Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Toxicokinetics assessment as a written paper.

Key value for chemical safety assessment

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

Additional information

The results of basic toxicity testing give no reason to anticipate unusual characteristics with regards to the toxicokinetics of the substance. The data indicate that whilst there is the possibility of potential dermal absorption, there are no predicted effects noted from this route. Minor systemic effects associated with absorption potential have been observed following oral ingestion; however, these appear to be adaptive and are negated, following cessation. Bioaccumulation and storage of the material in fatty tissue (adipose cells) of the substance can most probably be excluded due to the predictive assessment of bioaccumulation behaviour using QSAR tools and the known experimental values of the parent substance, diphenylamine. Based on the results of all mutagenicity assays and assessment of relevant literature, a metabolisation towards genotoxic structures can be ruled out. It is proposed that following ingestion, the substance will be hydrolysed in the stomach to more soluble forms, followed by further metabolism via oxidation using standard metabolic mechanisms to carbon dioxide and soluble forms for subsequent elimination. 

 

Taking the results of the sub-acute oral toxicity and developmental toxicity study into account, the substance appears to be absorbed from the gastrointestinal tract as evidenced by the liver and adrenal effects in the higher dose groups. This effect is anticipated, as it is known that the parent substance, diphenylamine is well absorbed from the gastrointestinal tract in man and in several animal species including rat, rabbit, dog and cow. Results for diphenylamine indicate that up to 3 % of the parent compound and approximately 80-90 % of the dose is excreted as 12 different metabolites, which include 4-hydroxydiphenylamine, 4,4’- 2 hydroxydiphenylamine and sulfate and glucuronide conjugates of these hydroxylated metabolites. In addition, indophenol has been identified as metabolite. From these results it can be assumed that a similar mechanism to that employed for diphenylamine is utilised in elimination processes for the substituted diphenylamine group. The substance is proposed to be readily metabolized and excreted and that accumulation seems to be unlikely. There are no data on dermal route of administration or exposure by inhalation. An absorption rate of 100% for the oral route is proposed to be taken for risk characterisation purposes, whereas dermal and inhalation absorption is assumed to be 100% (defaults). The assumption of a default dermal absorption value of 100% is supported by the effects noted in the irritation studies. Due to the potential for absorption and the lack of experimental data, a default absorption value of 100% is also assumed for inhalative uptake.