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Administrative data

Description of key information

OECD 422 (WIL Research Europe), NOEAL = 1000 mg/kg (systemic and local)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

A combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test of Hexane, 1,6-diisocyanato, homopolymer, N-butyl-1-butanamine-blocked was conducted in rats by oral gavage according to OECD 422 guideline and GLP (WIL Research Europe, 2013).

Rationale for dose levels

Based on the results of the 14-Day dose range finding study, the dose levels for this combined 28-day oral gavage study with reproduction/developmental toxicity screening test were 100, 300 and 1000 mg/kg bw/day.

 

Study outline

After acclimatization, four groups of ten male and ten female Wistar Han rats were exposed by oral gavage to the test substance at 0, 100, 300 and 1000 mg/kg bw/day. Males were exposed for 29 days, i.e. 2 weeks prior to mating, during mating, and up to termination. Females were exposed for 42-56 days, i.e. during 2 weeks prior to mating, during mating, duringpost-coitum, and during at least 4 days of lactation.

 

Evaluated parameters

The following observations and examinations were evaluated: mortality / viability, clinical signs (daily), functional observations and locomotor activity (males: Week 4; females: end of lactation),  body weight and food consumption (at least at weekly intervals), clinical pathology (males: Week 4; females: end of lactation), macroscopy at termination, organ weights and histopathology on a selection of tissues, and reproduction/developmental parameters, consisting of mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights and macroscopy).Formulations were analyzed once during the study to assess accuracy, homogeneity and stability.

Results/discussion

Accuracy, homogeneity and stability of formulations were demonstrated by analyses.

Parental results:

No parental toxicity was observed up to the highest dose level tested (1000mg/kg bw/day).

 

Reproductive results:

No reproduction toxicity was observed up to the highest dose level tested (1000mg/kg bw/day).

 

Developmental results:

No developmental toxicity was observed up to the highest dose level tested (1000mg/kg bw/day).

 

Conclusion

 

Treatment with Hexane, 1,6-diisocyanato, homopolymer, N-butyl-1-butanamine-blocked by oral gavage in male and female Wistar Han rats at dose levels of 100, 300 and 1000 mg/kg body weight/day revealed no parental, developmental or reproductive toxicity up to 1000 mg/kg body weight/day.

 

Based on these results, a parental, reproduction and developmental No Observed Adverse Effect Level (NOAEL) of at least 1000 mg/kg bw/day was determined.

Range-Finder

In a GLP compliant 14-day dose range finding study (WIL Research Europe B.V. 2013) Hexane, 1,6-diisocyanato, homopolymer, N-butyl-1 -butanamine blockedwas administered by daily oral gavage to Wistar Han rat (4 males and 4 females per dose group) at levels of 0 (vehicle exposed), 300 and 1000 mg/kg bw/day. The test substance was dissolved in propylene-glycol.Formulation analysis showed that the formulations were prepared accurately, were homogenous, and were stable for at least 5 hours. No mortality occurred during the study period. No clinical signs were noted during the observation period. There were no treatment related effects on body weights or body weight gains up to 1000 mg/kg bw/day. Females at 300 mg/kg bw/day had slightly lower absolute body weights through the entire treatment period. This was attributable to lower weights for these animals compared to controls at the initiation of the study. Food consumption before or after allowance for body weight was similar between treated and control animals. There were no toxicologically relevant effects on haematology parameters noted up to 1000 mg/kg bw/day. Females at 300 and 1000 mg/kg bw/day had lower prothrombin time (PT) and white blood cells (WBC) and higher eosinophil counts. These were not considered toxicologically relevant since they were not accompanied by any corroborative signs of toxicity, the differences from controls was in some cases slight, and/or occurred in the absence of a dose-related distribution. There were no toxicologically relevant effects on clinical biochemistry parameters noted up to 1000 mg/kg bw/day. Total protein and calcium were slightly lower for males at 1000 mg/ kg bw/day. However, the differences from controls were only slight and these were not considered to be toxicologically relevant. Organ weights and organ to body weight ratios of treated animals were similar to those of control animals. There were no macroscopic findings noted for any animal. Based on the results of this range finding study, dose levels of 100, 300 and 1000 mg/kg bw/day were chosen for the main study.

Justification for classification or non-classification

Based on the available data, the test substance is not classified with regard to repeated dose toxicity according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP), respectively.