Benzenamine, N-phenyl-, reaction products with 2,4,4-trimethylpentene

Endpoint summary

Description of key information

The UVCB substance is a viscous liquid of mixed branched alkylated diphenylamines. Systemic uptake after ingestion is shown by effects on liver upon repeated gavage dosing with a solution in corn oil. This is consistent with a molecular weight of the components of the UVCB substance of 225 - 520 g/mol and calculated log Pow values of >4.  All components offer functional group for xenobiotic metabolism and are not susceptible to stomach-acid catalysed hydrolysis.  If sterically unhindered, the secondary amine may be conjugated. Also branched side chains may become oxidated.  The technical function of the substance is to be an antioxidant in oil systems. The rate of metabolism and elimination will depend on the type of alkylation of the individual component.  Emulgation via bile acids is expected to facilitate oral uptake compared to the dermal route of exposure. It is expected that gavage dosing in corn oil will result in higher systemic peak exposures compared to dermal exposure. Modelling of skin permeability based on Fitzpatrick et al. (Chemosphere 55 (2004) 1309–1314), the components are slightly to marginally permeable. The mixture is non volatile. 
The substance causes an enlargement of liver that is accompanied by changes in histopathology and clinical chemistry. Some of the changes in clinical chemistry may be attributed to induction of xenobiotic metabolism in liver. An exemple is the increased rate of conjugation of bile acids and bilirubin. A secondary enlargement of thyroid is a known side effects in rats as xenobiotic enzymes also conjugate thyroid hormones.
Overall, the substance may only accumulate if the capacity for xenobiotic metabolism is in an overload situation. 

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

The multiconstituent substance consists of components sharing a diphenylamine core and differing in the number and location of branched C4 and C8 alkyl substitutents. The table below gives information on the substance itself and and on the branched nonyl-analogue.

For a figure with the representative components, it is referred to the robust study summary (7.1.1 Basic toxicokinetics), as it is technically not possible to show a picture in the endpoint summary.

Reaction products of benzeneamine, N-phenyl with nonene (branched)		Reaction products of Benzenamine, N-phenyl with 2,4,4-trimethylpentene
EC: 253-249-4		EC: 270-128-1
R = highly branched nonyl- (C9H19)		R = tert-butyl or tert. octyl
Sum of mono-nonyl-diphenylamine isomers	31.1%	Tert.-butyl-diphenylamine	14.3%
	MW=295		MW=225
	C21H29N		C16H19N
Sum of dialkyl-diphenylamine isomers	62.4%	Group A: sum of p- and o-substituted mono-tert. octyl or di-tert.butyl isomers	35.3%
	MW=421		MW=281
	C30H47N		C20H27N
		Group B: sum of p- and o-substituted tert.-butyl-tert. octyl or di-tert.butyl-mono-tert. octyl isomers (may be either di- or trialkylated)	32.0%
			MW=338
			C24H35N
		Group C: p-di-tetramethylbutyl-diphenylenamine and isomers of p-or o-substituted tert-octyl isomers	17.3%
			MW=394
	-		C28H43N
Sum of tri-alkyl diphenylamine isomers	2.2%	Sum of tri-alkyl diphenylamine isomers	0.3% + trialyl isomers of group B
	MW= 547		MW =449.77, or 505.88 or 337.55
	C39H66N
Sum of other mono- and poly-alkyl-diphe-nylamine isomers	4.3%

With respect to molecular weight, the lipophilic character and the high log P_OW, it is expected that the UVCB substance is absorbed in the gastro-intestinal tract after oral administration. Indeed, effects on liver have been observed upon subacute dosing of fairly high doses (125 and 300 mg/kg bw). In another studies, non-adverse effects on liver were seen at 25 mg/kg bw and a LOAEL of 75 mg/kg bw was found. For the analogue substance extra investigations regarding potential methaemoglobin formation were included in the 90 -day study. Since the rate of Heinz bodies was not increased up to the limit dose (1000 mg/kg bw), the alkylated diphenylamines are considered to be inactive regarding methaemoglobin formation.