2,6-bis({[bis(2-hydroxyethyl)amino]methyl})-4-[2-(3-{[bis(2-hydroxyethyl)amino]methyl}-4-hydroxyphenyl)propan-2-yl]phenol; 2,6-bis({[bis(2-hydroxyethyl)amino]methyl})-4-[2-(4-hydroxyphenyl)propan-2-yl]phenol; 2-[(2-hydroxyethyl)amino]ethan-1-ol; 2-{[bis(2-hydroxyethyl)amino]methyl}-4-[2-(3-{[bis(2-hydroxyethyl)amino]methyl}-4-hydroxyphenyl)propan-2-yl]phenol; 2-{[bis(2-hydroxyethyl)amino]methyl}-4-[2-(4-hydroxyphenyl)propan-2-yl]phenol; 4-[2-(4-hydroxyphenyl)propan-2-yl]phenol

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Test procedure in accordance with national standard methods (study conducted in collaboration with the National Institute of Environmental Sciences, US) According to ECHA Practical Guide 6 the maximum score for read across is rel. 2

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Toxicity of Diethanolamine. 2. Drinking Water and Topical Applicationn Exposures in B6C3F1 Mice

Author:

Melnick RL et al.

Year:

1994

Bibliographic source:

Journal of Applied Toxicology, 14, 11-19

Reference 2

Reference Type:

publication

Title:

Unnamed

Year:

1999

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Groups of 10 mice of each sex were administered 2,2'-iminodiethanol in 95 % ethanol once per day for 13 weeks (no recovery group). Examinations included clinical chemistry, complete necropsy, organ weights, histopathology, and statistical evaluation thereof.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

2,2'-iminodiethanol

EC Number:

203-868-0

EC Name:

2,2'-iminodiethanol

Cas Number:

111-42-2

Molecular formula:

C4H11NO2

IUPAC Name:

2,2'-iminodiethanol

Details on test material:

- Name of test material (as cited in study report): Diethanolamine (DEA; CAS no. 111-42-2)
- Analytical purity: > 99 %
- Source: Kodak Laboratory and Specialty Chemicals (Rochester, NY, USA)

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: B6C3F1 mice
- Source: Taconic Farms, Germantown, New York, US
- Age at study initiation: approx. 6 weeks
- Weight at study initiation (mean): males 22.5-23.2 g, females 18.6-19.5 g
- Housing: individually
- Diet and water: ad libitum
- Acclimation period: 12-13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2 +/- (72 +/- 3 °F)
- Humidity (%): 50 +/- 15
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:

open

Vehicle:

ethanol

Details on exposure:

2,2-iminodiethanol in 95 % ethanol: concentrations were 0, 37.5, 75, 150, 300 and 600 mg/mL. The volume of the dosing solution was adjusted weekly based on the most recent mean body weight of each dose group, to provide daily doses of 0, 80, 160, 320, 630, or 1250 mg/kg body wt.

The dosing solution was applied to the shaved back of each animal (unoccluded), from the mid-back to the interscapular region, using a calibrated micropipette. Mice were shaved at 1-week intervals.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Dose formulations were analyzed by gas chromatography before and after administration to animals and found to be within 15 % of the theoretical values.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

once daily, 5 days/week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 37.5, 75, 150, 300 and 600 mg/mL
Basis:
other: concentrations

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 80, 160, 320, 630, and 1250 mg/kg
Basis:
other: daily doses (converted values from NTP-report)

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

Groups of 10 animals per sex were administered 2,2'-iminodiethanol in 95 % ethanol once per day (excluding weekends) for 13 weeks (no recovery period).

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes, no further data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No

CLINICAL CHEMISTRY: Yes
Clinical pathology studies were performed on all mice that survived until the end of the studies. Biochemical analyses were performed on blood samples collected in Microtainers with no preservative or anticoagulant.
- Parameters examined included serum sorbitol dehydrogenase (SDH), alanine arninotransferase (ALT), total protein (TP), albumin, urea nitrogen (UN). creatinine, glucose and total bile acids.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, complete necropsies were performed on all animals. The brain, heart, right kidney, liver, lung, right testis and thymus were weighed.

HISTOPATHOLOGY: Yes, complete histopathological examinations were performed on all control animals, all early death animals and all animals in the highest dose groups with at least 60 % survivors. Target tissues were examined in animals from lower dose groups until a no-effect level was determined. All lesions observed at necropsy were examined microscopically.

