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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
Study period:
1986-03-19 to 1986-12-01
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report date:
2016

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
3-iodo-2-propynyl butylcarbamate
EC Number:
259-627-5
EC Name:
3-iodo-2-propynyl butylcarbamate
Cas Number:
55406-53-6
Molecular formula:
C8H12INO2
IUPAC Name:
3-iodoprop-2-yn-1-yl butylcarbamate
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Lot/batch No.of test material: P 2710-8511-R100

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga GmbH
- Age at study initiation: sexually mature
- Weight at study initiation: 175 - 245 g (females)
- Housing: individually after mating
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 25 °C
- Humidity: 40 - 70 %
- Photoperiod: 12/12 hrs dark / hrs light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Test article was daily prepared es solution in corn oil. Separate preparations were made for each dose level.

VEHICLE
- Justification for use and choice of vehicle: good solubility of test item
- Concentration in vehicle: 0, 2.0, 5.0, 12.5 mg/mL
- Amount of vehicle: 10 mL/kg bw/d
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1 : 4
- Length of cohabitation: overnight
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
ten consecutive days (gestation day 6 to 15)
Frequency of treatment:
daily
Duration of test:
animals were necropsied at gestation day 20
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
20 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
125 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Control: 38
Low Dose: 28
Mid Dose: 33
High Dose: 30
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Preliminary study
- Rationale for animal assignment: randomly allocation immediatly after mating

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: evaluation on gestation day 0, 6, 10, 15, 20

FOOD CONSUMPTION AND COMPOUND INTAKE: No

WATER CONSUMPTION AND COMPOUND INTAKE: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: ovaries and uteri
- Data recorded: live foetuses, early resorptions, late resorptions, dead foetuses, individual foetal weights, sex of foetuses
- Intrauterine deaths were classified as follows: Early resorptions showed decidual or placental tissues only; Late resorptions showed embryonic or foetal tissue in addition to placental tissue but excluded foetuses dying in utero within approximately two days prior to the terminal kill; Dead foetuses included only the foetuses dying in utero within approximately the last two days.
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
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No
- Other: Structural deviations were classified as:
- Malformations: rare and/or probably lethal e.g. hydrocephaly.
- Variations: changes which regularly occur also in control groups and which are not of functional significance.
- Retardations: delayed development as compared with the normal development at a particular point of time.
Statistics:
Data were processed where appropriate to give mean values, group mean values and standard deviations.
Group mean values for implantations, intra-uterine deaths and post-implantation losses were calculated in two ways:
Mean A: all animals with live foetuses at termination
Mean B: all surviving animals that provided evidence of pregnancy including those showing total intra-uterine deaths
For litter and mean foetal weights only Mean A was calculated.
Group mean calculations were normally based on individual values except for foetal weights where calculations were based on litter means.
All values expressed as a percentage were first calculated within the litter and then summarized per group as the mean of individual litter percentages (except sex ratio).

Group mean body weight, group mean body weight gain, and group mean foetal weight were statistically analysed using the Student's t-test.

All tests (control group versus dose groups) were carried out at 0.1 per cent, 1 per cent, and 5 per cent significance levels.
Indices:
Percentage pre-implantation loss was calculated for each litter as:
Number of corpora lutea - number of implantations divided by the Number of corpora lutea multiplied by 100

Percentage post-implantation loss was calculated for each litter as:
Number of implantations - number of live foetuses divided by the Number of implantations multiplied by 100

Percentage sex ratio was calculated as:
Number of males divided by Number of foetuses multiplied by 100
or
Number of females divided by Number of foetuses multiplied by 100

