1H-Pyrazolo[3,4-c]pyridine-3-carboxylic acid, 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-, ethyl ester

Basic toxicokinetics

Administrative data

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 June 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 requirements of Annex VIII (8.8).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Objective of study:

toxicokinetics

Test guideline

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 assessment 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

Test material

Test material information

Constituent 1

Reference substance name:

BMS-589152-01

IUPAC Name:

BMS-589152-01

Test material form:

solid: particulate/powder

Details on test material:

Identification: BMS-589152-01
Physical state/Appearance: Tan-colored powder
Batch: 2G72631N
Purity: 99.5%
Expiry date: 19 June 2014
Storage conditions: Room temperature in the dark
Intended use/Application: Chemical intermediate

Specific details on test material used for the study:

Substance name: BMS-589152-01
CAS Number: 536759-91-8
Batch number: AAG8999N (varies by study)
Lot No. : 15600T0001 (varies by study)
Appearance: Beige powder
Purity: 100.1% w/w (varies by study)

Results and discussion

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

TOXICOKINETIC BEHAVIOUR

BMS-589152-01 composed, as listed in Section 3, is a beige colored powder with physico-chemical properties which imply the risk of particle inhalation of BMS-589152-01 to be minimal. Furthermore, the supporting toxicological information suggests any inadvertent inhalation is unlikely to lead to an elevation in systemic toxicity. BMS-589152-01 was identified to be a mild ocular irritant and also to elicit a “positive” response in an Ames assay albeit supporting “negative” genotoxicity results would largely negate this isolated latter study outcome. The results from a single dermal dose toxicity study indicated only limited absorption might occur via the dermis. 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 1000 mg/kg/day and only limited effects on maternal or developmental toxicity.

Absorption

The general physico-chemical properties of BMS-589152-01 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 incorporating a 14-Day Recovery Period did not provide any evidence to suggest any significant levels of absorption from the gut.

Distribution

Information relating to the distribution of BMS-589152-01 is limited; however, the chemical characteristics and findings from the Oral (Gavage) Combined Repeated Dose Toxicity Study with Reproduction/Developmental Toxicity Screening Test incorporating a 14-Day Recovery Period implies systemic distribution would most likely occur via the serum following oral administration and gastric

absorption. Furthermore while the properties (i.e. poor water solubility) of BMS-589152-01 suggest a potential to accumulate in adipose tissue, none of the studies conducted showed any evidence of this.

Metabolism

BMS-589152-01 was identified in an Ames Assay to exert a clear mutagenic action (with or without metabolic activation). However, this indication of mutagenicity was an isolated finding and the lack of

any significant difference in response with/without S9 metabolising system suggests that the test item may not undergo hepatic transformation. Furthermore the results from the remaining 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 incorporating a 14-Day Recovery Period.

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.

Applicant's summary and conclusion

Conclusions:

The available information suggests that any absorption of BMS-589152-01 from the gastrointestinal 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-589152-01 also indicate absorption via inhalation of test item to be unlikely. Any absorbed test material is unlikely to undergo hepatic transformation and clearance is therefore expected to be via the bile with subsequent excretion in the faeces.

Executive summary:

The absorption, distribution, metabolism and excretion of BMS-589152-01 have been predicted based upon the physico-chemical properties and supporting toxicological information provided for this test material.

Based on the available data provided it is reasonable to conclude absorption of BMS-589152-01 following oral ingestion would occur in the gastrointestinal tract and that absorption is likely to be limited due to the physico-chemical characteristics of the test item. These characteristics together with the low volatility of BMS-589152-01 also indicate absorption via inhalation of test item to be unlikely. Any absorbed material is unlikely to undergo hepatic transformation and clearance is therefore expected to be via the bile with subsequent excretion in the faeces.