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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:
key study
Study period:
Mar 31, 1989 - April 27, 1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
1981
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Version / remarks:
Nov 1984
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Testing Guidelines for Toxicology Studies, pp. 48-49 (Japan/MAFF)
Version / remarks:
1985
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
(2RS,3RS)-3-(2-chlorophenyl)-2-(4-fluorophenyl)-[(1H-1,2,4-triazol-1-yl)methyl]oxirane
EC Number:
406-850-2
EC Name:
(2RS,3RS)-3-(2-chlorophenyl)-2-(4-fluorophenyl)-[(1H-1,2,4-triazol-1-yl)methyl]oxirane
Cas Number:
133855-98-8
Molecular formula:
C17 H13 Cl F N3 O
IUPAC Name:
1-{[(2R,3R)-3-(2-chlorophenyl)-2-(4-fluorophenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazole

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, FRG
- Age at study initiation: 11-12 weeks
- Weight at study initiation: ca. 242 g
- Fasting period before study: no
- Housing: single
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12 (illumination: 6 am to 6 pm)

IN-LIFE DATES: From: March 30/April 5/April 6, 1989 To: April 20/April 26/April 27, 1989

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
doubly distilled water with 0.5% CMC
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Freshly prepared each day before treatment of animals
- Volume of administration: 5 ml/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical verifications of the stability of the test substance in doubly distilled water and its distribution were carried out before the beginning of the study. Furthermore, samples of each preparation of the test substance in . doubly distilled water with 0.5% carboxymethyl were sent to the analytical laboratories twice during the study period for verification of the concentrations.The test substance suspensions were analyzed by HPLC.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1-4
- Length of cohabitation: From about 16.00 hours to 7.30 hours the following morning
- Further matings after two unsuccessful attempts: no
- 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:
From Day 6 through Day 15 post coitum
Frequency of treatment:
once daily
Duration of test:
15 days (without acclimatization)
Doses / concentrationsopen allclose all
Dose / conc.:
5 mg/kg bw/day (nominal)
Dose / conc.:
15 mg/kg bw/day (nominal)
Dose / conc.:
45 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: An acute oral toxicity study, single intraperitoneal administration, preceding test study in which pregnant rats were dosed, range-finding study
- Rationale for animal assignment (if not random): random
- Rationale for strain selection: This strain was selected since extensive experience is available on Wistar rats and this strain has been proved to be sensitive to substances with a teratogenic potential.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily for clinical symptoms, twice daily for mortality

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed on days 0, 1. 3. 6. 8. 10, 13. 15, 17 and 20 p.c. Furthermore, the corrected body weight gain was calculated after terminal sacrifice

FOOD 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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Uterus, ovaries

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
- Dead fetuses: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No
Statistics:
Dunnett's Test (1955, 1964) was used for statistical evaluation of food consumption, body weight, body weight change, corrected body weight gain (net maternal body weight change), weight of the uterus before it was opened, weight of fetuses, weight of placentae, corpora lutea, implantations, pre- and postimplantation losses, resorptions and live fetuses.
Fisher's Exact Test (1981) was used for statistical evaluation of conception rate, mortality (of the dams) and all fetal findings.
Significances resulting from these tests have been indicated in the tables (a for p < 0.05; b for p < 0.01).
Indices:
Conception rate, preimplantation loss, postimplantation loss
Historical control data:
available

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
- 45 mg/kg bw/day: reduced body weight gains during the first days of the treatment period (days 6 - 8 p.c.)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
- 45 mg/kg bw/day: reduced food consumption during the treatment period, especially on days 6 — 8 and 13 - 15 p.c.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
15 mg/kg bw and above: slight increase in placental weights; within historical controls; considered non-adverse
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
- 5 mg/kg bw/day: one animal, which did not become pregnant, showed hydrometra
Lung edema and/or marginal emphysema (findings. which have to be related to the sacrifice of the animals) were noted for several dams of test groups 0, 5 and 15 mg/kg body weight/day without any dose-response relationship.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
- The conception rate varied between 84% (control) and 96% (test group 5 mg/kg body weight)

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
effects observed, treatment-related
Description (incidence and severity):
- 45 mg/kg bw/day: marginally increased postimplantation loss (as a consequence of increased resorptions)
- no adverse effects on pre-implantation loss
Total litter losses by resorption:
no effects observed
Early or late resorptions:
effects observed, treatment-related
Description (incidence and severity):
- 45 mg/kg bw/day: slightly increased number of resorptions (especially late ones)
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
- number of corpora lutea
- conception rate
- implantation sites

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
15 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
early or late resorptions
food consumption and compound intake
pre and post implantation loss

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
not examined
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:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
- mg/kg bw/day: malformations (micrognathis, cleft palate, microtia) observed in just one fetus are assessed as being of spontaneous nature due to a missing dose-response relationship
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
- 45 mg/kg bw/day: Variations: markedly increased number of fetuses with skeletal variations (especially rudimentary cervical and/or accessory 14th rib(s))
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
- mg/kg bw/day: Two malformations (dilation of one or both heart ventricles) in two fetuses
Other effects:
effects observed, treatment-related
Description (incidence and severity):
- 45 mg/kg bw/day: statistically significantly increased placental weights
- 15 mg/kg bw/day: statistically significantly increased placental weights (within historical controls; considered non-adverse)
Details on embryotoxic / teratogenic effects:
Taking into account the summarized results of the external, soft tissue and skeletal examinations of the fetuses, the only findings, which are assessed as substance-induced ones, are the increased occurrence of high dose fetuses with rudimentary cervical and/or accessory 14th rib(s).
Due to the high frequency of both findings in the 45 mg/ kg fetuses, the incidence of skeletal and overall variations is statistically significantly increased in comparison to the control group.
A number of publications deals with the finding of supernumerary ribs in fetuses.
Various interpretations and assessments are given in these papers about the significance of increased occurrence of supernumerary ribs in rat fetuses for prenatal toxicity studies.
According to WICKRAMARATNE (1988) an increase in supernumerary ribs "should be considered not as indicative of fetal dysmorphogenesis but as a manifestation of a non—specific stress the dam is placed under in such (i.e. prenatal toxicity) studies.... An increase in frequency of supernumerary ribs could therefore be evidence that a minimal toxic dose had been achieved...."
KIMMEL and WILSON (1973) state that "when an increase in either rudimentary or extra ribs occurs during teratogenicity testing. it may be assumed that the maternal animal is being stressed sufficiently to express the developmental instability inherent in the species. The expectation would be if other teratogenic effects did not occur at that dose level. that at a higher dose, frank embryotoxicity would become evident“.
The latter statement is exactly in—line with the results of the preceding range-finding study in which at the highest dose level (180 mglkg body weight/day) and in the presence of overt maternal toxicity clear signs of embryotoxicity (including teratogenicity) were obvious.
Therefore, the increased number of 45 mglkg fetuses with rudimentary cervical and/or accessory 14th rib(s) in the present study is finally assessed as an embryotoxic effect representing a manifestation of a non-specific stress on the dams: it is, however. not interpreted as being a teratogenic effect of the test substance at this dose level.
All other differences between the actual control group and the substance-treated groups concerning fetal external. soft tissue and/or skeletal observations are without biological relevance and/or appear to about the same extent in the historical control data.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
15 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: increase in number of resorptions, postimplantation losses, skeletal variations

Fetal abnormalities

Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: rib

Overall developmental toxicity

Developmental effects observed:
yes
Lowest effective dose / conc.:
45 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects occurring together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes

Applicant's summary and conclusion