Registration Dossier

Administrative data

Key value for chemical safety assessment

Additional information

1,1’-(methylimino)-dipropane-2-ol did not lead to a biologically relevant increase in the number of revertant colonies in the Ames test either without S9 mix or after adding a metabolizing system in two experiments carried out independently of each other (standard plate test and preincubation assay). Besides, the results of the negative as well as the positive controls performed in parallel corroborated the validity of this study, since the values fulfilled the acceptance criteria of this study. The number of revertant colonies in the negative controls was within the range of the historical negative control data for each tester strain. In addition, the positive control substances both with and without S9 mix induced a significant increase in the number of revertant colonies within the range of the historical positive control data or above (BASF, 2012).

 

1,1’-(methylimino)-dipropane-2-ol and tris-(2-hydroxypropyl)-amine (CAS 122-20-3) are structurally very similar low molecular weight tertiary amines, which differ only in terms of a methyl group and an isopropanol moiety respectively. They are low volatile (vapour pressure ≤ 0.015 hPa) organic compounds with similar specific gravity (1,1’-(methylimino)-dipropane-2-ol: 147.22 g/mol and tris-(2-hydroxypropyl)-amine: 191.27 g/mol) and log Pow values between -0.03 for 1,1’-(methylimino)-dipropane-2-ol and -0.02 for tris-(2-hydroxypropyl)-amine. Moreover, the comparison of the available toxicity data for both compounds indicates a similar toxicological profile: the substances are showing low acute toxicity by the oral route (i.e. oral LD50 values for 1,1’-(methylimino)-dipropane-2-ol of 2150 mg/kg bw and beyond 5000 mg/kg bw for tris-(2-hydroxypropyl)-amine. Tris-(2-hydroxypropyl)-amine is irritating to the eyes, whereas 1,1’-(methylimino)-dipropane-2-ol shows corrosive properties. The chemical difference between those two structures apparently do not affect the anticipated toxicity. For a detailed read across justification see also attached assessment reports (Reporting Format for the analogue approach of 1,1’-(methylimino)-dipropane-2-ol– with comparison to tris-(2-hydroxypropyl)-amine).

 

The read across substance tris-(2-hydroxypropyl)-amine was also tested in the Ames reverse mutation assay using S. typhimurium strains TA 98, TA 100, TA 1535 and TA 1537 at 100 to 10,0000 µg/plate with and without metabolic activation. Treatment with tris-(2-hydroxypropyl)-amine was not associated with reverse mutations in any of the strains tested (Zeiger et al., 1987). Tris-(2-hydroxypropyl)-amine was also evaluated at concentrations of 50 to 5000 µg/mL in a HGPRT assay according to OECD TG 476 using Chinese hamster ovary cells with and without metabolic activation. No cytotoxicity was observed and negative, vehicle and positive control responses were valid. Tris-(2-hydroxypropyl)-amine was not associated with increased gene mutations (Sitek, 1993). Induction of chromosomal aberrations was tested in an OECD TG 473 study in which rat lymphocytes were exposed to 50 to 5000 µg/mL with and without metabolic activation. No cytotoxicity was observed and negative, vehicle and positive controls exhibited appropriate responses. No significant increases in chromosomal aberrations upon treatment with tris-(2-hydroxypropyl)-amine were observed (Dow, 1993).

Additionally, in an in vivo micronucleus test according to OECD TG 474, NMRI mice (5/sex/dose) received a single oral dose of 500, 1000 or 2000 mg/kg bw tris-(2-hydroxypropyl)-amine (BASF AG, 1995a). 24 and 48 hours after treatment, polychromatic erythrocytes were prepared from bone marrow and investigated for micronuclei. 30 minutes after treatment, irregular respiration and piloerection was observed at all dose levels, and squatting posture was observed in the 1000 and 2000 mg/kg bw dose groups. After 2-4 hours these signs were no longer observed. Moreover, treatment with tris-(2-hydroxypropyl)-amine did not induce any increase in the rate of micronuclei and no inhibition of erythropoiesis was observed. Vehicle and positive controls were valid.

In summary, these data indicate that tris-(2-hydroxypropyl)-amine and 1,1’-(methylimino)-dipropane-2-ol are not genotoxic.


Justification for selection of genetic toxicity endpoint
1,1’-(methylimino)-dipropane-2-ol and tris-(2-hydroxypropyl)-amine (CAS 122-20-3) are structurally very similar low molecular weight tertiary amines, which differ only in terms of a methyl group and an isopropanol moiety respectively. They are low volatile (vapour pressure ≤ 0.015 hPa) organic compounds with similar specific gravity (1,1’-(methylimino)-dipropane-2-ol: 147.22 g/mol and tris-(2-hydroxypropyl)-amine: 191.27 g/mol) and log Pow values between -0.03 for 1,1’-(methylimino)-dipropane-2-ol and -0.02 for tris-(2-hydroxypropyl)-amine. Moreover, the comparison of the available toxicity data for both compounds indicates a similar toxicological profile: the substances are showing low acute toxicity by the oral route (i.e. oral LD50 values for 1,1’-(methylimino)-dipropane-2-ol of 2150 mg/kg bw and beyond 5000 mg/kg bw for tris-(2-hydroxypropyl)-amine. Tris-(2-hydroxypropyl)-amine is irritating to the eyes, whereas 1,1’-(methylimino)-dipropane-2-ol shows corrosive properties. The chemical difference between those two structures apparently do not affect the anticipated toxicity. Therefore, tris-(2-hydroxypropyl)-amine is regarded as appropriate for read across.

Short description of key information:
Under the experimental conditions chosen, it is concluded that N-Methyldiisopropanolamine is not a mutagenic test substance in the bacterial reverse mutation test in the absence and the presence of metabolic activation.
A structural analogue of N-Methyldiisopropanolamine, tris-(2-hydroxypropyl)-amine also didn't cause gene mutations in Salmonella typhimurium (Ames test). Moreover, in Chinese hamster ovary cells (CHO/HGPRT; OECD TG 476) there were no gene mutations observed nor chromosomal aberrations induced in rat lymphocytes (OECD TG 473). All in vitro studies were performed in the absence and presence of metabolic activation. In addition, in an in vivo micronucleus test in mice (OECD TG 474) no clastogenic effects were observed afer single oral administration of tris-(2-hydroxypropyl)-amine at doses up to 2000 mg/kg bw. Thus, tris-(2-hydroxypropyl)-amine and N-Methyldiisopropanolamine are not considered to be genotoxic.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the available data, 1,1'-(methylimino)dipropan-2-ol does not need to be classified according to Directive 67/548/EEC and according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.