Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
16 December 1985 - 17 January 1986
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:
1986

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Specific details on test material used for the study:
Fenitrothion
Batch No.: 41208
Purity: 96.6%

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazelton, Denver
- Age at study initiation: 4 months
- Weight at study initiation: 2.7-3.2 kg
- Housing: Individual
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 28 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-23
- Humidity (%): 15-64
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 16 December 1985 To: 17 January 1986

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Groups of 16 inseminated female HRA(NZW)SPF rabbits each received fenitrothion dissolved in corn oil, at dose levels of 0, 3, 10 and 30 mg/kg bw/d by oral gavage, daily from Days 7 to 19 of gestation at a dosage volume of 1.0 mL/kg bw.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Reserve samples of the dosing solutions were analysed for stability and achieved concentration.
Details on mating procedure:
Ovulation was induced in each females by iv injection of 250 IU HCG; females were inseminated with the sperm of males from the same strain on two occasions. The day of inseminatiom was designated GD0.
Duration of treatment / exposure:
GD7-19 (13 consecutive days).
Frequency of treatment:
Daily
Duration of test:
Dams were terminated on GD 29
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Remarks:
Vehicle control
Dose / conc.:
3 mg/kg bw/day
Dose / conc.:
10 mg/kg bw/day
Dose / conc.:
30 mg/kg bw/day
No. of animals per sex per dose:
16 inseminated females
Control animals:
yes, concurrent vehicle
Details on study design:
Doses were selcetd on the basis of range-finding studies in pregnant and non-pregnant rabbits. Animals were assigned to the treatment groups using a weight randomisation technique.

Examinations

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

BODY WEIGHT: Yes
- Time schedule for examinations: GD 0, 7, 8, 9, 13, 16, 19, 20, 23, 26, 29

FOOD CONSUMPTION: Yes
- Time schedule for examinations: GD 0, 7, 8, 9, 13, 16, 19, 20, 23, 26, 29

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes / No / No data
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: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter
Statistics:
Data were analysed and test groups compared to the controls using appropriate statistical techniques
Indices:
Not applicable
Historical control data:
Not required for this study

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Anorexia was frequently noted in all groups during the treatment and posttreatment periods. Treatment-related clinical signs in rabbits receiving 30 mg/kg bw/d included reduction in motor activity, salivation, dyspnoea, and tremors. These signs were not seen in any animals of the control, 3 and 10 mg/kg bw/d groups at the pre-treatment and post-treatment intervals, with only one incidence of reduced motor activity (10 mg/kg bw/d group) noted during treatment, in the decedent rabbit.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
A total of six pregnant females receiving 30 mg/kg/ bwd were found dead during the treatment period and three pregnant females aborted or delivered prematurely (GD 22-29). One female receiving 10 mg/kg bw/d was found dead on GD18, and one control female was found dead on GD 8. Both females were anorexic prior to death. The two deaths in the 3 mg/kg bw/d group were the result of dosing errors (verified at necropsy).
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weight changes were significantly decreased for pregnant females receiving 30 mg/kg bw/d on GD7-13. These animals also displayed values slightly lower than the control for GD0-29 but this difference was not statistically significant.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Significantly decreased food consumption values were observed for pregnant females receiving 3 mg/kg bw/d on GD9-13 and were significantly increased for animals receiving 30 mg/kg bw/d on GD26-29 in addition to a significant negative trend on GD7-8. All other mean food consumption values were statistically similar for all groups.
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):
The findings were considered to be incidental and not related to treatment.
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:
effects observed, treatment-related
Description (incidence and severity):
Three pregnant females at 30 mg/kg bw/d aborted or delivered prematurely (GD 22-29).
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
Changes in number of pregnant:
effects observed, treatment-related
Other effects:
no effects observed
Details on maternal toxic effects:
A total of six pregnant females receiving 30 mg/kg/ bwd were found dead during the treatment period and three pregnant females aborted or delivered prematurely (GD 22-29). One female receiving 10 mg/kg bw/d was found dead on GD18, and one control female was found dead on GD 8. Both females were anorexic prior to death. The two deaths in the 3 mg/kg bw/d group were the result of dosing errors (verified at necropsy). Anorexia was frequently noted in all groups during the treatment and posttreatment periods. Treatment-related clinical signs in rabbits receiving 30 mg/kg bw/d included reduction in motor activity, salivation, dyspnoea, and tremors. These signs were not seen in any animals of the control, 3 and 10 mg/kg bw/d groups at the pre-treatment and Mean body weight changes were significantly decreased for pregnant females receiving 30 mg/kg bw/d on GD7-13. These animals also displayed values slightly lower than the control for GD0-29 but this difference was not statistically significant.post-treatment intervals, with only one incidence of reduced motor activity (10 mg/kg bw/d group) noted during treatment, in the decedent rabbit. Significantly decreased food consumption values were observed for pregnant females receiving 3 mg/kg bw/d on GD9-13 and were significantly increased for animals receiving 30 mg/kg bw/d on GD26-29 in addition to a significant negative trend on GD7-8. All other mean food consumption values were statistically similar for all groups. Gross necropsy diod not reveal any effects of treatment.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
clinical signs
mortality
body weight and weight gain

