1,4-Benzenediamine, N,N'-mixed Ph and tolyl derivs.

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
Two separate studies on the oral administration of different radio-labelled main constituents of 1,4-benzenediamine, N,N’-mixed Ph and tolyl derivs. to rats are available. Both studies have shown that the radioactivity is excreted primarily in the feces (≥75%).  In total, 30-35% of the dosed amount enters into the gastro-intestinal tract via the biliary route. Less that 2% was excreted via the urine. About 22-24% of the ingested radioactivity was not yet excreted by the end of the experimental observation period.
Short description of key information on absorption rate: 
Comparison of excreted radioactivity following administration of a 14C-radiolabeled main constituents of 1,4-benzenediamine, N,N’-mixed Ph and tolyl derivs. following dermal application versus intravenous dosing indicated that 60% of the dermally-applied test chemical was absorbed during the 7-day study. The bulk (> 95%) of the absorbed test chemical was excreted via the feces.

Key value for chemical safety assessment

Absorption rate - dermal (%):

60

Additional information

Three reliable studies (Jeffcoat, 1998a, Jeffcoat, 1998b and Hui, 1997) are available on the toxicokinetic behaviour of the main constituents of 1,4-benzenediamine, N,N’-mixed Ph and tolyl derivs. upon administration to rats. From a practical point of view it was not feasible to use the multi-constituent substance as such as the testing material for these studies since radio-labelling is required to enable the tracing of the substances in the different excretion pathways. However, due to the great structural similarity between the 3 main constituents of 1,4-benzenediamine, N,N’-mixed Ph and tolyl derivs. it can be assumed that the main constituents will all have comparable toxicokinetic behaviour. This reasoning is confirmed by the results of the two available studies assessing the excretion pathways of orally administered test substances, which are in good agreement with each other.

Discussion on bioaccumulation potential result:

Two studies (Jeffcoat, 1998a and Jeffcoat, 1998b) were performed to assess the routes of excretion of two main constituents of 1,4-benzenediamine, N,N’-mixed Ph and tolyl derivs. – namely N,N’-bis(2-methylphenyl)benzene-1,4-diamine and N-(2-methylphenyl)-N’-phenylbenzene-1,4-diamine – upon oral administration of the 14C-radiolabeled test substances to Sprague-Dawley rats. Rats received a single dose of this radiolabeled component as a solution in corn oil via oral gavage.

Urine, fecal and bile samples were collected over a period of 48 hours following oral dosing to bile duct-cannulated animals. Results showed that 76 to 78% of the administered radioactivity was excreted within this 48 hour observation period. The main part, about 75% of the dosed radioactivity is excreted in the feces. Urinary excretion consisted of metabolites and accounted for maximally 2.5% of the total amount of radioactivity.

Analysis of the biliary fraction showed that 30-35% of the administered radioactivity entered into the gastro-intestinal tract via the biliary route. HPLC analysis of bile demonstrated that > 95% of the metabolites excreted by this route exhibited greater polarity than the parent compound, suggesting metabolic formation of oxidation and conjugation products of these components.

Discussion on absorption rate:

Radio-labelled [14C] N,N’-bis(2-methylphenyl)benzene-1,4-diamine, one of the main constituents of 1,4-benzenediamine, N,N’-mixed Ph and tolyl derivs. was dermally and intravenously administered to female rats. (Hui, 1997) The intravenous administration served as benchmark for 100% absorption of test material. Collection of urinary and fecal excretion over a period of 168h after dosing demonstrated 70% recovery of radioactivity following intravenous dosing whereas a recovery of 88% of dermally-applied test compound was achieved. The latter included skin site rinses, tape stripping and skin digestion samples to recover unabsorbed topically-applied residues. Comparison of excreted radioactivity from groups of rats following dermal application versus intravenous dosing indicated 60% of the dermally-applied test chemical was absorbed during the 7-day study. The bulk (>95%) of absorbed test chemical was excreted via the feces. Percutaneous uptake of chemicals by rats is known to be substantially higher than that for primates and humans.