2,2'-[(4-methylphenyl)imino]bisethanol

Endpoint summary

Description of key information

Oral: NOAEL (rat, male/female) = 100 mg/kg bw/day (based on read-across)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Increased liver weights (female) at 300 mg/kg bw/day coinciding with elevated levels of ALAT, total bilirubin, and cholesterol (levels increased in exposed groups in a dose-dependent way).

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

300 mg/kg bw/day (actual dose received)

System:

hepatobiliary

Organ:

liver

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Conclusions:

A sub-acute 28 days repeated dose study was performed with the source substance Reaction mass of 2,2'-[(4-methylphenyl)imino]bisethanol and Ethanol 2-[[2-(2-hydroxyethoxy)ethyl](4-methylphenyl)amino]- (EC 911-490-9) according to OECD 407 and GLP principles. Based on effects seen at 300 mg/kg bw/day (enlarged liver with dose-related changes in biochemical parameters), the NOAEL was found to be 100 mg/kg bw/day. Applying the read-across approach similar results are expected for the target susbtance N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products and similarities in PC/ECO/TOX properties. The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

System:

hepatobiliary

Organ:

liver

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There are no data available regarding repeated dose toxicity for N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1). Therefore, read-across from an appropriate structural analogue substance is conducted in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5. in order to fulfil the standard data requirements defined in Regulation (EC) No 1907/2006, Annex VIII, 8.6. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13). For repeated dose toxicity information from the analogue substance Reaction mass of 2,2'-[(4-methylphenyl)imino]bisethanol and 2-[[2-(2-hydroxyethoxy)ethyl](4-methylphenyl)amino]-ethanol (EC 911-490-9) will be taken into account to fulfil the standard data requirements defined in Regulation (EC) No 1907/2006, Annex VIII, 8.6.

In a sub-acute repeated dose study performed according to OECD 407 and GLP principles, rats were treated with 100, 300 or 1000 mg/kg bw/day of the source substance Reaction mass of 2,2'-[(4-methylphenyl)imino]bisethanol and 2-[[2-(2-hydroxyethoxy)ethyl](4-methylphenyl)amino]-ethanol (EC 911-490-9) (WIL Research, 2013c). Due to mortality in the highest dose group on day 1 (2/5 males and 3/5 females), the highest dose was lowered to 600 mg/kg bw/day and the animals were replaced. 1/5 males and 1/5 females died shortly after the first dose of 600 mg/kg bw/day. At macroscopic examination these animals showed foci in the thymus and/or lungs and thickened thymus. No further mortality occurred. Clinical signs were noted during the study period at 600 mg/kg bw/day (lethargy, clonic spasms, tremors, flat and/or hunched posture, quick breathing, rales, laboured and/or shallow respiration, piloerection, salivation and/or chromodacryorrhoea). During the first week the body weight gain was slightly lower but recovered from week 2 onwards. No changes were noted compared to control animals in food consumption or functional behaviour observations. At the highest dose level of 600 mg/kg bw/day higher liver weights and thyroid gland weights were noted in males and females, coinciding with changes in total bilirubin and cholesterol levels. Liver weights were also increased in females at 300 mg/kg bw/day. In females ALAT-values, total bilirubin, and cholesterol were elevated in all groups and increased in a dose-dependent way (significant at 600 mg/kg bw/day). Microscopic examination revealed in some females diffuse hyperplasia of the urothelium of the urinary bladder (2/5 females at 600 mg/kg bw/day). Based on the low grade and the absence of additional histopathologic findings, this was considered to be not toxicologically relevant. Based on the effects on liver at 300 mg/kg bw/day with dose-related changes in biochemical parameters (ALAT, cholesterol, total bilirubin and bile acids), a No Observed Adverse Effect Level (NOAEL) for the test substance of 100 mg/kg bw/day was established.

Justification for classification or non-classification

Reliable data from a structural analgoue substance on repeated dose toxicity indicate that the registered substance do not meet the classification criteria according to Regulation (EC) 1272/2008.