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Registration Dossier
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EC number: 429-270-1 | CAS number: 136210-30-5
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The toxicokinetic was assessed considering physico-chemical properties and toxicological data from aspartic acid, N,N'-[methylenebis(2-methyl-4,1-cyclohexanediyl)]bis-, 1,1',4,4'-tetraethyl ester which is a structural analogue to aspartic acid, N,N'-(methylenedi-4,1-cyclohexanediyl)bis-, 1,1',4,4'-tetraethyl ester. Both substances are diethyl esters of aspartic acid linked to a dicyclohexylmethyldiamine moiety. The difference between these two substances is merely the presence of two methyl groups connected to the cyclohexane rings. This structural analogy was confirmed by the Member State responsible for the notification of both substances under the NONS regulation. The Member State decided that test results obtained for one substance can be transferred to the other substance and that testing of both substances is usually not required. This decision is in accordance with the grouping of substances and read-across approach in Annex XI, 1.5 of the REACH Regulation.
The substance herein named as ZWI 579 is identical to aspartic acid, N,N'-[methylenebis(2-methyl-4,1-cyclohexanediyl)]bis-,1,1',4,4'-tetraethyl ester.
Toxikokinetic-assessment:
"The following remarks on the toxicokinetic evaluation of ZWI 579 are based on the studies performed within the process of registration of a new chemical under the Chemicals Act. Experimental studies on toxicokinetics were not performed.
The fact that the water solubility and n-octanol/water partition coefficient log Pow could not be determined experimentally limits the possibility to estimate the absorption and elimination with regard to these parameters. Nevertheless limited absorption via oral route is assumed based on the calculated log Pow of 6,4 in combination with the relatively large mol mass of 582.78. The results of the acute oral toxicity study in male and female rats do not contradict this assumption: the LD50 is > 2000 mg/kg bw after single oral dose. There were no signs of toxicity and therefore there was no evidence of systemic availability of toxicological relevant amounts of ZWI 579 (E. Bomhard, Bayer AG, report 19779, 1990).
Under normal conditions ZWI 579 is a liquid with a low vapour pressure. Therefore an inhalation exposure via vapour is not assumed. The calculated saturated vapour concentration is 0.382 mg/m³ at 20° C. The results of the available study on acute inhalation toxicity with exposure of an aerosol give not evidence of a systemic availability of toxicological relevant amounts (J. Pauluhn, Bayer AG, report 28049, 1998a). No mortality is reported for the highest concentration tested (4224 mg/m³). The major signs observed (unregular breathing pattern, bristled and ungroomed hair-coat, nostrils reddened and hypothermia), which were observed only at 4224 mg/m³, should be interpreted as local irritation.
The results of the subacute study (E. Bomhard, Bayer AG, report 21908, 1992b) in which up to 1000 mg/kg bw/day was administered via gavage to rats, give no evidence of a potential for accumulation, because no adverse effects were observed including the highest dose groups.
The results of the acute dermal study (E. Bomhard, Bayer AG, report 21662, 1992a) with male and female rats demonstrate that after single dermal exposure to 2000 mg/kg bw no toxicological relevant amounts are absorbed. Despite local irritation no systemic toxicity was observed.
Based on the results of the genotoxicity tests in vivo and in vitro (Mikronucleus Assay, Ames-Test, IVC-Test) (B. Herbold, Bayer AG, report 21574, 1992, Bayer AG, report 20390, 1991, Bayer AG, report 32278, 2002) it could be concluded, that DNA-reactive metabolites most probably will not be generated in mammalian organisms due to hepatic biotransformation."
Subsequent entry: In a two-generation reproductive study with aspartic acid, N,N'-[methylenebis(2-methyl-4,1-cyclohexanediyl)]bis-,1,1',4,4'-tetraethyl ester (Eiben, BSP AG, report AT05695, 2009) in which doses of 40, 200 and 1000 mg/kg bw/day were administered by gavage to rats, histopathological effects in the kidneys of F0 males and indications of changes in kidney function for F0 females and F1 males/ females were observed, all in the highest dose group. This supports resorption for this route of exposure and indicates renal excretion.
Based on the known physico-chemical properties and the available toxicologic studies a reliable assessment of the toxicokinetic and biotransformational properties of the structural analogue aspartic acid, N,N'-[methylenebis(2-methyl-4,1-cyclohexanediyl)]bis-,1,1',4,4'-tetraethyl ester could be made. Moreover, according to the so far available toxicological studies there is no evidence for substance-relating critical adverse effects. Thus, the conducting of an in vivo toxicokinetic study is at present neither for the structural analogue nor for aspartic acid, N,N'-(methylenedi-4,1-cyclohexanediyl)bis-, 1,1',4,4'-tetraethyl ester an urgent requirement.
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