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
effects observed, treatment-related
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
The mean number of implantations was lower in the high dose group, resulting in a lower litter size. Other parameters were unaffected by treatment. There was no dose-related increase in the incidence of any particular malformation or in the incidence of any type (i.e. external, visceral, or skeletal) of malformation. Although the litter incidence of skeletal malformations was slightly higher than controls in the 3 and 10 mg/kg bw/d groups, no malformations were noted in the seven litters of the 30 mg/kg bw/d group available for evaluation. Overt evidence of maternal toxicity was seen in animals receiving 30 mg/kg/ bwd but was not accompanied by adverse effects on fetal growth or development

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
30 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:
no

Any other information on results incl. tables

Summary of maternal findings

Dose level

0 mg/kg bw/d

3 mg/kg bw/d

10 mg/kg bw/d

30 mg/kg bw/d

GD 7-19 (treatment period)

Number of animals observed

16

16

16

16

Found dead

1

0

1

6

Accidental death

0

2

0

0

Reduction in motor activity

0

0

1

14

Salivation

0

0

0

14

Dyspnoea

0

0

0

14

Tremors

0

0

0

14

GD 20-29 (post-treatment period)

Number of animals observed

15

14

15

10

Premature delivery/abortion

0

0

0

3

Reduction in motor activity

0

0

0

1

Food consumption (g)

GD 0-7

1124

1137

1161

1183

GD 7-8

126

102

108

91

GD 8-9

138

112

134

104

GD 9-13

548

441*

531

465

GD 13-16

329

316

307

296

GD 16-19

364

221

307

294

GD 19-20

95

101

107

83

GD 20-23

385

372

372

403

GD 23-26

333

352

314

387

GD 26-29

278

396

307

457*

Bodyweight change (g)

GD 0-7

169

149

166

148

GD 7-8

-31

-42

-47

-48

GD 7-9

-10

-38

-18

-68

GD 7-13

51

-2

29

-62*

GD 7-16

45

33

61

-83

GD 7-19

92

-25

27

-73

GD 7-20

85

-9

35

-104

GD 7-23

168

63

87

4

GD 7-26

192

114

141

50

GD 7-29

228

203

192

141

*significantly different to controls (p<0.05)

Summary of litter parameters

Dose level

0 mg/kg bw/d

3 mg/kg bw/d

10 mg/kg bw/d

30 mg/kg bw/d

Number of females inseminated

16

16

16

16

Pregnancy rate (%)

87.5

93.8

100.0

100.0

No. of pregnant females

13

13

15

8

Number of litters with live foetuses

13

13

13

7

Mean number of corpora lutea

11.7

11.4

11.0

10.1

Mean number of implantations

8.3

7.6

8.3

5.7

Mean implantation efficiency (%)

72.5

67.9

76.8

61.5

Mean number of resorptions

1.7

1.2

1.3

1.1

Mean incidence of resorptions (%)

18.4

15.0

22.4

21.1

Mean incidence of foetal viability (%)

81.6

84.0

77.6

78.9

Mean number of live foetuses per litter

6.6

6.4

6.9

4.6

Mean number of dead foetuses per litter

0.0

0.1

0.0

0.0

Mean percent of males per litter

60.0

40.0

48.4

66.9

Mean fetal weight (g)

 

 

 

 

 Male

44.6

43.6

41.1

48.0

 Female

42.9

42.6

40.5

45.0

Summary of foetal findings

Dose level

0 mg/kg bw/d

3 mg/kg bw/d

10 mg/kg bw/d

30 mg/kg bw/d

Number of foetuses (fetal incidence %)