Statistics:

Organ and body weight data were analyzed using the parametric multiple comparisons procedures of Williams (Biometrics 27, 103-1 17, 1971; Biometrics 28, 519-531, 1972) and Dunnett (J. Am. Stat. Assoc. 50, 1095-1121, 1955). Clinical chemistry and hematology data were analyzed using the non-parametric multiple comparison methods of Shirley (Biometrics 33, 386-389, 1977) and Dunn (Technometrics 6, 241-252, 1964).

Results and discussion

Results of examinations

Details on results:

Text from NTP report:

"Two males and four females administered 1,250 mg/kg died before the end of the study. Final mean body weights of males receiving 1,250 mg/kg were slightly less than that of the vehicle controls, but final mean body weights of other dosed groups were similar to those of the vehicle controls. Liver and kidney weights were significantly increased compared to the vehicle controls in groups of males administered 160 mg/kg or greater and females receiving 80 mg/kg or greater. Serum alanine aminotransferase and sorbitol dehydrogenase activities were significantly increased in males that received 630 or 1,250 mg/kg, and serum alanine aminotransferase activity was increased in females that received 1,250 mg/kg.

Acanthosis occurred at the site of application in all animals administered diethanolamine but was not observed in the vehicle controls. Cytologic alteration of the liver was observed in all groups of male mice administered diethanolamine and in females receiving 160 mg/kg or greater. Hepatocellular necrosis was also present in several dosed groups of males, especially groups receiving 320 mg/kg or greater. Renal tubule necrosis and cardiac degeneration were observed in males and females receiving 1,250 mg/kg."

Effect levels

1

Dose descriptor:

LOAEL

Remarks:

local

Effect level:

80 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: Based on local effects at the site of application up to the lowest dose (80 mg/kg)

2

Dose descriptor:

other: no reliable systemic threshold identified

Sex:

male/female

Basis for effect level:

other: Cytological alteration of the liver was evident up to the lowest dose (80 mg/kg). However, since ingestion by licking must be assumed (cp. MAK documentation for Diethanolamine, 2000) no reliable dermal, systemic threshold identified.

Remarks on result:

not measured/tested

Remarks:

Effect level not specified (migrated information)

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

The substance contains approx. 40 % 2,2'-iminodiethanol (CAS No 111-42-2), therefore data of 2,2'-iminodiethanol are relevant for toxicological assessment and were thus included in the IUCLID.

Applicant's summary and conclusion

Executive summary:

Groups of 10 male and 10 female B6C3F mice received doses of 0, 80, 160, 320, 630, or 1250 mg/kg 2,2'-iminodiethanol by dermal application to the shaved interscapular region 5 days per week for 13 weeks. All surviving animals were sacificed at the end of the exposure period, that means no recovery group was implemented. The examinations included clinical chemistry, complete necropsy, organ weights, histopathology, and statistical evaluation thereof.

The result is summarized in the NTP-report:

"Two males and four females administered 1,250 mg/kg died before the end of the study. Final mean body weights of males receiving 1,250 mg/kg were slightly less than that of the vehicle controls, but final mean body weights of other dosed groups were similar to those of the vehicle controls. Liver and kidney weights were significantly increased compared to the vehicle controls in groups of males administered 160 mg/kg or greater and females receiving 80 mg/kg or greater. Serum alanine aminotransferase and sorbitol dehydrogenase activities were significantly increased in males that received 630 or 1,250 mg/kg, and serum alanine aminotransferase activity was increased in females that received 1,250 mg/kg.

Acanthosis occurred at the site of application in all animals administered diethanolamine but was not observed in the vehicle controls. Cytologic alteration of the liver was observed in all groups of male mice administered diethanolamine and in females receiving 160 mg/kg or greater. Hepatocellular necrosis was also present in several dosed groups of males, especially groups receiving 320 mg/kg or greater. Renal tubule necrosis and cardiac degeneration were observed in males and females receiving 1,250 mg/kg."

According to Melnick et al., 1994, a "NOAEL was not achieved for cytological alteration of the liver .....".

However, no reliable dermal threshold can be established since, "the substance was applied non-occlusively in 95 % ethanol as a vehicle. Therefore, ingestion by licking must also be assumed" (MAK documentation for Diethanolamine, 2000; http://onlinelibrary.wiley.com/doi/10.1002/3527600418.mb11142e3014/pdf).