prolonged exposure". However, this is only appropriate where effects are observed in rats following oral administration at 50 mg/kg bw/day in a repeated administration study or at levels circa three-fold higher in a subacute study. Since the effects were not apparent at 150 mg/kg bw/day and only observed at the next higher dose level, classification as R48 is not considered appropriate for PTH-decahydroamide.

Translation of the DSD classification to Regulation 1272/2000 (GHS) classification can be applied directly to R48/X decisions and consequently no classification for STOT-RE is required.