Reaction mass of 2-aminoethanol and 6-[(p-tosyl)amino]hexanoic acid, compound with 2-aminoethanol (1:1)

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:

supporting study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

publication

Title:

Evaluation of the pre-, peri-, and postnatal toxicity of monoethanolamine in rats following repeated oral administration during organogenesis.

Author:

Hellwig J, Liberacki AB

Year:

1997

Bibliographic source:

Fundam Appl Toxicol. 1997 Nov;40(1):158-62.

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

Exposure to the test substance limited to the period of organogenesis (days 6 to 15 of gestation)

Principles of method if other than guideline:

40 pregnant rats/group were exposed to different dose levels of the test item through day 6 to 15 of gestation. On day 20, 25 animals/group were sacrificed and the foetuses extracted for analysis. The remaining 15 animals/group delivered, parents and pups were sacrificed at day 21 post-partum for analysis.

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

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report): Monoethanolamine (MEA) provided by BASF AG (Ludwigshafen, Germany)- Physical state: Liquid- Analytical purity: 100%

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Karl Thomae (Biberach an der Riss, Germany)- Weight at study initiation: 200 - 300 g (female rats)- Housing: Stainless steel wire-bottom cages during breeding and until day 18 of gestation. At day 18, pregnant females were put in nesting cages with cellulose wadding).- Diet: ad libitum- Water: ad libitum- Acclimation period: 5 daysENVIRONMENTAL CONDITIONS- Temperature: 22°C +/- 2°C- Humidity: 50% +/- 20%- Photoperiod: 12hrs dark / 12hrs light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

VEHICLE- Amount of vehicle: 10 ml/kg

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: cohoused- M/F ratio per cage: 1 male / 2-4 females- Length of cohabitation: one 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:

Through day 6 to 15 of gestation.

Frequency of treatment:

Daily

Duration of test:

25 animals/group are sacrificed at day 20 of gestation15 animals/group are sacrificed at day 21 post-partum

No. of animals per sex per dose:

40 pregnant rats

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: A preliminary study was performed. Highest dose was selected in order to induce maternal toxicity but no death or suffering.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes- Time schedule: dailyDETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: dailyBODY WEIGHT: Yes- Time schedule for examinations: Days 0, 1, 3, 6, 8, 10, 13, 15, 17, and 20 of gestation, and days 4, 7, 14, and 21 post-partumFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes. Starting on Day 0 of gestation: every 2-3 days.WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data- Time schedule for examinations:POST-MORTEM EXAMINATIONS: Yes- Sacrifice on gestation day 20

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: YesExaminations included:- Gravid uterus weight: Yes- Number of corpora lutea: Yes- Number of implantations: Yes- Number of resorptions: Yes

Fetal examinations:

- External examinations: Yes: [all per litter]- Soft tissue examinations: Yes: [all per litter]- Skeletal examinations: Yes: [half per litter]- Head examinations: No data

Statistics:

- Fisher's exact test used for maternal mortality, pregnancy rate, female fertility and gestation indexes, number of liveborn and stillborn pups, and pup survival.- Dunnett's test and Analysis of variance used for feed consumption, body weight, body weight changes, body weight gain, gravid uterine weight, fetal and placental weights, number of corpora lutea, implants, resorptions, live fetuses and pre-implantation/post-implantation lossess, pup body weights, duration of gestation, number of pups delivered per litter.- Wilcoxon test used for evaluation of the proportion of fetuses with malformations/variations.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: significant reduction of the body weightsDetails on maternal toxic effects:Animals treated at 450 mg/kg bw/day showed significant reduction in food consumption. No significant reduction was observed for the other doses.Animals treated at 450 mg/kg bw/day showed significant reduction in body weight and body weight gain. No significant reduction was observed for the other doses.One animal treated at 40 mg/kg bw/day died. It was not considered as significant.No significant differences were observed regarding pregnancy rate, numbers of corpora lutea, number of implantations, resorptions, and viable fetuses, litter size, mean fetal body weight, or gravid uterine weight at any dose.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

> 450 mg/kg bw/day (actual dose received)

Basis for effect level:

other: developmental toxicity

2

Dose descriptor:

NOAEL

Effect level:

> 120 mg/kg bw/day (actual dose received)

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effectsDetails on embryotoxic / teratogenic effects:No significant differences in the sex ratio and mean fetal weights were observed at any dose.No dose-related increased in the incidence of malformations were observed. Sporadic malformations included microphthalmia, dilated renal pelvis, hydroureter, dilatation of the right or both heart ventricles, dextrocardia, unilobular lung, hyperplasia or hypoplasia of the kidneys, and asymmetrical thoracic vertebral bodies.One fetus from the 450 mg/kg bw/day group showed anasarca as a malformation. This was not considered as significant. No significant effects were observed for pups from litters in any dose group, apart from sporadic reductions of body weights until Day 14 post-partum in treated litters. These effects were not considered as dose-related.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The developmental toxicity of the test item was determined according to a method similar to OECD 414. The NOAEL (developmental) is above 450 mg/kg bw/day, which is the highest concentration evaluated during this study. As the highest dose was selected in order to induce maternal toxicity, the NOAEL (maternal) is 120 mg/kg bw/day.

Executive summary:

The prenatal developmental toxicity of the test substance was determined according to a method similar to the OECD Guideline for Testing of chemicals 414. The developmental toxicity of the substance dispersed in water was studied in rats following a daily exposure through day 6 to 15 of gestation during the organogenesis. A preliminary study was performed in order to determine a highest dose that would induce some maternal toxicity but not death or severe suffering. The selected doses were 0, 40, 120 and 450 mg/kg bw/day.

25 animals per dose were sacrificed at Day 20 of gestation - one day before the parturition - while 15 animals per dose were allowed to deliver. Remaining parents and pups were sacrificed at Day 21 post-partum at the end of the lactation.

Body weights were recorded on days 0, 1, 3, 6, 8, 10, 13, 15, 17, and 20 of gestation, and days 4, 7, 14, and 21 post-partum. All animals were observed daily for appearance and behaviour. Food consumption was determined every 2-3 days.

Sacrificed animals were all subject to post-morterm examination. Gravid animals were examined from uterus weight, and number of corpora lutea, implantations, and resorptions. Fetuses underwent external examination, along with soft tissue examination. Half were stained with alizarin red-S for skeletal examination.

Animals delivered by the surviving females were examined for liveborn and stillborn, sexed, weighed on Day 1, 4, 7, 14, and 21 post-partum. Litters were examined daily for mortality and clinical symptoms. All animals were examined for external and internal examination.

In accordance with the preliminary testing, the highest dose of 450 mg/kg bw/day induced some maternal toxicity with a significant reduction of the food consumption, which led to a significant reduction in body weight and body weight gain. No other significant effects were reported for any dose. It was concluded that the NOAEL (developmental toxicity) was 450 mg/kg bw/day, as the highest dose tested had no significant effects.