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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:
15 September 1987 – 31 January 1988
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline 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
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
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

Constituent 1
Chemical structure
Reference substance name:
heptan-2-yl [(5-chloroquinolin-8-yl)oxy]acetate
EC Number:
619-447-3
Cas Number:
99607-70-2
Molecular formula:
C18H22ClNO3
IUPAC Name:
heptan-2-yl [(5-chloroquinolin-8-yl)oxy]acetate
Details on test material:
- Name of test material (as cited in study report): CGA185072 technical
- Analytical purity: 91.6%

Test animals

Species:
rat
Strain:
other: strain Tif:RAIf (SPF), hybrids of RII/1 x RII/2
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: about 2 months
- Weight at study initiation: 200-203 g
- Source of animals: Animal Production, Ciba-Geigy Ltd. CH-4332 Stein, Switzerland
- Housing: Individually in standard macrolon cages with wire mesh tops and granulated soft wood bedding material
- Diet: pelleted, certified standard diet (Nafag No. 890 Tox) ad libitum
- Source of diet: Naehr- und Futtermittel AG, Gossau, Switzerland
- Water: tap water in plastic bottles ad libitum
- Acclimatisation: between mating and start of dosing

ENVIRONMENTAL CONDITIONS
- Temperature: 21±2°C
- Humidity: 55±10%
- Air changes (per hr): 16
- 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 on 2 occasions (for dosing September 21-October 6 and for October 7 & 8). The test substance was mixed with the vehicle in a grinder using glass beads and a low speed rotor, portioned for each dosing day and refrigerated until use. Homogeneity was maintained using a magnetic stirrer. Doses were adjusted daily for body weight. Dose volume was 5 mL/kg body weight. The dosing solutions contained 0, 2, 20 or 80 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 for both batches. Homogeneity and chemical stability were confirmed.
The achieved concentrations varied: 67.9-80% low dose; 90.7-95.9% mid dose and 83.1-99.6% high dose. Values were considered to be within acceptable limits.
Details on mating procedure:
Nulliparous females were mated overnight with males of the same strain and of proven fertility; 3 females were housed with 1 male. Successful mating was confirmed by a vaginal plug or by spermatozoa in a vaginal smear and was defined as day 0 of pregnancy.
Duration of treatment / exposure:
Pregnancy days 6 - 15 inclusive
Frequency of treatment:
Once daily
Duration of test:
Pregnancy days 0 - 21; termination on day 21
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Negative control
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
400 mg/kg bw/day (nominal)
No. of animals per sex per dose:
24 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 6, 11, 16 and 21

WATER CONSUMPTION: Not measured, visually assessed

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- 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: one third of each litter. Examination of fixed foetus by slicing technique of Wilson - head and body.
- Skeletal examinations: Yes: two thirds of each 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

General toxicity (maternal animals)

Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At 400 mg/kg: reduced body weight gain (3-7% from day 9-21)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
At 400 mg/kg: reduced food consumption days 6-11 and 11-16
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
400 mg/kg bw/day: increased water consumption
Other effects:
effects observed, treatment-related
Description (incidence and severity):
At 400 mg/kg: increased wet bedding, odorous urine;

Maternal developmental toxicity

Number of abortions:
no effects observed
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:
no effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
A 7% decrease of the foetal bodyweight for the sexes combined was observed at 400 mg/kg bw.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
100 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:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

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

100

400

0-6

33

32

32

31

6-11

30

30

28

22**

11-16

42

45

43

31**

16-21

70

70

73

67

0-21

176

176

176

150**

6-21

142

144

144

119**

6-16

72

74

71

52**

P<0.01 ** statistically significant difference from control

 

Table 2 Group Mean Litter data

 

Dose level (mg/kg bw/day)

0

10

100

400

No. pregnant females

24

24

22

24

No. corpora lutea

17.0

18.2

18.0

18.7

No. implantations

15.1

15.2

15.4

15.4

% pre-implantation loss

11.7

17.0

14.5

16.9

% post-implantation loss

3.8

3.3

3.9

7.1

No. live foetuses

14.5

14.7

14.8

14.4

% males

48.0

48.3

49.8

47.0

Foetal weight (g)

5.6

5.6

5.6

5.1**

P<0.01 ** statistically significant difference from control

 

Table 3 Group Mean Foetal Observations

 

Dose level (mg/kg bw/day)

0

10

100

400

No. litters examined

24

24

22

24

No. foetuses examined – external malformations

348

352

325

345

No. foetuses with external malformations

7

0

0

1*

No. foetuses examined – visceral malformations

110

119

110

115

No. foetuses with visceral malformations

0

0

0

1

No. foetuses with visceral anomalies

0

0

0

1

No. foetuses examined – skeletal malformations

238

233

215

230

No. foetuses with skeletal anomalies

12

10

4

6

P<0.05 * statistically significant difference from control

Applicant's summary and conclusion

Conclusions:
Oral administration of cloquintocet-mexyl to pregnant rats at doses of 10, 100 and 400 mg/kg bw produced some maternal toxicity and resulted in reduced foetal bodyweight at the highest dose. There was no increase in incidence of external, visceral or skeletal malformations or anomalies due to the test substance and no evidence of teratogenicity.
Executive summary:

The developmental toxicity of the substance was studied under GLP to OECD TG 414. The substance was administered in peanut oil by oral gavage to pregnant rats at doses of 10, 100 or 400 mg/kg bw/day from day 6 through to day 15 of gestation. A dose level of 400 mg/kg bw was toxic to pregnant rat resulting in increased water consumption, increased wet bedding and odorous urine, reduced body weight and reduced food consumption. Lower mean foetal weight was seen in the presence of this maternal toxicity but there was no increase in incidence of external, visceral or skeletal malformations or anomalies. There was no evidence of teratogenicity at any dose level.