heptan-2-yl [(5-chloroquinolin-8-yl)oxy]acetate

Developmental toxicity / teratogenicity

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 guideline

Test guideline 1

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

Test guideline 2

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

Test material information

Constituent 1

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 / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Negative control

Doses / concentrations 2

Dose / conc.:

10 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

100 mg/kg bw/day (nominal)

Doses / concentrations 4

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.