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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key 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

Referenceopen allclose all

Reference Type:
publication
Title:
Toxicity of Diethanolamine. 1. Drinking Water and Topical Applicationn Exposures in F344 Rats
Author:
Melnick RL et al.
Year:
1994
Bibliographic source:
Journal of Applied Toxicology, 14, 1-9
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 rats of each sex received drinking water solutions containing 2,2'-iminodiethanol ad libitum daily for 13 weeks (no recovery group). Examinations included urine analysis, clinical pathology, complete necropsy, organ weights, histopathology, and statistical evaluation thereof.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
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:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: F344/N rats
- Source: Taconic Farms, Germantown, New York, US
- Age at study initiation: approx. 6 weeks
- Weight at study initiation (mean): males 117-123 g, females 102-105 g
- Housing: five per cage
- Diet and water: ad libitum
- Acclimation period: 12-13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2 +/- 2 (72 +/- 3 °F)
- Humidity (%): 50 +/- 15
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
For the drinking water studies, solutions of 2,2'-iminodiethanol were prepared in deionized water and the pH was adjusted to 7.4 +/- 0.2 with 1 N hydrochloric acid.
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:
drinking water was provided ad libitum
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 320, 630, 1250, 2500, and 5000 ppm (male rats)
Basis:
nominal in water
Remarks:
Doses / Concentrations:
0, 25, 48, 97, 202, and 436 mg/kg (male rats)
Basis:
other: Actual estimated daily intakes (converted values from NTP-report)
Remarks:
Doses / Concentrations:
0, 160, 320, 630, 1250, and 2500 ppm (female rats)
Basis:
nominal in water
Remarks:
Doses / Concentrations:
0, 14, 32, 57, 124, and 242 mg/kg (female rats)
Basis:
other: Actual estimated daily intakes (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 rats of each sex received drinking water solutions containing 2,2'-iminodiethanol ad libitum daily for 13 weeks. All surviving animals were sacrificed at the end of the 13-weeks exposure period (no recovery group).

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: Yes
Clinical pathology studies were performed on all rats that survived until the end of the studies. Blood samples were collected in Microtainers containing dipotassium EDTA.
- Parameters examined included erythrocyte count (RBC), leukocyte count (WBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), hemoglobin (HGB), hematocrit (HCT), differential leukocyte count, erythrocyte morphological assessment, reticulocyte count, platelet count and platelet morphological assessment. Differential leukocyte counts were determined by microscopic evaluation of blood smears stained with Wright Giemsa. Reticulocytes were stained by mixing equal volumes of whole blood with methylene blue.

CLINICAL CHEMISTRY: Yes
Clinical pathology studies were performed on all rats 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: Yes
- Time schedule for collection of urine: Urine samples were collected over a 16-h period from rats housed individually in polycarbonate metabolism cages during the 12th week of the study. Food was removed from the cages and collection tubes were immersed in ice-water baths.
- Parameters examined: Volume, appearance, specific gravity, pH, glucose, protein, urea, nitrogen, creatinine, and activities of alkaline phosphatase and lactate dehydrogenase.

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 exposed to 5,000 ppm died before the end of the study. Mean body weights of males exposed to 630 ppm or greater and females exposed to 320 ppm or greater were less than those of the controls during the study. Hematology evaluations conducted at study termination indicated the presence of a normochromic, microcytic anemia similar to that observed in the dermal study. Histopathologic lesions associated with exposure to diethanolamine included exposure-related increases in the severities of nephropathy and incidences of renal tubule mineralization in males and females, demyelination of the brain and spinal cord in females exposed to 1,250 or 2,500 ppm and males exposed 2,500 or 5,000 ppm, and degeneration of the seminiferous tubules in males exposed to 2,500 ppm or greater."

Effect levels

Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
630 other: ppm (equivalent to an actual dose of approx. 48 mg/kg for male and 57 mg/kg for female rats)
Sex:
male/female
Basis for effect level:
other: Based on kidney effects (tubular mineralisation, tubular epithelial necrosis) at the next higher dose (1250 ppm).

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 rats of each sex received drinking water solutions containing 2,2'-iminodiethanol ad libitum daily for 13 weeks. All surviving animals were sacrificed at the end of the exposure period; no recovery group was implemented. The examinations included urine analysis, clinical pathology, complete necropsy, organ weights, histopathology, and statistical evaluation thereof.

The result is summarized in the NTP-report:

"Two males exposed to 5,000 ppm died before the end of the study. Mean body weights of males exposed to 630 ppm or greater and females exposed to 320 ppm or greater were less than those of the controls during the study. Hematology evaluations conducted at study termination indicated the presence of a normochromic, microcytic anemia similar to that observed in the dermal study. Histopathologic lesions associated with exposure to diethanolamine included exposure-related increases in the severities of nephropathy and incidences of renal tubule mineralization in males and females, demyelination of the brain and spinal cord in females exposed to 1,250 or 2,500 ppm and males exposed 2,500 or 5,000 ppm, and degeneration of the seminiferous tubules in males exposed to 2,500 ppm or greater."

According to Melnick et al., 1994, a "NOAEL was not achieved in the drinking water studies for hematological changes or nephropathy...." Deviating from the authors conclusion the observed chronic progressive nephropathy (CPN) is not regarded to be of relevance, as it is a common rat-specific age-related degenerative disease with no counterpart in humans (Hard et al., Toxicol. Sci. 132 (2), 268 -275, 2013; Melnick et al., Toxicol. Sci., 128 (2), 346 -356, 2012). Consequently, a NOAEL is set at 630 ppm (eq. to approx. 48 mg/kg for male and 57 mg/kg for female rats) based on tubular mineralization (males) and tubular epithelial necrosis and demyelination of the brain (females) evident at the next higher dose (1250 ppm; eq to approx. 97 mg/kg for male and 127 for female rats).

The NOAEL of 48 mg/kg and the LOEL of 97 mg/kg are already acknowledged in a recent evaluation of ECHA for 2,2'-iminodiethanol, published on the ECHA website (ECHA decision on substance evaluation pursuant to article 46(1) of Regulation (EC) No 1907/2006 for 2,2'-iminodiethanol - CAS No 111 -42 -2 (EC No 203 -868 -0; http://echa.europa.eu/documents/10162/d34b5848-6b8e-4944-8ce7-4d0200ea43d7).