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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
Remarks:
peer reviewed article

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

1
Chemical structure
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
Specific details on test material used for the study:
- Name of test material (as cited in journal article): Monoethanolamine
- Source: BASF AG (Ludwigshafen, Germany).
-100% purity (analzyed by GC using FID)

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Chbb:THOM (SPF)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Sexually mature, virgin Wistar rats (Chbb :THOM (SPF)) supplied by Karl THOMAE, Biberach an der Riss, Germany,
- Weight at study initiation: 200 – 300 g
- Housing: singly in stainless steel wire mesh cages
- Diet: Ground Kliba laboratory diet rat/mouse maintenance GLP 343, Klingentalmuhle AG, Kaiseraugst, Switzerland.
- Water: tap water ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Test solutions were prepared fresh daily before the test substance was administered. The volume of dosing solution administered to each rat (10 mL/kg) remained constant and was calculated based upon the dam's body weight on GD 6.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations of 2-aminoethanol in the dosing solutions, homogeneity, and stability throughout the dosing period were confirmed analytically.
Details on mating procedure:
Virgin female rats were bred overnight with untreated adult males of the same strain (one male:two-four females). The day on which sperm were detected in the vaginal smear was designated GD 0. Sperm positive females were randomly assigned to test groups according to their day 0 of gestation.
Duration of treatment / exposure:
days 6-15 of gestation (during the period of major organogenesis)
Frequency of treatment:
daily, once per day
Duration of test:
up to day 21 postpartum
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
40 mg/kg bw/day
Dose / conc.:
120 mg/kg bw/day
Dose / conc.:
450 mg/kg bw/day
No. of animals per sex per dose:
40 dams per dosing group
Control animals:
yes
Details on study design:
On day 0, the sperm-positive females were assigned to the different test groups according to a randomization plan. The test substance was administered to the animals orally (by gavage) once a day during days 6 to 15 GD. The volume administered each day was 10 mL/kg body weight. On day 20 of gestation, 25 dams/group were euthanized and the fetuses were delivered by caesarean section, weighed, sexed, and examined for external, visceral, and skeletal alterations. The remaining dams (15/group) were allowed to litter and rear their pups to day 21 postpartum. The dams and pups were then euthanized and examined for gross pathologic changes both externally and internally.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were examined at least once daily for treatment-related clinical signs of toxicity.
- the nesting, littering, and lactation behaviour of dams allowed to deliver and rear their litters was evaluated.

BODY WEIGHT: Yes
- Time schedule for examinations: Maternal body weights were recorded on GD 0, 1, 3, 6, 8, 10, 13, 15, 17, and 20. Body weights of dams which littered were also determined on the day of parturition and on days 4, 7, 14, and 21 postpartum (pp).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Beginning on GD 0, feed consumption was determined at 2-3 day intervals.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #: On GD 20, the first 25 animals per dose group were sacrificed in a randomized sequence
- Organs examined: number of corpora lutea, number and position of implantations, resorptions, and live/dead foetuses. Uteri with no visible implantations were stained with a 10% sulfide solution and examined for evidence of early resorptions
- Individual placental weights were recorded.
OTHER:
- Litters delivered naturally by the remaining dams were examined as soon as possible on the day of birth to determine the total number of liveborn and stillborn pups in each litter
- The duration of gestation was determined for each dam
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: live/dead fetuses
Fetal examinations:
- External examinations: Yes - fetuses were dissected from the uterus, weighed, sexed, and examined macroscopically for any external changes. All of the fetuses in each lifter were fixed in Bouin's solution and examined at a later date for visceral alterations.
- Skeletal examinations: Yes - Approximately, one-half of the fetuses were eviscerated and stained with alizarin red-S, according to a modified method of Dawson (1926), and examined for skeletal defects

