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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Proprietary study, guideline comparable and well reported

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1976
Reference Type:
publication
Title:
Teratogenicity of Acrylonitrile Given to Rats by Gavage or by Inhalation
Author:
Murray FJ, Schwetz BA, Nitschke KD, John JA, Norris JM & Gehring PJ
Year:
1978
Bibliographic source:
Food and Cosmetics Toxicology, Vol. 16, pages 547-551

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Remarks:
: study pre-dates GLP
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Acrylonitrile
EC Number:
203-466-5
EC Name:
Acrylonitrile
Cas Number:
107-13-1
Molecular formula:
C3H3N
IUPAC Name:
acrylonitrile

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
Female pregnant (mated) Sprague-Dawley rats

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
Mated female rats were exposed to 0, 10, 25, or 65 mg/kg bw/d acrylonitrile by gavage on days 6 -15 of gestation
Analytical verification of doses or concentrations:
no
Details on mating procedure:
No information available
Duration of treatment / exposure:
Daily on days 6 through 15 of gestation
Frequency of treatment:
Daily
Duration of test:
10 days
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Remarks:
Vehicle control
Dose / conc.:
10 mg/kg bw/day
Dose / conc.:
25 mg/kg bw/day
Dose / conc.:
65 mg/kg bw/day
No. of animals per sex per dose:
29-39 females per group
Control animals:
yes, concurrent vehicle
Details on study design:
Pregnant rats were exposed to 0, 10, 25, or 65 mg/kg/day acrylonitrile by gavage on days 6 through 15 of gestation

Examinations

Maternal examinations:
Daily clinical examination and periodic determination of bodyweight, food and water consumption.
Ovaries and uterine content:
The numbers and positions of implantation sites, live, dead and resorbed foetuses were recorded.
Fetal examinations:
All foetuses were examined macroscopically for external abnormalities and cleft palate, one-third were then examined for visceral abnormalities under a dissecting stereo-microscope and the heads were examined by the razor-section technique of Wilson. Examinations included sex and body weight. All remaining foetuses were examined for skeletal alterations.
Indices:
Incidence of pregnancy, numbers of implantations per dam, live foetuses per litter, resorptions per litter, foetal body weight and crown-rump length
Historical control data:
No information available.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: Clinical signs, reduced weight gain and food consumption at 65 mg/kg bw/d. Local gastric irritation at 25 and 65 mg/kg bw/d.

Details on maternal toxic effects:
Animals receiving 65 mg/kg bw/d acrylonitrile in drinking water showed hyperexcitability and excessive salivation, and body weight was significantly decreased compared with controls between days 6 and 15. Food consumption was decreased in the early stages of the study while water consumption was increased in the later stages. One dam at this dose level died on day 1 of the study. Bodyweight was unaffected by acrylonitrile administration at the lower dose levels.

Treated dams had increased liver weights. Thickening of the glandular forestomach was observed in the majority of animals receiving 65 mg/kg bw/d and in 3/39 animals receiving 25 mg/kg bw/d. Sialodacryadenitis (indicated by the presence of swollen salivary glands) was noted in many animals including controls.

The incidence of pregnancy was significantly decreased in rats at 65 mg/kg bw/d (69% compared with 88% in controls, p <0.05) and implantation sites were detected in 4 apparently non-pregnant dams at this dose level (14%). No effect on the incidence of pregnancy was seen at lower dose levels, and no effect was detected on numbers of implantations per dam, live foetuses per litter or resorptions per litter at any dose level.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: Reduced pup weight and skeletal abnormalities

Details on embryotoxic / teratogenic effects:
Foetal body weight was significantly decreased at 65 mg/kg bw/d (7.4% decrease, p < 0.05) and crown rump length was also decreased (1.9% decrease, p < 0.05).
In foetuses examined for skeletal and visceral abnormalities, short tail occurred significantly more often among the litters of dams given 65 mg/kg bw/d than in control litters (in 8/212 foetuses examined at 65 mg/kg bw/d, compared with 1/443 in controls, p < 0.05). Short-tailed foetuses also had missing vertebrae, ranging from lack of one lumbar vertebra to lack of all sacral, lumbar and most thoracic vertebrae, with associated ribs. Additional malformations in these foetuses included short trunk (3/212 foetuses, with 0/443 in controls) imperforate anus (2/212), right-sided aortic arch (1/212), missing kidney (1/212) and anteriorly-placed ovaries (1/212). There were also increases in the incidence of minor skeletal abnormalities in the 65 mg/kg bw/d offspring compared with controls, these included delayed ossification of sternebrae, split sternebrae and delayed ossification of cervical vertebrae. At 25 mg/kg/day no malformation occurred with an incidence statistically that was significantly different to that seen in the controls, although a number of the same malformations seen in the 65 mg/kg bw/d group also occurred at this dose level.