Total number of foetuses examined

86

83

104

32

External malformations

1 (1.2)

0 (0.0)

3 (2.9)

0 (0.0)

External variations

0 (0.0)

0 (0.0)

1 (1.0)

0 (0.0)

Visceral malformations

0 (0.0)

2 (2.4)

0 (0.0)

0 (0.0)

Visceral variations

4 (4.7)

1 (1.2)

5 (4.8)

1 (3.1)

Skeletal malformations

2 (2.3)

6 (7.2)

4 (3.8)

0 (0.0)

Skeletal variations

67 (78)

64 (77)

79 (76)

25 (78)

Number of litter (litter incidence %)

Total number of litters examined

13

13

13

7

External malformations

1 (7.7)

0 (0.0)

2 (15)

0 (0.0)

External variations

0 (0.0)

0 (0.0)

1 (7.7)

0 (0.0)

Visceral malformations

0 (0.0)

2 (15)

0 (0.0)

0 (0.0)

Visceral variations

3 (23)

1 (7.7)

4 (31)

1 (14)

Skeletal malformations

1 (7.7)

2 (15)

3 (23)

0 (0.0)

Skeletal variations

13 (100)

13 (100)

13 (100)

7 (100)

Applicant's summary and conclusion

Conclusions:
Maternal and developmental NOAELs of 10 mg/kg bw/d can be determined for this study, based on maternal toxicity (mortality, clinical signs, bodyweight effects) and reduced litter size at the highest dose level.
Executive summary:

In a developmental toxicity study, groups of 16 inseminated female HRA(NZW)SPF rabbits each received fenitrothion dissolved in corn oil, at dose levels of 0, 3, 10 and 30 mg/kg bw/d by oral gavage, daily from Days 7 to 19 of gestation at the dosage volume of 1.0 mL/kg bw. Clinical observations, body weights and food consumption were recorded for all females. On day 29 of gestation, all surviving pregnant females were sacrificed and a cesarean section performed. All live fetuses were evaluated for external findings, visceral findings (Staples' technique) and for skeletal findings following staining with Alizarin Red S. A total of six pregnant females receiving 30 mg/kg/ bwd were found dead during the treatment period and three pregnant females aborted or delivered prematurely (GD 22-29). One female receiving 10 mg/kg bw/d was found dead on GD18, and one control female was found dead on GD 8.  Both females were anorexic prior to death. The two deaths in the 3 mg/kg bw/d group were the result of dosing errors (verified at necropsy). Anorexia was frequently noted in all groups during the treatment and posttreatment periods. Treatment-related clinical signs in rabbits receiving 30 mg/kg bw/d included reduction in motor activity, salivation, dyspnoea, and tremors.  These signs were not seen in any animals of the control, 3 and 10 mg/kg bw/d groups at the pre-treatment and Mean body weight changes were significantly decreased for pregnant females receiving 30 mg/kg bw/d on GD7-13. These animals also displayed values slightly lower than the control for GD0-29 but this difference was not statistically significant.post-treatment intervals, with only one incidence of reduced motor activity (10 mg/kg bw/d group) noted during treatment, in the decedent rabbit.  Significantly decreased food consumption values were observed for pregnant females receiving 3 mg/kg bw/d on GD9-13 and were significantly increased for animals receiving 30 mg/kg bw/d on GD26-29 in addition to a significant negative trend on GD7-8.  All other mean food consumption values were statistically similar for all groups.  Gross necropsy did not reveal any effects of treatment. The mean number of implantations was lower in the high dose group, resulting in a lower litter size.  Other parameters were unaffected by treatment.  There was no dose-related increase in the incidence of any particular malformation or in the incidence of any type (i.e. external, visceral, or skeletal) of malformation. Although the litter incidence of skeletal malformations was slightly higher than controls in the 3 and 10 mg/kg bw/d groups, no malformations were noted in the seven litters of the 30 mg/kg bw/d group available for evaluation. Overt evidence of maternal toxicity was seen in animals receiving 30 mg/kg/ bwd but was not accompanied by adverse effects on foetal growth or development. Maternal and developmental NOAELs of 10 mg/kg bw/d can be determined for this study, based on maternal toxicity (mortality, clinical signs, bodyweight effects) and reduced litter size at the highest dose level.

The highest dose level in this study was sufficient to cause maternal toxicity (including mortality) and was associated with a slight reduction in implantations and litter size. Findings are considered to be secondary to maternal effects.