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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:
24 February 1986 to 28 March 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP study compliant with test guidelines of the time. However, current guidelines for prenatal developmental toxicity require an extended dosing period - from implantation to termination. Available as unpublished report, adequate for assessment although only minimal maternal toxicity seen at highest dose tested.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
1981 (current guideline adopted 2001)
Deviations:
yes
Remarks:
does not meet current guideline specification
Qualifier:
according to
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Version / remarks:
1982 (current guideline adopted 1998)
Deviations:
yes
Remarks:
does not meet current guideline specification
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: Approximately 17 weeks
- Weight at gestation day 0: 3.21-3.98 kg
- Housing: Individually in elevated stainless steel cages
- Diet: Purina Certified Rabbit Chow ® #5322 ad libitum
- Water: Tap water ad libitum
- Acclimation period: 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 70-76°F
- Humidity: 18-55%
- Air changes (per hr): Not reported
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 24 February 1986 To: 28 March 1986

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: distilled water containing 0.5% carboxymethylcellulose and 0.1% Tween 80
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Fresh preparations were made weekly and stored under refrigeration. The dose volume was 1 mL/kg body weight on day 7 of gestation.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Prior to initiation, samples were taken to determine homogeneity. Day 0 and day 7 stability analyses were performed on the vehicle, low and high dose dosing solutions. Freshly prepared samples of all dose levels from the first and last mixed batches were analysed for achieved concentration.

The dosing preparations were found to be stable (95-101% of target on day 7), homogeneous (91.9-103% of target) and the achieved concentrations ranged from 94.6-108% of target.
Details on mating procedure:
Artificial insemination
Duration of treatment / exposure:
13 days, gestation days 7-19 inclusive
Frequency of treatment:
Once daily
Duration of test:
29 days, gestation days 0-29
No. of animals per sex per dose:
15 mated females
Control animals:
yes, concurrent vehicle

Examinations

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: days 0, 7, 9, 11, 15, 20, 24 and 29

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 7, 9, 11, 15, 20, 24 and 29

FOOD CONSUMPTION: Yes
Time schedule for examinations: days 0, 7, 9, 11, 15, 20, 24 and 29

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Macroscopic examination: main organs of the thoracic, pelvic and abdominal cavities

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:
- Body weight and sex: Yes: all per litter
- 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
- Classification of foetal observations: Yes


Statistics:
Levene's test of homogeneity of variances initially. Homogeneous data were then analysed using one-way ANOVA; heterogeneous data were transformed where possible. When ANOVA was significant Dunnett's t-test was used to compare each group with the control. The Terpstra-Jonckheere nonparametric test for trend was performed on homogeneous and heterogeneous data. The Cochran-Armitage test for linear trend followed by the Fischer-Irwin 'exact' test was used for the percent of total foetuses and litters with a particular skeletal variant.
Indices:
Mean implantation efficiency
Historical control data:
Yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
No treatment-related effects on maternal body weight.
62.5 mg/kg bw/day: food consumption significantly decreased between days 11 to 15 of gestation.
No treatment-related macroscopic changes observed at necropsy.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
12.5 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
62.5 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
62.5 mg/kg bw/day: lower mean foetal body weight (not significant when litter size used as the covariate in the analysis). The incidence of foetal external, soft tissue or skeletal variations was not treatment-related nor was the incidence of foetal external or soft tissue malformations. Eight foetuses with skeletal malformations at the highest dose were not clearly treatment-related due to the findings being consistent with those found in historical control data.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
62.5 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1 Group Mean Maternal Body Weight Change (g) During Gestation

Days

Dose level (mg/kg bw/day)

0

0.5

2.5

12.5

62.5

0-7

0.14

0.14

0.09

0.13

0.16

7-20

0.16

0.08

0.16

0.17

0.06

20-29

0.11

0.13

0.05

0.08

0.17

0-29

0.41

0.36

0.31

0.38

0.43

7-29

0.27

0.21

0.22

0.25

0.27

No statistically significant differences

Table 2 Group Mean Food Consumption (g) During Gestation

Days

Dose level (mg/kg bw/day)

0

0.5

2.5

12.5

62.5

0-7

1192

1220

1112

1274

1187

7-9

360

359

329

365

297

9-11

315

324

308

325

267

11-15

561

506

556

585

373*

15-20

777

673

758

731

604

20-24

608

551

543

539

591

24-29

515

482

431

453

634

P< 0.05 * statistically significant difference from control

 

Table 3 Group Mean Litter data

 

Dose level (mg/kg bw/day)

0

0.5

2.5

12.5

62.5

No. pregnant females

14

13

14

14

13

No. corpora lutea

11.1

11.2

10.7

11.6

13.2

No. implantations

7.4

7.6

6.1

7.9

8.8

% mean implantation efficiency

66.6

66.6

59.2

67.4

67.8

No. live foetuses

6.7

6.6

5.9

7.1

8.3

% males

41.5

56.0

42.4

44.8

55.1

Foetal weight (g) - covariate adjusted

46.2

46.8

45.8

46.7

46.1

No statistically significant differences

Table 4 Group Mean Foetal Observations

 

Dose level (mg/kg bw/day)

 

0

0.5

2.5

12.5

62.5

No. litters examined

14

13

14

14

13

No. foetuses examined

95

86

82

99

108

No. foetuses with external variations

0

1

0

0

0

No. foetuses with external malformations

0

0

0

0

1

No. foetuses with soft tissue variations

7

7

5

6

5

No. foetuses with soft tissue malformations

2

1

0

0

0

No. foetuses with skeletal variations

69

65

49

73

68

No. foetuses with skeletal malformations (% foetuses)

2 (2.1)

3 (3.5)

3 (3.7)

4 (4.0)

8 (7.4)

No statistically significant differences

Applicant's summary and conclusion

Conclusions:
Administration of 62.5 mg/kg bw/day CGA154281 to pregnant rabbits during the period of organogenesis resulted in minimal maternal toxicity (a small, transient reduction in food consumption). The NOAEL for maternal toxicity was therefore 12.5 mg/kg bw/day. The NOAEL for developmental toxicity and teratogenicity was 62.5 mg/kg bw/day

Executive summary:

The study was designed to evaluate the developmental toxicity and teratogenic potential of benoxacor (CGA154281 technical) in rabbits. The test material was administered orally at 0.5, 2.5, 12.5 or 62.5 mg/kg bw/day during the period of organogenesis (days 7-19 of gestation). On gestation day 29, the dams were terminated and caesarean sections performed. Live foetuses were weighed and examined for external, soft tissue and skeletal malformations and variations.

The only effect of treatment at the highest dose of 62.5 mg/kg bw/day, was a small reduction in maternal food consumption during the dosing period. There was no clear evidence of developmental toxicity at this dose level and no evidence of teratogenicity.