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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:
10 August 1987 - 31 December 1987
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 Available as unpublished report, fully adequate for assessment.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report Date:
1989

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
Details on test material:
- Name of test material (as cited in study report): CGA185072 technical
- Analytical purity: 91.6%

Test animals

Species:
rabbit
Strain:
Chinchilla
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 16 weeks old
- Weight at study initiation: 2.9 - 3.1 kg
- Housing: Individually in Heinkel batteries with wire mesh bottom
- Diet: pelleted, certified standard diet ad libitum (Nafag No. 814)
- Water: tap water ad libitum
- Acclimatisation: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 18±2°C
- Humidity: 55±10%
- Air changes: 16-20 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
peanut oil
Remarks:
arachidis oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Made weekly by mixing the test substance with the vehicle in a grinder using glass beads and a low speed rotor, portioned for each dosing day and refrigerated until use. Doses were adjusted daily for body weight. Dose volume was 4 mL/kg body weight. The dosing solutions contained 0, 2.5, 15 or 75 mg/mL CGA185072 tech.
VEHICLE
- arachidis oil, PHHVI (Siegfried AG, Zofingen, Switzerland)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Achieved concentration was determined and homogeneity and chemical stability were confirmed. The achieved concentrations ranged from 93.6-94.5%. Stability was confirmed for at least one week.
Details on mating procedure:
Each nulliparous female was mated with one male of proven fertility from the same strain of rabbit. Coitus was observed. The rabbits then remained together for at least one additional hour.
Duration of treatment / exposure:
Pregnancy days 7 - 19 inclusive
Frequency of treatment:
Once daily
Duration of test:
Pregnancy days 0 - 29, termination on day 29
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 60, 300 mg/kg bw/day
Basis:
nominal conc.
No. of animals per sex per dose:
20 mated females
Control animals:
yes, concurrent vehicle

Examinations

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION: Yes
- Time schedule: days 4, 8, 12, 16, 20, 24 and 29

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Macroscopic examination: main organs of the thoracic 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
- Other: abortion sites and dead foetuses. Uteri without visible signs of implantation were stained with ammonium sulphide to confirm pregnancy status.

Fetal examinations:
- Body weight and sex: Yes: all per litter
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter. Examination of viscera by fresh dissection. Examination of head by slicing technique of Wilson following fixation.
- Skeletal examinations: Yes: all per litter. Examination following staining of the skeleton with Alizarin red S
- Classification of foetal observations: Yes
Statistics:
Standard methods were applied for statistical analysis. Continuous data were analysed using student’s t-test, foetal observations were analysed using the Chi square test.
Indices:
Pre- and post-implantation losses

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:
300 mg/kg bw/day: 5 animals found dead between days 12 and 18 (treatment-related on basis of pathological findings); in addition one rabbit aborted on day 21 and was killed. No effect on maternal body weight or food consumption.
60 mg/kg/day: no deaths related to test substance (one rabbit found dead day 27 considered to be incidental).

Effect levels (maternal animals)

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

Details on embryotoxic / teratogenic effects:
No effect of treatment on foetal weight. No increase in incidence of external, visceral or skeletal malformations or anomalies due to test substance. There was some indication of a delay in ossification although the incidence of foetuses affected overall was not statistically significant. There was no evidence of teratogenicity at any dose level.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
300 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

10

60

300

0-7

261

280

300

235

7-10

-121

-52*

-81

-61

10-14

95

55

87

42

14-19

63

63

85

63

19-24

189

143*

142

171

24-29

124

129

133

149

0-29

613

618

667

598

7-29

352

338

367

363

7-19

38

66

92

43

P<0.05 * Statistically significant difference from control

 

Table 2 Group Mean Litter data

 

Dose level (mg/kg bw/day)

0

10

60

300

No. pregnant females

17

19

14

12

No. corpora lutea

10.1

10.9

10.9

11.0

No. implantations

8.7

8.5

8.8

8.6

% pre-implantation loss

14.7

20.9

18.5

22.1

% post-implantation loss

4.4

5.0

16.2**

10.0

No. live foetuses

8.3

8.2

7.7

7.6

% males

46.8

52.3

47.6

41.8

Foetal weight (g)

34.8

35.6

34.7

35.1

P<0.01 ** Statistically significant difference from control

 

Table 3 Group Mean Foetal Observations

 

Dose level (mg/kg bw/day)

0

10

60

300

No. litters examined

17

19

14

12

No. foetuses examined – external malformations

141

155

105

91

No. foetuses with external malformations

0

0

0

2

No. foetuses examined – visceral malformations

141

153

105

91

No. foetuses with visceral malformations

0

2

0

3

No. foetuses with visceral anomalies

0

1

0

0

No. foetuses examined – skeletal malformations

141

155

104

91

No. foetuses with skeletal malformations

0

0

0

2

No. foetuses with skeletal anomalies

3

3

2

3

No statistically significant differences from control

Applicant's summary and conclusion

Conclusions:
A dose level of 300 mg CGA185072/kg bw was toxic to the pregnant female and resulted in the death of 5 animals. There was no effect on foetal weight, no increase in incidence of external, visceral or skeletal malformations or anomalies due to the test substance and no evidence of teratogenicity. A slight delay in foetal development was described for 300 mg/kg bw/day.
Based on the findings observed at 300 mg/kg bw/day the NOAEL for both dams and foetuses was 60 mg/kg bw/day.
Executive summary:

A dose level of 300 mg CGA185072/kg bw was toxic to the pregnant female resulting in the premature death of 5 rabbits (found dead between days 12 and 18). There was no effect of this dose on the body weight or food consumption of the surviving rabbits and neither was there any effect on foetal weight. There was no increase in incidence of external, visceral or skeletal malformations or anomalies although a slight delay in development was ascribed to 300 mg/kg bw/day. There was no evidence of teratogenicity at any dose level of CGA185072.