Oxirane, reaction products with ammonia, distn. residues

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

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: Comparable to a guideline study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Evaluation of the developmental toxicity of dermally applied monoethanolamine in rats and rabbits

Author:

Liberacki AB, et al.

Year:

1996

Bibliographic source:

Fundamental and Applied Toxicology 31, 117-123

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

Pregnant Sprague-Dawley rats were exposed dermally to 0, 10, 25, 75 and 225 mg/kg/day of monoethanolamine (MEA) for approximately 6 hr/day on Days 6 through 15 of gestation .

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-aminoethanol

EC Number:

205-483-3

EC Name:

2-aminoethanol

Cas Number:

141-43-5

Molecular formula:

C2H7NO

IUPAC Name:

2-aminoethanol

Details on test material:

- Analytical purity: 100 % pure as analyzed by Analysis by gas chromotography using flame ionization detection
- supplier: The Dow Chemical Company

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. (Kingston, NY), USA
- Age at study initiation:
- Weight at study initiation: 250-300 g)
- Housing: in wire-bottom cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 40-60

Administration / exposure

Route of administration:

dermal

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: shaved skin of the back
- Type of wrap if used: absorbant gauze pad followed by nonabsorbant cotton; an elastic bandage was wrapped securely around the animal to hold the patch in place and to prevent accidental ingestion of the test material via grooming during the exposure.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): water-dampened towel was used to wipe remaining test material off
- Time after start of exposure: 6 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1 ml/kg
- Constant volume or concentration used: no

Details on mating procedure:

- Impregnation procedure: [cohoused]
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: over night
- Verification of same strain and source of both sexes: [yes]
- Proof of pregnancy: [sperm in vaginal smear] referred to as [day 0] of pregnancy

Duration of treatment / exposure:

day 6 - 15 of gestation

Frequency of treatment:

6 hours/day, daily

Duration of test:

up to day 21 of gestation

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 10, 25, 75, 225 mg/kg bodyweight
Basis:
nominal conc.

No. of animals per sex per dose:

30-45 rats

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose levels selected for these studies were chosen based upon the results of dermal range-finding and teratology probe studies conducted in rats

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: gestation days 0, 3, 6-16, and 21

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: weights of liver, kidneys

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
- Other: Uteri with no visible implantations were stained with a 10% sulfide solution.

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 ]


All fetuses were weighed and examined for evidence of external alterations and palate closure. At least one-half of the rat fetuses in each litter were examined for visceral alterations (Staples,1974). The sex of all live fetuses was determined. The heads of rat fetuses not selected for skeletal examination were removed, placed in Bouin's solution, and subsequently sectioned and examined for craniofacial defects (Wilson, 1965; Van Julsingha and Bennet, 1977). All fetuses were eviscerated and stained with alizarin red-S ( Dawson, 1926; Crary, 1962). Skeletal examinations were conducted only on the rat fetuses not selected for Bouin's examination.

Statistics:

Continuous data were evaluated for homogeneity of variance using Bartlett's test (Winer, 1971). Based upon the outcome of these tests, a parametric or nonparametric analysis of variance (ANOVA) was performed. If the ANOVA was significant, analysis by Dunnett's test (Steel and Torrie, 1960), the Wilcoxen Rank-Sum test with Bonferroni's correction (Miller, 1966), or a pooled t test was performed as appropriate. The level of statistical significance was set a priori at a = 0.05. Nonparaznetric data were statistically treated using the Kruskal-Wallis test followed by the Mann-Whitney U test (Sokal and Rohlf, 1969), when appropriate. Incidence data for rats were analyzed using the Wilcoxon test as modified by Haseman and Hoel (1974). Fetal sex ratios were analyzed using a binomial distribution test (Steel and Torrie, 1960).

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Rats administered 225 mg MEA/kg/day exhibited a treatment-related increased incidence of skin irritation at the site of exposure. In general, the dermal irritation followed a progression, beginning with erythema and leading to necrosis, scabs, and scar formation.
No significant dermal irritation or lesions were observed among rats administered lower doses of MEA.

There were no postmortem treatment-related effects observed in any dose group. No significant differences were observed in the feed or water consumption of MEA exposed rats relative to controls.

The body weight gain of rats given 225 mg MEA/kg/day was significantly decreased during the exposure period. No effect on weight gain was observed in dams treated with lower levels of MEA.No effects on liver or kidney weights were observed at any dose level.

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

75 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Despite maternal effects observed among dams given 225 mg/kg/day, reproductive parameters among MEA exposed rats were unaffected at this or lower dose levels. There were no differences in pregnancy rate, number of corpora lutea, number of implantations, resorptions, litter size, number of dead fetuses, fetal sex ratio, fetal body weight, or gravid uterine weight among any of the dose groups when compared to controls.

There were no treatment-related increases in the incidence of variations or malformations observed externally, viscerally or at skeletal examination by individual category, or in total variations or malformations when compared to controls. Among controls, the following types of malformations were observed: microphthalmia, retroesophageal right subclavian artery, and an extra cervical rib. No malformed fetuses were observed in the 10 mg/kg/day dose group. Malformations observed in the 25 mg MEA/kg/day dose group included retroesophageal right subclavian artery and an extra cervical rib. A single fetus was malformed in the 75 mg MEA/kg/day dose group. This fetus had multiple craniofacial
malformations consisting of micrognathia, cleft lip and soft palate, and aglossia. No malformations were observed in fetuses from dams administered 225 mg MEA/kg/day.

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Effect level:

225 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: developmental toxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified