Registration Dossier
Registration Dossier
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EC number: 201-663-0 | CAS number: 86-30-6
Endpoint summary
Administrative data
Link to relevant study record(s)
Description of key information
Key value for chemical safety assessment
Additional information
The following statement on the toxicokinetics of nitrosodiphenylamine are based on the available data. According to the REACH guidance document R7.C (2014), information on absorption, distribution, metabolism and excretion may be deduced also from the physical-chemical properties, including:
-Molecular weight: 198,22 g/mol
-Water solubility: 35 mg/L
-Partition coefficient Log Kow: 3.13
ABSORPTION
The physical-chemical characteristics of Nitrosodiphenylamine and the molecular mass (198 g/mol) are in the range suggestive of absorption after oral and dermal exposure (with a molecular weight below 500, and a log Kow between -1 and 4, and moderately water solubility). This assumption of an oral absorption is confirmed by the acute oral toxicity study in which mortality was observed at the dose of 2000 mg/kg bw. And the hypothesis of good dermal absorption is confirmed with the skin sensitization study (which concluded that the substance is skin sensitizer).
DISTRIBUTION
As a small molecule a wide distribution of nitrosodiphenylamine is expected.
METABOLISM
The metabolism of nitrosodiphenylamine was investigated in phenobarbital-induced mouse liver microsomes and some of the metabolites were also tested. One metabolite was identified as diphenylamine whereas the others were identified as a ring-hydroxylated derivative of diphenylamine and its corresponding quinoneimine (Appel 1987, see section 7.1.1).
Formation of nitrite during the metabolism of N-nitrosamines had been showed by Appel at al. (1979, 1980). It was proposed that nitrite formation occurs through Cyt. P-450 which catalyses a one-electron reduction of the nitrosamine to from the secondary amine and NO. This suggests that formation of nitrite represents an alternative pathway to the generation of an alkylating intermediate and may represent a detoxification rather than an activation.
One major metabolite found in the urine after in vivo administration of nitrosodiphenylamine to rats was nitrate. Nitrite and diphenylamine were found in minor amounts. In a somewhat higher concentration, a mono-hydroxylated diphenylamine was detected. From these results, it was concluded that nitrosodiphenylamine was denitrosated to NO and diphenylamine in the organism and that NO was ten converted to nitrite and nitrate (Appel et al. 1984, see section 7.1.1). This assumption is confirmed in the OECD 422 study: nitrites were found in the urines of rat exposed to nitrosodiphenylamine after gavage exposure of 28 days (see section 7.5.1).
EXCRETION
Nitrosodiphenylamine is probably excreted in the urine, because it is a water-soluble substance with a low molecular weight (below 300); and generally, they are conjugated metabolites from Phase II biotransformation. This assumption is confirmed with the OECD 422 study, in which, nitrites, metabolites of nitrosodiphenylamine were found in the urines (see section 7.5.1).
Appel KE et al. (1979): Binding of nitrosamines to cytochrome P-450 of liver microsomes. Chem.Biol.Interact 28:17-33.
Appel KE et al. (1980): Denitrosation of N-nitrosomorpholine by liver microsomes: possible role of cytochrome P-450. Cancer Lett 9: 13-20.
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