BMS 233110-01

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

Assessment of toxicokinetic behaviour

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Materials and methods

Test guideline

Qualifier:

no guideline followed

Version / remarks:

A qualitative assessment of the toxicokinetics of the substance has been performed, based upon its physical properties and the results of toxicological studies.

Principles of method if other than guideline:

Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance Version 2.0 November 2014

GLP compliance:

no

Results and discussion

Any other information on results incl. tables

Acute oral toxicity- LD50 >200 and <2000mg/kg bw: No adverse effects were observed at the highest dose.

Acute dermal toxicity- discriminating dose 2000 mg/kg bw. No deaths or any other adverse effects were observed at the highest dose.

28-day oral repeat dose toxicity: All Surviving but effects seen in the highest dose 165 mg/kg/day and intermediate dose of 55 mg/kg/day in both male and females.

Female/Males treated with 0, 5, 15 or 50 mg/kg. NOAEL determined to be 15 mg/kg bw/day in both male and female. Reproductive NOAEL was 50mg/kg.

Applicant's summary and conclusion

Conclusions:

Absorption
Inhalation: It is a non-volatile powder with a limited proportion of particles in the respirable range. The physical properties of the test substance suggest there is limited potential for inhalation of the dust of this material with the majority of particle size >300um. There is relatively high-water solubility and molecular weight of 299 and a low vapour pressure supporting the low potential for uptake via the inhalation route.The octanol/water partition coefficient indicates that if the substance was bioavailable, it would have limited potential to bioaccumulate.

Dermal: The lack of systemic toxicity in the acute dermal toxicity study suggests that, when applied dermally, the test substance was not absorbed. This is also supported by the low partitiion co-efficient which would indicate little risk of accumuluation in the fatty tissue.

Oral:
The clinical effects seen in the acute oral toxicity study indicated that the substance was absorbed by the oral route. Clinical signs such hunched posture, pilo-erection, lethargy and decreased respiration indicate that the substance has crossed the blood: brain barrier. Oral absorption, and subsequent distribution, were also demonstrated in the 28-day sub-acute study, with similar clinical signs at the high dose to those of the acute toxicity study in addition to decreased forelimb grip strength and slightly reduced motor activity in the intermediate and high dose groups. Increased liver weights seen in animals from the high dose group with microscopically, slight to moderate centrilobular hepatocytic hypertrophy seen in most animals of the high and intermediate dosage groups. Increased adrenal weights was a also present in male and female animals in the intermediate to high dose groups.

Metabolism:
Findings from the acute and subacute studies are considered to be adaptive in nature, indicating metabolism of the test substance. In addition metabolism was also seen in the in-vitro genotoxicity studies in the presence of S9 fraction.

Excretion: No specific excretion studies have been conducted however the physical characteristics (MW, water solubility and partition coefficient) and would suggest that the substance is excreted by the kidneys. The substance is non-volatile so elimination via the lungs, in expired air, would not be expected.