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related clinical signs were observed in the treated animals.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One animal in group 2 (20 mg/kg bw/d) died on day 8 of gestation probably due to improper gavaging.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In group 4 (125 mg/kg), body weight gain was statistically significantly reduced from day 6 to 10 of gestation. From day 10 onwards, weight gain was comparable with the control group. At 20 and 50 mg/kg (group 2 and 3) body weight gain was comparable with the control group in spite of statistical significances found for group 3.
Food consumption and compound intake (if feeding study):
not examined
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:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
Occasional minor findings at necropsy of the remaining animals killed on day 20 of gestation were detected in all groups including the controls.
Macroscopic examination at necropsy showed no treatment-related changes.
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
Description (incidence and severity):
There was no effect of treatment on implantations. Intergroup variations in pre-implantaion loss were not compound-related.
When all intra-uterine deaths are included the post-implantation loss was increased in group 3 (50 mg/kg bw/d) and group 4 (125 mg/kg bw/d) by the occurrence of 100 per cent intra-uterine death in two and one animal, respectively. This finding is considered to be incidental.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
Two animals in group 3 (50 mg/kg) and one animal in group 4 (125 mg/kg) showed 100 per cent intra-uterine death at necropsy.
The mean number of total intra-uterine death calculated from animals with live foetuses in utero at necropsy was comparable in all groups.
Changes in pregnancy duration:
not examined
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
Description (incidence and severity):
Pregnancy was not affected by treatment.
Other effects:
no effects observed

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Key result
Dose descriptor:
LOAEL
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
The mean foetal weight was comparable in all groups.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex distribution in the treated groups was comparable with the control group.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
The mean number of foetuses per dam was comparable in all groups.
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
On control foetus showed externally one finger of the right forelimb reddened.
In group 3 (50 mg/kg bw/d) one foetus showed viscerally a cleft palate and bilateral anophthalmia.
In group 4 (125 mg/kg bw/d) two foetuses with malformations were observed. One foetus showed a scoliosis and the second an open eye and a shortened mandible.

The nature and low incidence of these defects were such that their occurrence must be considered incidental.
Skeletal malformations:
no effects observed
Description (incidence and severity):
The incidence of skeletal variations was comparable in all groups.
However, in group 4 (125 mg/kg), a higher incidence of incompletely ossified cranial bones was observed. This delayed ossification is probably only a temporary condition which can be an incidental finding or is due to other reasons than an embryotoxic effect, e.g. decreased maternal body weight gain during the early treatment period.
Visceral malformations:
no effects observed
Description (incidence and severity):
Visceral variations as dilatation of the renal pelvis were observed in one foetus of group 2 (20 mg/kg bw/d) and 3 (50 mg/kg bw/d).
Other effects:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
> 125 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

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Oral administration of test item at a dose level of 125 mg/kg bw/d by oral route during the period of organogenesis (day 6 to 15 of gestation) revealed slight maternal toxicity in form of reduced body weight gain from day 6 to 10 p.c. An embryotoxic effect, especially a teratogenic effect, was not observed. Dose levels of 20 and 50 mg/kg bw/d did not elicit maternal toxicity, embryotoxicity, or teratogenicity.
Executive summary:

Groups of 28, 33, or 30 sexually mature and mated female Sprague Oawley Albino rats received test item by oral route at dosages of 20, 50, or 125 mg/kg bw/d for ten consecutive days from day 6 to 15 of qestation. A further group of 38 rats which received the vehicle (corn oil) over the same period served as the control group. The animals were sacrificed on day 20 of gestation. Results can be summarized as follows:

1. No effects of dosing on clinical condition and no treatment-related necropsy findings were observed in the treated animals or in the control

2. Treatment with the test item at 125 mg/kg bw/d was associated with a slight reduction of body weight gain from day 6 to 10 p.c.

3. There was no effect of treatment on pregnancy incidence, pre-implantation loss, or post-implantation loss.

4. There was no effect of treatment with the test item on the number, weight, or sex of the foetuses.

5. There was no indication for an effect of treatment on the incidence of malformations.

At 125 mg/kg, a slightly retarded ossification of cranial bones was observed.This finding is probably only a temporary condition which can be an incidental finding or is due to other reasons than an embryotoxic effect.

Administration of test item at a dose level of 125 mg/kg bw/d by oral route during the period of organogenesis (day 6 to 15 of gestation) revealed slight maternal toxicity in form of reduced body weight gain from day 6 to 10 p.c. An embryotoxic effect, especially a teratogenic effect, was not observed. Administration of test item at dose levels of 20 and 50 mg/kg bw/d did not elicit maternal toxicity, embryotoxicity, or teratogenicity.