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
external malformations

Fetal abnormalities

Key result
Abnormalities:
effects observed, treatment-related
Localisation:
external: tail
Description (incidence and severity):
hort tail occurred significantly more often among the litters of dams given 65 mg/kg bw/d than in control litters (in 8/212 foetuses examined at 65 mg/kg bw/d, compared with 1/443 in controls, p < 0.05). Short-tailed foetuses also had missing vertebrae, ranging from lack of one lumbar vertebra to lack of all sacral, lumbar and most thoracic vertebrae, with associated ribs. Additional malformations in these foetuses included short trunk (3/212 foetuses, with 0/443 in controls) imperforate anus (2/212), right-sided aortic arch (1/212), missing kidney (1/212) and anteriorly-placed ovaries (1/212). There were also increases in the incidence of minor skeletal abnormalities in the 65 mg/kg bw/d offspring compared with controls, these included delayed ossification of sternebrae, split sternebrae and delayed ossification of cervical vertebrae.

Overall developmental toxicity

Key result
Developmental effects observed:
not specified
Lowest effective dose / conc.:
65 mg/kg bw/day
Treatment related:
yes

Any other information on results incl. tables

Whilst the study is well-conducted, it may have been compromised by SDA virus infection.

Foetal toxicity

Dose (mg/kg/day)

0

10

25

65

Foetal body weight (g)

5.68±0.28

5.78±0.25

5.80±0.33

5.26*±0.32

Foetal crown-rump length (mm)

44.4±1.0

44.5±1.3

45.0±1.2

43.6*±1.2

* statistically significant (p< 0.05)

Selected developmental anomalies and variants

Dose (mg/kg/day)

 

0

10

25

65

External

Number evaluated (foetuses/litters)

443/38

388/35

312/29

212/17

Missing tail

Fa

0

0

2(0.6)b

4(2)*

L

0

0

2(7)

4(23)

Missing or short tail

F

1(0.2)

0

2(0.5)

8(4.0)*

L

1(3)

0

2(7)

6(35)

Short trunk

F

0

0

0

3(1)*c

L

0

0

0

3(18)

Imperforate anus

F

0

0

0

2(1)c

L

0

0

0

2(12)

Soft tissue

Number evaluated (foetuses/litters)

154/38

135/35

111/29

71/17

Right sided aortic arch

F

0

0

1(1)

1(1)c

L

0

0

1(3)

1(6)

Anteriorly displaced ovaries

F

0

0

1(1)c

1(1)c

L

0

0

1(3)

1(6)

Skeletal

Number evaluated (foetuses/litters)

443/38

388/35

312/29

217/17

Missing vertebra (other than 1 thoracic and 1 lumbar)

F

1(0.2)c

0

2(0.6)c

4(2)*c

L

1(3)

0

2(7)

6(35)

Missing vertebral centra (other than C1 and C2)

F

23(5)

30(8)

31(10)

71(34)*

L

11(29)

16(46)

13(46)

15(88)

Missing ribs (more than 1 pair)

F

0

0

2(1)c

4(2)*c

L

0

0

2(7)

4(24)

* statistically significant (p< 0.05)

a F= foetuses; L= litters

b Number affected (% affected)

c Alteration seen only in foetuses that also showed short or no tail at this dose level

Applicant's summary and conclusion

Conclusions:
Some evidence of developmental toxicity was seen in this study at the highest (and maternally toxic) dose level of 65 mg/kg bw/d.
Executive summary:

Mated female Sprague-Dawley rats (29 -39/group) were gavaged with acrylonitrile (in water) at dose levels of 0, 10, 25 or 65 mg/kg bw/d on Days 6 -15 of gestation. Dams were observed for clinical signs, bodyweight, food and water consumption. Dams were killed on Day 21 and the uterine contents examined. All foetuses were examined for external abnormalities, one third for visceral abnormalities and two thirds for skeletal findings.

Mortality, signs of toxicity (hyperactivity and salivation), reduced weight and food consumption and increased water consumption were noted in the high dose group. Necropsy revealed gastric irritation in most animals at 65 mg/kg bw.d and a small number at 25 mg/kg bw/d. Post-implantation loss was increased at the high dose level; reduced foetal weight and length was also apparent in this group. No effects were seeen in the other treated groups. A higher incidence of short tail was seen in foetuses at 65 mg/kg bw/d, with other abnormalities and skeletal variations also increased in this group. No effects were seen in the lower dose groups.

Some evidence of developmental toxiicty was seen in this study at the highest (and maternally toxic) dose level of 65 mg/kg bw/d. The NOAEL for maternal toxicitiy is therefore 10 mg/kg bw/d based on the signs of gastric irritation at 25 mg/kg bw/d; the NOAEL for developmental toxicity is 25 mg/kg bw/d.