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Toxicological information

Developmental toxicity / teratogenicity

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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

Referenceopen allclose all

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 Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Pregnant New Zealand White rabbits were exposed dermally to 0, 10, 25, and 75 mg/kg/day of monoethanolamine (MEA) for approximately 6 hr/day on Days 6 through 18 of gestation.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): monoethanolamine
- Analytical purity: 100 % pure as analyzed by Analysis by gas chromotography using flame ionization detection
- supplier: The Dow Chemical Company
- no further data.

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazelton Research Products, Inc. (Denver, PA), USA
- Weight at study initiation: 3 .0-4 .0 kg)
- Fasting period before study: none
- Housing: in wire-bottom cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12/12



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: sterile gauze held in place by Lycra-Spandex jacket

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): 2 ml/kg
- Constant volume or concentration used: no
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: [cohoused]
- If cohoused:
- M/F ratio per cage: 2/1
- Length of cohabitation: over night
- Verification of same strain and source of both sexes: [yes]
- Proof of pregnancy: [copulation] referred to as [day 0] of pregnancy
Duration of treatment / exposure:
day 6 - 18 of gestation
Frequency of treatment:
6 hours/day, daily
Duration of test:
up to day 29 of gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 25, 75 mg/kg bodyweight
Basis:
nominal conc.
No. of animals per sex per dose:
15 dams/group
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 rabbits

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, 9, 12, 15, 18, 24 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: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: weights of liver, kidneys

OTHER: Blood analysis prior to caesarian section; skin irritation was evaluated once daily during the postdosing period
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: [all 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. All of the rabbit fetuses in each litter were examined for visceral alterations (Staples,1974). The sex of all live fetuses was determined. The heads of one half of the rabbit fetuses not selected for skeletal examination were removed, placed in Bouin's solution, and subsequently sectioned and examined for craniofacial defects (Wilson, 1 965 ; Van Julsingha and B ennet, 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 Levene's test (Levene, 1960). Based upon the outcome of this test, 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. Nonparametric data were compared using Fischer's exact probability test (Siegel, 1956).

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
Rabbits administered 75 mg/kg/day of MEA exhibited severe skin irritation (erythema, edema, ecchymosis, necrosis, exfoliation, and crusting) at the site of exposure. Subsequent to the dosing period, exfoliation, crusting, and areas of necrosis persisted. The skin of the majority of these rabbits began to heal as evidenced by scab formation late in the gestation period. Crusting, transient erythema, and edema were noted in a few rabbits administered 25 mg MEA/kg/day. No significant dermal irritation or lesions were observed among rabbits administered 10 mg MEA/kg/day.

No females died, aborted, delivered early, or were removed from the test during the study. There were also no significant treatment-related effects observed on feed consumption, hematologic parameters, or kidney and liver weights of MEA-exposed rabbits at any dose level tested.

No statistically identified changes were observed in body weight and body weight gain, the average body weight gain of high-dose rabbits over the course of gestation was decreased when compared to that of the control and other dose groups, mainly due to weight loss or very little weight gain during the treatment period.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 75 mg/kg bw/day
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No treatment-related effects were observed on reproductive parameters including 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 MEA exposed rabbits at any dose level when compared to controls.
There were no statistically or biologically significant treatment-related differences in the incidence of any fetal variation or malformation, or in the number of malformed fetuses in any dose group. Among control litters the following types of malformations were noted: ventricular septal defect, common opening at entry of the vessels of the heart, missing lung lobe, missing gallbladder, and extra lumbar centrum and arches.

Malformations observed in litters from rabbits given 10 mg/kg/day included dilated lateral cerebral ventricle with tissue depression, missing lung lobe, missing gallbladder, misaligned or fused thoracic centra, extra lumbar centrum and arches, and fused ribs. Limited numbers of malformations noted at 25 mg/kg/day included dilated lateral cerebral ventricle with tissue depression and missing lung lobe. Malformations observed in fetuses from the 75 mg/kg/day dose group litters included the following: dilated lateral cerebral ventricle with tissue depression, missing lung lobe, diagonally displaced thoracic centra, missing thoracic arch, and a single missing rib.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion