Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: 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:
Not applicable
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Relevant studies were reviewed with a view to fulfilling the requirements of Annex VIII (8.8.1).

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 followed
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, June 2017)
GLP compliance:
no

Results and discussion

Any other information on results incl. tables

Tokicokinetic Behaviour:

The substance is an amber colored viscous liquid with general irritant characteristics implying this test material can be hazardous if vapor inhalation was to occur. Additional information verified the test material would cause skin and eye irritation but not skin sensitization. Single dose oral gavage and topical dermal exposure studies indicated only a low risk of systemic toxicity. Evidence from an oral (gavage) combined repeat dose toxicity study with reproduction/developmental toxicity screening test in the rat (OECD 422) incorporating a post treatment recovery phase provided evidence of lower dose tolerance (systemic/reproductive NOAEL 75 mg/kg bw/day) primarily due to gastric intestinal changes.

Absorption:

Supporting information from the repeated dose “OECD 422” study provided evidence which implied the gastro-intestinal tract to be the primary route of test item or metabolite toxicity following oral administration. Results from the single dose exposure studies and the OECD 422 at the dose levels investigated established the direct risk of systemic toxicity to be low. Neither was there any evidence of absorption via the skin. The low water solubility of the test item is likely to inhibit absorption from the gastro-intestinal tract but does exclude simple diffusion processes.

Distribution:

A verifiable route of systemic distribution was not determined although it may be inferred from the repeated dose systemic toxicity/reproductive screening OECD 422 study that distribution would involve the normal circulatory processes.

Metabolism:

Results from the rodent toxicity/reproductive screening OECD 422 study provided no evidence of test item influenced hepatic metabolism. The results of the genotoxicity assay also proved negative, which suggests the test material genotoxic characteristics remained unchanged in the presence or absence of metabolic activation (S9-mix).

Excretion:

There is no evidence to indicate the route of excretion however, as poor water-soluble products are not favourable for urinary excretion it is reasonable to assume biliary excretion to be the most probable primary route for clearance of this material with any non-absorbed test item excreted in the faeces.

Applicant's summary and conclusion

Conclusions:
The available information suggests that absorption of the test substance from the gastrointestinal tract may take place but may be inhibited by the general physico-chemical characteristics of the test substance. However, once absorbed, the test substance would in all probability be distributed in the serum where it
would be transported to the liver for potential hepatic transformation and clearance via the bile. Excretion of any non-absorbed test material would be in the faeces. There was no evidence to suggest that the test substance may be metabolised, however no studies have been conducted to identify the presence of metabolites.
Executive summary:

The absorption, distribution, metabolism and excretion of X-19574 - for Amines, C16-18 and C18- unsatd. alkyl, O,O-di-Bu phosphorothioates (CAS RN 97808-07-6) have been predicted based on the physico-chemical properties and supporting toxicological information presented for this material. The information provided supports the view that absorption of the test substance in all likelihood would take place via the gastrointestinal tract but that the general physico-chemical properties including irritant characteristics may limit absorption from the gut. The chemical characteristics of the test material would also greatly reduce the risk of systemic aborption via vapor inhalation although inhaled vapor’s could lead to inflammation of the respiratory tract. A skin sensitization proved negative for sensitisation. Once absorbed, the substance would in all probability be distributed in the circulatory system via serum with any absorbed material likely to undergo hepatic transformation and clearance expected to be in the bile with subsequent excretion of any unabsorbed test material and/or metabolites in the faeces. None of information provided indicated any evidence to suggest that the test substance may be metabolised, however no studies have been conducted to identify the presence of metabolites.