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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014
Report date:
2014

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
January 22, 2001
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:
Aug, 1998
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-mercaptoethanol
EC Number:
200-464-6
EC Name:
2-mercaptoethanol
Cas Number:
60-24-2
Molecular formula:
C2H6OS
IUPAC Name:
2-sulfanylethanol
Test material form:
liquid
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source: ATOFINA
- Lot/batch No. of test material: 63133756P0
- Appearance: Liquid / colorless, clear
- Expiration date of the lot/batch: 01 May 2014
- Purity: 99.6%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature, protected from light and under nitrogen atmosphere. The stability of the test substance under storage conditions over the test period was guaranteed by the sponsor, and the sponsor holds this responsibility.

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 10-13 weeks
- Weight at study initiation:
- Housing: 1 rat per cage
- Diet: Ground Kliba maintenance diet ad libitum
- Water : filtered tap water ad libitum
- Acclimation period: From GD 0 (day of supply) to the beginning of administration (GD6), the animals will be accustomed to the environmental conditions and to the diet

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr): 15 airchanges per hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: isotonic saline solution
Details on exposure:
5 mL/kg body weight; for test substance preparation, the specific amount of test substance will be weighed, topped up with cooled isotonic saline solution (fresenius) in a graduated flask and intensely mixed by shaking; all constituents are cooled before and during preparation; preparations are prepared at intervals which guarantee that the test substance concentrations in the vehicle remain stable
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical investigations of the test substance preparations were carried out at the Analytical Chemistry Laboratory of Experimental Toxicology and Ecology of BASF SE, Ludwigshafen, Germany.
Analytical verifications of the stability of the test substance in isotonic saline solution (Fresenius) over a period of 9 days in a refrigerator were conducted prior to the start of the study.
Samples of the test substance preparations were sent to the analytical laboratory at the beginning of administration for verification of the concentrations.
Details on mating procedure:
Animals paired by the breeder (time-mated animals) were supplied at noon on the day of evidence of mating; this day is referred to as GD0
Duration of treatment / exposure:
Animals are treated once daily from GD6-GD19
Frequency of treatment:
Once daily
Duration of test:
Dams are sacrificed on day 20
Doses / concentrationsopen allclose all
Dose / conc.:
5 mg/kg bw/day (actual dose received)
Dose / conc.:
15 mg/kg bw/day (actual dose received)
Dose / conc.:
25 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The high dose was selected based on signs of toxicity noted at a dose level of 50 mg/kg bw/d in a previously conducted OECD 422 study (test facility CIT, laboratory study number 24847 RSR, 2004) and in a maternal toxicity range-finding study (BASF project 10R0234/04R034) which preceded this definitive prenatal developmental toxicity study.

In the OECD 422 combined repeated dose with the reproductive/developmental screening test, 2 out of 10 Sprague-Dawley dams in the 50 mg/kg bw/d group died immediately prior to or during parturition with another death occurring during early lactation. Although the OECD Guideline 414 study design does not continue the dose administration through the period immediately prior to and during parturition, the presence of this toxicity was pertinent in the selection of dose levels for the definitive prenatal developmental toxicity study.

In the maternal toxicity range-finding study, 10 pregnant Wistar rats were administered the test substance by oral gavage from gestational day (GD) 6 through GD 19. One dam died on GD 18 and one dam was sacrificed in moribund condition on GD 20, showing signs of piloerection, semiclosed eyelids, apathy, and hypothermia. While it is possible that the mortality observed and the clinical signs were due to gavage errors in administering the test substance (as they were not observed in the OECD 422 study at the 50 mg/kg and higher dose levels), a conservative interpretation is that the toxicity observed was due to the test substance. For these reasons, the dose level of 50 mg/kg bw/d was considered to be potentially lethal to the dams in the OECD 414 study.

