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

Endpoint summary

Description of key information

Oral: LD50 (rat) = 959 mg/kg bw

Dermal: LD50 (rat) > 2000 mg/kg bw (based on read-across)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Necropsy was not performed.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

adopted 1987

Deviations:

yes

Remarks:

Necropsy was not performed.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

Wistar TNO W 74

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Age at study initiation: 9 weeks (males); 14 weeks (females)
- Weight at study initiation: 166 - 189 g (males); 168 - 192 g (females)
- Housing: 5 animals/group were housed in macrolon typ III cages with wood granulat as bedding material
- Diet: Altromin R 1324 (Altromin GmbH, Lage, Germany), ad libitum
- Water: Tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1.5
- Humidity (%): 60 ± 5
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DOSAGE PREPARATION:
The test substance was slightly heated prior to administration.

Doses:

0.1, 0.5, 1.0, 1.5, 2.0 and 2.5 mL/kg bw (equivalent to 109, 545, 1090, 1635, 2180 and 2725 mg/kg bw)

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for signs of toxicity and mortality several times on the day of administration, twice daily thereafter and once daily on weekends and public holidays. The body weight was recorded prior to the administration and thereafter once weekly.
- Necropsy of survivors performed: no

Statistics:

Probit analysis was used for the calculation of the LD50 value.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

0.88 mL/kg bw

Based on:

test mat.

Remarks on result:

other: Probit analysis

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

959 mg/kg bw

Based on:

test mat.

Remarks on result:

other: by calculation using a density of 1.09 g/cm³

Mortality:

109 mg/kg bw: no mortality occurred.
545 mg/kg bw: 2/5 males and 1/5 females died 1 h post-administration.
1090 mg/kg bw: 3/5 males and 2/5 females died 1 h post-administration.
1635 mg/kg bw: 4/5 males and 3/5 females died 1 h post-administration.
2180 mg/kg bw: 5/5 males and 3/5 females died 1 day post-administration.
2725 mg/kg bw: 3/5 males died on Day 2 and 2/5 males died on Day 3 after administration of the test substance, respectively. All females died on Day 1 after administration of the test substance.

Clinical signs:

other: 109 mg/kg bw: no clinical signs occured in all animals. 545 mg/kg bw: tremor, convulsions and a decline in general conditions were observed in all males and females 10 min after administration of the test substance. These effects persisted in 3/5 males up

Gross pathology:

Necropsy was not performed.

Interpretation of results:

other: CLP/EU GHS Category 4, H302 according to Regulation (EC) No. 1272/2008.

Conclusions:

In an acute oral toxicity study with rats, performed similar to OECD 401, a LD50 of 959 mg/kg bw was determined.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

959 mg/kg bw

Quality of whole database:

The available information comprises an adequate, reliable (Klimisch score 2) and consistent study, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation(EC) No. 1272/2008

Conclusions:

In an acute dermal toxicity study with rats, performed according to OECD/EC test guidelines, an LD50 >2000 mg/kg bw was determined for 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). Applying the read-across approach, similar results are expected for the target substance N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

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, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Additional information

Acute oral toxicity

There are reliable data available regarding acute oral toxicity for N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1).

An acute oral toxicity test was conducted with five male and five female Wistar TNO W 74 rats similar to OECD 401 (Bayer AG, 1981). The test substance was slightly heated prior to administration, and thereafter administered unchanged at dose levels of 0.1, 0.5, 1.0, 1.5, 2.0 and 2.5 mL/kg bw (equivalent to 109, 545, 1090, 1635, 2180 and 2725 mg/kg bw) via gavage. Mortality occurred at a dose level ≥ 545 mg/kg bw. Tremor, convulsions and a decline in general conditions were observed at 545, 1090 and 1635 mg/kg bw in all males and females 10 min after administration of the test substance. At higher dose levels (2180 and 2725 mg/kg bw) tremor, convulsions, a decline in general conditions, cyanosis and lateral and abdominal position were noted in all males and females 10 min after administration of the test substance. Necropsy was not performed. Based on the observed results, a LD50 of 959 mg/kg bw was determined.

A second acute oral toxicity test was available and used as supporting information. In this study 2 male cats/dose level were treated with 10 and 50 mL N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1) per kg bw in Lutrol via gavage (Bayer AG, 1985). Clinical signs such as a decline of the general condition, anorexia, narcosis, respiratory dysfunction, mydriasis and spasms were observed after administration with the test substance at both dose levels. At the low dose level, no mortality occurred. At 50 mL/kg bw 2/2 animals died 3 h after administration with the test substance, therefore the LD100 was considered to be 50 mL/kg bw.

Acute dermal toxicity

As there is no data available regarding acute dermal toxicity for N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1), 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, 8.5. 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 acute dermal 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, 8.5.

EC 911-490-9

An acute dermal toxicity test was conducted with five male and five female rats following OECD 402 and according to GLP principles with 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, 2013a). The test substance was applied occlusive at 2000 mg/kg bw for 24 h. No mortality occurred. No unexpected changes in body weight gain were reported. Hunched posture, piloerection and/or chromodacryorrhoea were noted in all males and three females on Days 1 and/or 2. Hypothermia was noted in one male on Day 2. 2/5 males showed many reddish foci in the thymus and 3/5 females showed enlarged size of mandibular lymph nodes during macroscopic post mortem examination. No abnormalities were found in the other animals. Based on these results, the test substance has an acute dermal LD50 > 2000 mg/kg bw. Similar results are expected for the target substance N,N-Dihydroxyethyl-p-toluidine (CAS 3077-12-1).

The available data with the registration substance on acute oral toxicity meet the classification criteria as Acute oral Tox. 4, H302 according to Regulation (EC) 1272/2008. The available data with a structural similar substance on acute dermal toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.

Justification for classification or non-classification

The available target substance data on acute oral toxicity meet the classification criteria as Acute oral Tox. 4, H302 according to Regulation (EC) 1272/2008. The available source substance data on acute dermal toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.