- All surviving pups (of the remaining dams allowed to litter and rear their pups) were sexed and weighed on days 1, 4, 7, 14, and 21 postpartum. All litters were examined daily for viability/mortality and clinical symptoms. All dams and pups were euthanized on day 21 postpartum and examined macroscopically both externally and internally.
Statistics:
- Analysis of variance along with Dunnett's test (Dunnett, 1955, 1964) was used to statistically compare continuous data including: feed consumption, body weight, body weight changes, corrected body weight gain, gravid uterine weight, fetal and placental weights, the number of corpora lutea, implants, resorptions, live fetuses and pre- or post implantation losses, pup body weights, duration of gestation, and number of pups delivered per litter.
- For body weight evaluations of the pups, the mean weight of each litter was used for the statistical analysis.
- The Fisher's exact test (Dixon, 1981) was used for evaluating incidence data including maternal mortality, pregnancy rate, female fertility and gestation indexes, number of liveborn and stillborn pups, and pup survival.
- The Wilcoxon test (Nijenhuis and Wilf, 1978; Hettmansperger, 1984) was used for statistical evaluation of the proportion of fetuses with malformations/ variations. The level of statistical significance for each of these tests was set a priori at a = 0.05.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
- with the exception of a single dam from the 40 mg/kg bw/day group (which died during parturition), no treatment-related clinical observations were noted during the study at any dose level.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
- a single dam from the 40 mg/kg bw/day group died during parturition. All other dams survived the test period.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
- Statistically significant decreases in mean maternal body weights on GD 15, 17, and 20 were noted in dams administered 450 mg/kg bw/day. Body weight gains for these dams were also significantly reduced during GD 15-20 and 0-20. The body weight effects noted during gestation for the 450 mg/kg bw/day dams were consistent with decreases noted in feed consumption at similar time points.

- No significant treatment-related effects were observed on gestational body weights or body weight gains of dams administered 40 or 120 mg/kg/day.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
- Dams administered 450 mg/kg bw/day exhibited significant decreases in feed consumption on GD 6 -8 (8%) and 17-20 (5%). A statistically significant reduction in feed consumption (18%) was also noted for the remaining 450 mg/kg/day dams early in the lactation period on days 0-4.
- No significant differences were observed for the feed consumption of dams administered 40 or 120 mg/ kg/day, at any time during gestation or lactation, relative to controls.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
- For dams sacrificed on GD 20, there were no differences in gravid uterine weight among any of the dose groups when compared to controls.
Gross pathological findings:
no effects observed
Description (incidence and severity):
- For dams sacrificed on GD 20, there were no differences in number of corpora lutea among any of the dose groups when compared to controls.

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
- For dams sacrificed on GD 20, there were no differences in number of implantations among any of the dose groups when compared to controls.

- Reproductive data collected for those dams sacrificed on day 21 postpartum showed no treatment-related differences when compared to control values for number of implantations or post implantation loss at any dose level tested.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
- For dams sacrificed on GD 20, there were no differences in resorptions among any of the dose groups when compared to controls.
Dead fetuses:
no effects observed
Description (incidence and severity):
- For dams sacrificed on GD 20, there were no differences in number of viable fetuses among any of the dose groups when compared to controls.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
- Reproductive data collected for those dams sacrificed on day 21 postpartum showed no treatment-related differences when compared to control values for gestation length at any dose level tested.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
- For dams sacrificed on GD 20, there were no differences in pregnancy rate among any of the dose groups when compared to controls.
Details on maternal toxic effects:
Gavage administration of 450 mg/kg bw/day of 2-aminoethanol to pregnant rats resulted in maternal toxicity as evidenced by statistically significant (a = 0.05) decreases in feed consumption on gestation days 6-8 and 17-20 and on postpartum days 0-4. Additionally, statistically significant decreases in mean maternal body weights were observed on gestation days 15, 17, and 20 and on lactation days 0, 4, 7, and 21. Body weight gains of the 450 mg/kg/day dams were also significantly decreased (13% relative to controls) on gestation days 15-20. There was no evidence of maternal toxicity at 40 or 120 mg/kg bw/day of 2-aminoethanol.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOEL
Effect level:
120 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Dose descriptor:
LOEL
Effect level:
450 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
- no significant differences in mean placental or fetal weights in any of the treated groups compared to control values
- Of the pups delivered naturally, statistically significant decreases in mean male and female pup body weights were noted sporadically during the first 2 weeks of lactation in all treated groups when compared to controls. These decreases were considered incidental and unlikely due to treatment with 2-aminoethanol as no clear dose-response was observed, the effect was transient, no effects on pup weights were noted at any dose level for those litters delivered by caesarean section, and postnatal pup weights in all dose groups were comparable by day 21 postpartum.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
- Of the pups delivered naturally, no treatment-related effects were observed concerning number of pups born alive, pup viability or survival (days 0 and 21 postpartum) at any dose level tested.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
- No significant differences in fetal sex ratio