The selected high dose for the present study represented half of this lethal dose. This approved procedure of decreasing a lethal dose by a factor of two to become the high dose in a subsequent regulatory study meets the principles of guidelines OECD 414 (adopted 2001) and OPPTS 870.3700 (US EPA), as well as ECHA practical guide 10 (“how to avoid unnecessary testing on animals”; chapter 4 “animal welfare”; ECHA-10-B-17-EN, 2010) which is in compliance with EU Directive 86/609/EEC on animal protection.

The oral route was selected since this has proven to be suitable for the detection of a toxicological hazard.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS:
- Time schedule: daily, abnormalities and changes are documented

DETAILED CLINICAL OBSERVATIONS:
- Time schedule: daily

BODY WEIGHT:
- Bw is recorded on day 0, 1, 3, 6, 7, 8, 9, 10, 13, 15, 17, 19 and 20

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consuption is recoreded from GD0-1, 1-3, 3-6, 6-7, 7-8, 8-9, 9-10, 10-13, 13-15, 15-17, 17-19, 19-20

POST-MORTEM EXAMINATIONS:
- Sacrifice on gestation day #20
- Organs examined: Adrenal glands, Heart, Kidneys, Liver, Spleen

Ovaries and uterine content:
The ovaries and uterine content was examined after termination:
Examinations included:
- Weight of the unopened uterus
- Number of corpora lutea
- Number of implantations
- Number of early resorptions
- Site of implantations in the uterus
Fetal examinations:
After removal of fetuses from the uterus, the following examinations have been made:
- Weight of each fetus
- Sex
- Weight of placentas
- Gross pathological examination of fetuses after dissection from uterus
- Half of the fetuses of each dam is skines, fixed in ethyl alcohol and the skeloton and cartilage stained (method by Kimmel and Trammell)
- The other half of the fetuses is fixed in Harrisons fluid and soft tissues examined
Statistics:
Dunnett's test, Fishers exact test and Wilcoxon test

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs or changes of general behavior, which may be attributed to the test substance, were detected in any female.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
There were no substance-related or spontaneous mortalities in any females of all test groups
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The mean body weight of the dams in test groups 1-3 (5, 15 or 25 mg/kg bw/d) were generally comparable to the concurrent control group throughout the whole study period.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The mean food consumption of the dams in test groups 1-3 (5, 15 or 25 mg/kg bw/d) were generally comparable to the concurrent control group throughout the whole study period.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment-related changes among haematological parameters were observed.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No treatment-related changes among clinical chemistry parameters were observed.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No changes of behaviour were observed
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
- The mean gravid uterus weights of the animals of test groups 1-3 (5, 15 and 25 mg/kg bw/d) were not influenced by the test substance.
- There were no test substance-related differences between the test groups 0, 1, 2 and 3 (0, 5, 15 and 25 mg/kg bw/d) in absolute and relative organ weights.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
The conception rate reached 100% in all test groups (0, 5, 15 and 25 mg/kg bw/d). There were no test substance-related and/or biologically relevant differences between test groups 0, 1, 2 and 3 (0, 5, 15 and 25 mg/kg bw/d) in conception rate, in the mean number of corpora lutea and implantation sites or in the values calculated for the pre- and the postimplantation losses, the number of resorptions and viable fetuses.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
>= 25 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
One male control fetus had more than one malformation affecting the head (i.e. mandibular micrognathia, aglossia and microphthalmia). The total incidence of external malformations in treated animals did not differ significantly from the control group and was comparable to the historical control data.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
One male control fetus had associated external malformations. Furthermore, one male mid-dose fetus (15 mg/kg bw/d) had more than one malformation affecting the skeleton in different areas. The total incidence of skeletal malformations in treated animals did not differ significantly from the control group.
Visceral malformations:
no effects observed
Description (incidence and severity):
Two soft tissue variations, i.e. dilated renal pelvis and dilated ureter, were detected in all test groups including the control (test groups 0-3; 0, 5, 15 and 25 mg/kg bw/d). The incidences of these variations were neither statistically significantly different from control nor dose-dependent and therefore, not considered biologically relevant.
Other effects:
no effects observed

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 25 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion