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Diss Factsheets

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:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report date:
1981

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Remarks:
Current study is similar to the guideline study. The measurement of thyroid hormones in dams is a new endpoint which has been added to the guideline in 2018, and has not been conducted in this study.
Principles of method if other than guideline:
One hundred untreated, sexually mature, virgin female Charles River COBS CD rats were used to determine teratogenic potential of the substance. The rats were approximately 14-weeks old at the time of mating. Rats were acclimated for a minimum of 10 days prior to the start of study. Animals were individually housed, except during mating. Temperature and humidity were maintained, 12-hour light and dark cycle was also controlled. Purina, certified rodent chow (5002) and tap water were provided ad libitum.

Mating.
One female and one male rat of the same strain were placed together for mating. The occurrence of copulation was determined by daily inspection for copulatory plug or by vaginal smear for sperm. The day that evidence of mating was detected was designated day 0 of gestation and the females were returned to an individual cage.

Caesarean section.
On day 20 of gestation all animals were sacrificed by carbon dioxide inhalation. Immediately following sacrifice the uterus were excised and weight prior to removal of the foetuses. The number and the location of viable and non-viable foetuses, early and late resorptions and the number of total implantations and corpora lutea were recorded. The abnormal and thoracic cavities and organs of dams were examined for grossly evident morphological changes. All foetuses were individually weight and examined for external malformations and variations, including the palate. Each foetus were externally sexed and numbered and tagged for identification.

Positive control.
Aquasol® Vitamin A was used a positive control. Fourteen sexually active female Charles River COBS CD rats were approximately 17 weeks of age at the time of mating used in the study. Vitamin A was administered orally by gavage as a single dose on day 10 of gestation at 100, 000 I.U./rat and constant volume of 2 ml/rat. The negative control group received Mazola® corn oil at constant volume of 10 ml/mg as a single daily dose from days 6 through 19 of gestation. A 100 % survival was seen in both groups. There was a mass located in the right lateral neck region in one dam (Vitamin A group), which has been identified by histopathology as mammary adenocarcinoma. A slight decrease was observed in mean maternal body weight gain over the entire gestation period. Malformations were observed in 100% of the litters examined in Vitamin A treated group, which was statistically significant. The following malformations were noted in 96.3% of examined foetuses: eye anomalies, cleft palate, facial papillae and other head anomalies, scoliosis, vertebral variations and increased incidence of 14th rudimentary ribs.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Propiononitrile
EC Number:
203-464-4
EC Name:
Propiononitrile
Cas Number:
107-12-0
Molecular formula:
C3H5N
IUPAC Name:
propanenitrile
Test material form:
liquid
Specific details on test material used for the study:
Identification: Propionitrile
Lot number: PCN sample dated October 10th, 1979 @ 1000 HRS
Batch number: PCN sample dated October 10th, 1979 @ 1000 HRS
Physico-chemical properties: Dark amber liquid, MP-91.8 °C, BP 97.2 °C
Purity: >90%
Supplier: Monsanto Company, St Louis, Missouri
Date received: November 6th, 1979
Shelf life: Stable indefinitely
Storage conditions: Ambient temperature, closed container

Test animals

Species:
rat
Strain:
other: COBS CD
Details on test animals or test system and environmental conditions:
One hundred untreated, sexually mature, virgin female Charles River COBS CD rats were used to determine teratogenic potential of the substance. The rats were approximately 14-weeks old at the time of mating. Rats were acclimated for a minimum of 10 days prior to the start of study. Animals were individually housed, except during mating. Temperature and humidity were maintained, 12-hour light and dark cycle was also controlled. Purina, certified rodent chow (5002) and tap water were provided ad libitum.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
no
Details on mating procedure:
One female and one male rat of the same strain were placed together for mating. The occurrence of copulation was determined by daily inspection for copulatory plug or by vaginal smear for sperm. The day that evidence of mating was detected was designated day 0 of gestation and the females were returned to an individual cage.
Duration of treatment / exposure:
Single dose administered on days 6 through 19 of gestation.
Frequency of treatment:
Daily as a single dose
Duration of test:
Days 0 through 20 of gestation.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
20 mg/kg bw/day
Dose / conc.:
40 mg/kg bw/day
Dose / conc.:
80 mg/kg bw/day
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
Prior to and during the treatment animals were observed daily for mortality, overt changes in appearance and behaviour and weight changes. Animals were observed daily for mortality and clinical signs of toxicity on days 6 through 20 of gestation. Any dam not surviving to the scheduled sacrifice date was necropsied to determine the cause of death.
Maternal individual body weights were recorded on days 0, 6, 9, 12, 16 and 20 of gestation. Maternal tissue were preserved for microscopic examination in 10% neutral buffered formalin when deemed necessary by gross findings.
Ovaries and uterine content:
Uterus weights have been reported for individual animals in all treatment and control groups.
Fetal examinations:
All foetuses were individually weighed and examined for external malformations and variations.
Morphological observations. All external, visceral and skeletal malformations and developmental and genetic variations were recorded.
Malformations observed: scoliosis with associated rib anomalies, bent ribs, hydrophthalmia, diaphragmic hernia, abdominal closure defect, foetal anasarca.
Total malformations of both foetuses and litters were recorded, including external, soft and skeletal tissue malformations.
Variations - developmental and genetic observed: 27 presacral vertebrae, 14th rudimentary bibs, 14th full ribs, 12 full pair of ribs with 13th rudimentary ribs, reduced ossification of scull, sternebrae 5 and /or 6 and other sternebrae unossidied, hyoid body and pubis unossidied, sternebrae misaligned, renal papillae not developed and /or distended ureter.
Statistics:
All statistical analysis compared the treatment groups to the control group with the level of significance at p<0.05. The male to female foetal sex distribution and the number of litters with malformations were compared using Chi-square test criterion with Yates correction for 2 x 2 contingency tables and /or Fisher's exact probability test to judge significance of the difference.
The number of early and late resorptions and post implantation loss were compared by the Mann-Whitney U-test to determine the significant difference.
The mean number of viable foetuses, total implantations, corpora lutea and mean foetal body weights were compared by analysis of variance (one-way classification) Bartlett's test for homogeneity of variances and the appropriate t-test (for equal or unequal variances) using Dunnett's multiple comparisons tables to determine the significant difference.
Historical control data:
This laboratory has historical control data on the incidence of foetal malformations and variations in this strain from the source. This laboratory has historical control data (768 animals) on the incidence of foetal malformations and variations in this strain from the source. As reported, 0 animals have died, 1 anomaly that delivered, 767 animals examined at C-section, 57 of nongravid,710 of gravid, 4 dams with only resorptions, 706 dams with live foetuses, 13.2 live foetuses/dam, 0.9 post implantation loses/dam, 14.1 implantations/dam, 15.7 of corpora lutea/dam. Foetal male : female ratio of 4710:4687. Mean foetal body weight 3.6 g.
Diaphragmic hernia was observed in foetuses in historical control.
A slight increase in the number of foetuses and litters with sternebrae and/or unossified was noted in the 40 mg/kg/day, and this number was nearly comparable to historical control.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
There were no biologically meaningful differences in the appearance or behaviour of rats in the 20 and 40 mg/kg/day substance treated groups comparing to the control. Occasional instances of hair loss, primarily from the forelimbs, and matted haircoat were noted with similar frequency in all dosage groups.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One animal died in the 80 mg/kg/day dosage group on gestation day 9. The cause of death could not be determined at necropsy examination for this animal. Survival was 100% in the remaining treatment groups and the control group.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was a slight to moderate reduction in mean maternal body weight gain over the entire treatment period observed in the 80 mg/kg/day treatment group.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Postpartum finding revealed hydrometra in one dam in the 20 mg/kg/day group. One dam in the 80 mg/kg/day group also developed hydrometra with an associated pouch (2 mm x 3 mm) containing a clear fluid extending from the right oviduct. In the 40 mg/kg/day group one dam had a mottled kidney.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
In the 40 mg/kg day group one dam presented with subcutaneous hard mass (1 cm x 1 cm). The mass was removed from the left longitudinal region and histopathological examinations revealed it to be adenocarcinoma derived from mammary gland tissue.

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant post implantation loss reported only in the 80 mg/kg/day dose group, which accounted for 40 early and late resorptions in total.
Total litter losses by resorption:
effects observed, treatment-related
Description (incidence and severity):
Dams in the 80 mg/kg/day dose group had a statistically significant high number of early resorptions (total of 40 late and early resorptions) compared to the control group.
Early or late resorptions:
effects observed, treatment-related
Description (incidence and severity):
Dams in the 80 mg/kg/day dose group had a statistically significant high number of resorptions (1 late resorptions and 39 early resorptions) compared to the control group (17 resorptions, all of which were early).
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
A reduced mean maternal body weight gain was noted in the 80 mg/kg/day treatment group.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
40 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
early or late resorptions
pre and post implantation loss
total litter losses by resorption

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
A slight reduction in mean foetal body weight observed in the 40 mg/kg/day group and a statistically significant reduction (p<0.01) in the 80 mg/kg/day treatment group.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
A slight reduction in mean foetal body weight observed in the 40 mg/kg/day group and a statistically significant reduction (p<0.01) in the 80 mg/kg/day treatment group.
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
There were no biologically meaningful or statistically significant differences in the number of litters with malformation in any of the treatment groups comparing to the control.
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
There was a moderate increase in the number of foetuses and litters with sternebrae ( 5 and/ or 6 unossified) and a slight increase in the number of foetuses and litters with sternebrae (1 and/ or 2, 3, and 4 unossified) in the 80 mg/kg/day group.
Visceral malformations:
no effects observed
Other effects:
not specified

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes

Fetal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: sternum
Description (incidence and severity):
Moderate increase in the number of foetuses and litters with sternebrae ( 5 and/ or 6 unossified) and a slight increase in the number of foetuses and litters with sternebrae (1 and/ or 2, 3, and 4 unossified) in the 80 mg/kg/day group.

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
80 mg/kg bw/day
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
In a reliable prenatal toxicity study the substance did not produce a teratogenic response when administered orally (via gavage) to pregnant rats at doses of up to 80 mg/kg bw/day.
Executive summary:

Pregnant Charles River COBS CD rats were used to determine the teratogenic potential of the substance. Dose levels of 20, 40 and 80 mg/kg bw/day was administered orally by gavage as a single daily dose on gestation days 6 to 19. The control group received the vehicle (distilled water) only on a comparable regime. Caesarean sections were performed on all surviving dams on gestation day 20. There were no biologically meaningful differences in appearance, behaviour or mean maternal body weight gain in the 20 and 40 mg/kg bw/day treatment groups. There were no significant differences observed in the incidence of malformations in any of the substance treatment groups when compared to the vehicle control group. There was 100% survival in the control group and the low and mid dose groups. One animal died in the 80 mg/kg bw/day treatment group on gestation day 9, however the cause of death could not be determined.  A reduced mean maternal body weight gain was noted over the entire treatment period in the high dose group. There was a statistically significant increase in the number of early resorptions and a corresponding increase in the number of post-implantation losses in the high dose group. A slight decrease in mean foetal body weight was observed in the mid dose group which was comparable to the control group. The reduction in mean foetal body weight reached statistical significance in the high dose group. An increase in the number of foetuses and litters with reduced ossification of sternebrae was noted in the high dose group. This effect was attributed to maternal toxicity and parallels the reduced mean foetal weight observed in this high dose group. The substance was considered to not produce a teratogenic response when administered to pregnant rats at dose levels of up to 80 mg/kg bw/day.