Acetic acid, 2-[(5-chloro-8-quinolinyl)oxy]-, 1-methylhexyl ester

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:

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 Available as unpublished report, fully adequate for assessment.

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
- 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
- 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

Remarks:

Doses / Concentrations:
0, 10, 100, 400 mg/kg bw/day
Basis:
nominal conc.

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

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
400 mg/kg bw/day: increased water consumption, increased wet bedding, odorous urine; reduced body weight gain (3-7% from day 9-21); reduced food consumption days 6-11 and 11-16. No effects seen at lower dose levels.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

100 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:
400 mg/kg bw/day: reduced foetal body weight. No effect at lower dose levels. 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:

400 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	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:

A dose level of 400 mg CGA185072/kg bw was toxic to the pregnant female and resulted in lower mean foetal weight. There was no increase in incidence of external, visceral or skeletal malformations or anomalies due to the test substance and no evidence of teratogenicity. The NOAEL for maternal and developmental toxicity was 100 mg/kg bw/day.

Executive summary:

A dose level of 400 mg CGA185072/kg bw was toxic to the pregnant female 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 of CGA185072.