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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Developmental toxicity study with N-methyldiethanolamine by repeated cutaneous application to CD rats.
Author:
Leung HW and Ballantyne B
Year:
1998
Bibliographic source:
J. Toxicol.-Cut. & Ocular Toxicol., 17(4), 179-190

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2,2'-methyliminodiethanol
EC Number:
203-312-7
EC Name:
2,2'-methyliminodiethanol
Cas Number:
105-59-9
Molecular formula:
C5H13NO2
IUPAC Name:
2-[(2-hydroxyethyl)(methyl)amino]ethan-1-ol

Test animals

Species:
rat
Strain:
other: CD
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage, MI
- Age at study initiation: male: 77 days; females: 70 days;
- Weight at study initiation: Female rats weighed at least 200 g at the time of mating.

Administration / exposure

Route of administration:
dermal
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: dorsal trunk
- Type of wrap if used: refolded eight-ply sterilized gauze square and a 2.75 x 2.25 inch area of polyvinyl film.
- Time intervals for shavings or clipplings: 3 days prior to the first dose and subsequently as needed throughout the study.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the dosing site was wiped gently with a paper towel dampened with warm water and blotted dry.
- Time after start of exposure: 6 ha fter the application.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4 mL
- Concentration (if solution): Range finding study: Definitive study: 250, 500, and 1000 mg/kg/day (Range finding study: 100, 500, 750, and 1000 mg/kg/day).

VEHICLE
- Amount(s) applied (volume or weight with unit): 4 mL
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
MDEA concentrations in dosing solutions were verified using a gas chromatograph equipped with a flame ionization detector.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
days 6 - 15 of gestation
Frequency of treatment:
6 hours per day
Duration of test:
21 days
Doses / concentrationsopen allclose all
Dose / conc.:
250 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Twenty-five plug-positive females were assigned to each group (range finding test: 8 plug-positive females)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on results of the range finding study where the following concentrations were tested: 0, 100, 500, 750, and 1000 mg/kg bw/day

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: on gd 0, 6, 9, 12,15, 18, and 21

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes

WATER CONSUMPTION AND COMPOUND INTAKEy: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: gravid uterus, ovaries including corpora lutea, cervix, vagina, and peritoneal and thoracic cavities were examined grossly

Other: blood was used for erythrocyte, platelet, total and differential leukocyte counts, hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
Data from quantitative, continuous variables were intercompared for the dosed groups and the control group by use of Levene's test for equality of variances, analysis of variance, (ANOVA), and t-tests. Nonparametric data were evaluated using the Kruskal- Wallis test, followed by the Mann-Whitney U test when appropriate incidence data were compared using the Fisher's Exact Test. The probability value of p < 0.05 (two-tailed) was used as the critical level of significance.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
Skin reactions at the dosing site were observed in the 500 and 1000 mg/kg bw/day groups. Effects included exfoliation, excoriation, crusting, ecchymoses, and necrosis.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The erythrocyte count and hematocrit were reduced in the 1000 mg/kg bw/day group. Also, while not statistically significant, hemoglobin was reduced by about 6% in the 1000 mg/kg bw/day group. However, there were no effects on mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, and total or differential leukocyte counts.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no effects of dosing with MDEA on gravid uterine weight, or liver and kidney weights.

Maternal developmental toxicity

Other effects:
no effects observed
Description (incidence and severity):
There were no effects on the number of ovarian corpora lutea, the number of total, viable or nonviable implantations, preimplantation loss, and fetal body weights.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Basis for effect level:
dermal irritation

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:
There were no increased incidences of total external, visceral, and skeletal malformations or variations or individual malformations compared to controls. Among individual variations, there was a statistically significant decrease in the incidence of a soft-tissue variation (dilated bilateral renal pelvis) and a skeletal variation (split number 1, 2, 3, and/or 4 cervical centra) at 1000 mg/kg bw/day. These decreases are not considered characteristic of a developmental delay.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Occluded cutaneous applicatation of methydiethanolamine to pregnant rats during organogenesis resulted in maternal toxicity as indicated by skin irritation and mild anaemia from 500 mg/kg bw/day onwards, but no treatment-related developmental effects were observed.

Applicant's summary and conclusion