- Of the pups delivered naturally, no treatment-related effects were observed concerning sex ratio (days 0 and 21 postpartum) at any dose level tested.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
- Of the pups delivered naturally, no treatment-related effects were observed concerning mean litter size (days 0 and 21 postpartum) at any dose level tested.
Changes in postnatal survival:
no effects observed
Description (incidence and severity):
- Of the pups delivered naturally, no treatment-related effects were observed concerning mean litter size, number of pups born alive, pup viability or survival, or sex ratio (days 0 and 21 postpartum) at any dose level tested.
External malformations:
no effects observed
Description (incidence and severity):
- There were no treatment-related increases in the incidence of variations or malformations observed externally by individual category, or in total variations or malformations when compared to controls.
- The only external malformation noted was that of anasarca and was recorded in a single 450 mg/kg bw/day fetus. No external variations were noted in any dose group.
Skeletal malformations:
no effects observed
Description (incidence and severity):
- There were no treatment-related increases in the incidence of variations or malformations observed at skeletal examination by individual category, or in total variations or malformations when compared to controls.
- The only skeletal malformations noted were asymmetrical (dumb-bell shaped or bipartite) thoracic vertebral bodies. One or both of these malformations were found in a few fetuses in each dose group. Minor skeletal variations relating to the thoracic vertebrae, ribs, and/or sternebrae were recorded at similar frequencies in all dose groups.
Visceral malformations:
no effects observed
Description (incidence and severity):
- There were no treatment-related increases in the incidence of variations or malformations observed viscerally by individual category, or in total variations or malformations when compared to controls.
- Visceral malformations including microphthalmia, dilation of the right or both heart ventricles, dextrocardia, unilobular lung, or hyper-/hypoplasia of the kidneys were noted sporadically throughout all dose groups, including the control, and did not show any relation to dose level. Two visceral variations, dilated renal pelvis and hydroureter, occurred in several fetuses from all dose groups without any dose-response relationship.
Details on embryotoxic / teratogenic effects:
- Of the pups delivered naturally, gross examination at necropsy on day 21 postpartum noted single occurrences of post mortem autolysis, sloped incisors, and dilated renal pelvis were noted in pups from the 0, 40, or 450 mg/kg bw/day groups, respectively. Due to the very low incidence of each necropsy finding and the lack of similar findings at 120 mg/kg/ day, all were considered of spontaneous origin.

Effect levels (fetuses)

Dose descriptor:
NOEL
Effect level:
450 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: Not embryotoxic, fetotoxic, or teratogenic at highest dose tested

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
A pre-, peri-, and postnatal repeated dose toxicity study was conducted to evaluate the effects of oral (gavage) exposure to 2-aminoethanol on embryonic, fetal, and postnatal development in pregnant rats. Maternal toxicity was evidenced primarily as decreased feed consumption and decreased body weight/body weight gain in rats administered 450 mg/kg bw/day. As such the NOEL for maternal toxicity was determined to be 120 mg/kg bw/day. The present study showed that 2-aminoethanol was not embryotoxic, fetotoxic, or teratogenic following gavage exposure of pregnant Wistar rats to maternally toxic dose levels. Thus, a NOEL for developmental effects was established at 450 mg/kg bw/day, the highest dose tested. Based on all of the available data, the weight of evidence would suggest that 2-aminoethanol has a low potential for developmental effects even at doses which are maternally toxic.

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