Registration Dossier

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other: In accordance with REACH Annex VIII (8.8) an assessment of toxicokinetic behavior has been conducted to the extent that can be derived from the relevant available information.
Adequacy of study:
key study
Study period:
The assessment was conducted in November 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Relevant studies were reviewed by a qualified toxicologist with a view to fulfilling the requ irements of Annex VIII (8.8).
Qualifier:
no guideline required
Principles of method if other than guideline:
In accordance with REACH Annex VIII (8.8) an assessment of toxicokinetic behaviour has been
conducted to the extent that can be derived from the relevant available information. The assessmen
t is based on the Guidance on information requirements and chemical safety assessment R.7c:
Endpoint specific guidance (ECHA, November 2014)
GLP compliance:
no
Remarks:
Not relevant for assessment

TOXICOKINETIC BEHAVIOUR

BMS-589172-01 composed, as listed is a white coloured powder. The physico-chemical properties imply potential risk of particle inhalation of BMS-589152-01 with approbatory 15% of the particle size <10µm. However, the substance has very low water solubility (11.2 µg/L), vapour pressure and a large molecular weight (577.03) therefore limited inhalation of the substance would be expected. The octanol/water partition co-efficient indicate that is the substance may be bioavailable that there this potential to bioaccumulate however the supporting toxicological information suggests any inadvertent inhalation is unlikely to lead to an elevation in systemic toxicity. BMS-589172-01 showed no irritant or corrosive effects to the eyes and skin and was negative in a skin sensitisation study. Acute oral toxicity results showed the LD50 to be >2000 mg/kg body weight and an Oral (Gavage) Combined Repeated Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test incorporating a 14-Day Recovery Period in the rat did not provide any convincing evidence of systemic toxicity up to a dose level of 400 mg/kg/day and only limited effects on maternal or developmental toxicity. The results from a single dermal dose toxicity study indicated limited absorption might occur via the dermis.

 

Absorption

The general physico-chemical properties of BMS-589172-01 including the relatively high molecular weight and the low water solubility would be factors that would inhibit significant absorption. Supporting results from the Oral (Gavage) Combined Repeated Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test did provided some evidence from the gut based on effects seen in the kidney and pitutary however it is not expected to be significant levels of absorption from the gut.

 

Distribution

Information relating to the distribution of BMS-589172-01 is limited; however, the chemical characteristics and findings from the Oral (Gavage) Combined Repeated Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test implies systemic distribution would most likely occur via the serum following oral administration and gastric absorption. Evidence of distribution was detected in the kidneys and thyroid but not considered dose dependent. Furthermore, while the properties (i.e. poor water solubility and log kow of 4.75) of BMS-589172-01 suggest a potential to accumulate in adipose tissue, none of the studies conducted showed any evidence of this.

Metabolism

BMS-589172-01 was identified to show no genotoxic effects with or without metabolic activation as both in vitro and in vivo genotoxicity studies were all negative. Additionally, there was no evidence of test item or metabolite influenced hepatic metabolism from the Oral (Gavage) Combined Repeated Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test.

Excretion

The most plausible route of clearance for relatively low water-soluble chemicals would be by transfer of test material and/or metabolites from the plasma to the bile through the hepatocytes leading to clearance of any metabolic breakdown products primarily via the faeces. However changes in the urea levels indication that excretion via the kidneys may also occur.

Conclusions:
The available information suggests that any absorption of BMS-589172-01 from the gastrointesti-nal tract following oral ingestion is likely to be limited due to the test items physico-chemical characteristics.
These characteristics together with the low volatility of BMS-589172-01 also indicate absorption via inhalation of test item to be unlikely and dermal absorption is not expected to be limited
Executive summary:

The absorption, distribution, metabolism and excretion of BMS-589172-01 have been predicted based upon the physico-chemical properties and supporting toxicological information provided for this test material.

Based on the available data is is reasonable to conclude that any absorption of BMS-589172-01 from the gastrointesti-nal tract following oral ingestion is likely to be limited due to the test items physico-chemical characteristics. These characteristics together with the low volatility of BMS-589172-01 also indicate absorption via inhalation of test item to be unlikely and dermal absorption is not expected to be limited

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
50

Additional information

Based upon the results of repeat dose toxicity testing and the physical properties of the substance, it can be predicted that absorption and distribution can be expected by the oral routes thereby assuming 100%. Uptake is unlikely by the dermal route, a default value of 10% is assigned based upon the physical properties of the substance.