4,7-dichloroquinoline

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

data is from peer reviewed journals

Data source

Reference

Reference Type:

publication

Title:

Teratologic assessment of the test chemical in rats

Author:

K.S. Khera et.al

Year:

1979

Bibliographic source:

Journal of Environmental Science and Health, Part B: Pesticides, Food Contaminants, and Agricultural Wastes, 1979

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Teratogenicity studies were conducted in rats treated orally from days 6-15 of gestation with single daily doses of the test chemical

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ethoxyquin

EC Number:

202-075-7

EC Name:

Ethoxyquin

Cas Number:

91-53-2

Molecular formula:

C14H19NO

IUPAC Name:

6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline

Test material form:

liquid

Details on test material:

Name of the test chemica: Ethoxyquin
IUPAC: 6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline
Molecular Formula: C14H19NO
Molecular Weight: 217.307 g/mol
Substance Type: Organic
Physical State: Liquid

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g : females: 175-225 g in body weight

Administration / exposure

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: test doses, representing the levels of the composite samples and not the active ingredients, on a per kg basis were 125, 250 or 500 mg of the test chemical suspended in corn oil

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: The volume of vehicle or vehicle plus chemical was 10 ml/kg body weight.
- Amount of vehicle (if gavage): The volume of vehicle or vehicle plus chemical was 10 ml/kg body weight.

Details on mating procedure:

- M/F ratio per cage: Female Wistar rats were paired overnight with proven males, and the morning that a positive vaginal smear was observed was counted as day 1 of gestation.
- Length of cohabitation:
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: Female Wistar rats were paired overnight with proven males, and the morning that a positive vaginal smear was observed was counted as day 1 of gestation.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

day 6- day 15 of gestation,

Frequency of treatment:

single time daily

Details on study schedule:

no data available

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Remarks:

125, 250 or 500 mg/kg/day

No. of animals per sex per dose:

Twenty mated females, randomly selected, were assigned to each experimental group

Control animals:

yes, concurrent vehicle

Details on study design:

no data available

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes / No / No data: yes
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:

BODY WEIGHT: Yes / No / No data: yes
- Time schedule for examinations:Females were weighed at frequent intervals during gestation.

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: [yes/no]
- If yes, maximum of [...] pups/litter ([...]/sex/litter as nearly as possible); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring:
[number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), pup weight on the day of AGD, presence of nipples/areolae in male pups, other. Particular attention should be paid to the external reproductive genitals which should be examined for signs of altered development; gross evaluation of external genitalia]

GROSS EXAMINATION OF DEAD PUPS:
[no / yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead]

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY:

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY:

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]
- Maternal animals: All surviving animals [describe when, e.g. after the last litter of each generation was weaned.]: On the 22nd day of gestation, each dam was killed, its uterine contents removed, its
number of corpora lutea determined, and was then necropsied.

GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]: On the 22nd day of gestation, each
dam was killed, its uterine contents removed, its number of corpora lutea determined, and was then necropsied.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#?] days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.: The fetuses were weighed and examined for viabilitand external malformations. Early resorptions
or implantation sites and fetuses dying at a late stage in their development, were recorded. Two-thirds of the live fetuses from each litter were examined for skeletal development after alizarin red staining. The remainder, fixed in Bouin's fluid, were dissected to study visceral anomalies.

Statistics:

To determine effects on maternal body weight, the mean and standard error were calculated for each experimental group, and values of t_ were obtained for test and control group differences in means. Fetal values were analysed with the litter as the basic unit. The proportion (p_) of litter having a particular attribute was calculated and transformed to a normally distributed variable arc sin/p_ value . The mean and standard error of these values for various.test groups were then derived . The t_ test was used for comparison of test and the respective control values.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Description (incidence and severity):

No sign of toxicity was noticed during pregnancy, in any treatment or control group

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Any adverse effect on maternal body weight was noticed during pregnancy, in any treatment or control group

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No adverse effect was related to any treatment were observed

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Description (incidence and severity):

Number of females pregnant in the different test groups varied within the control range and was unrelated to treatment.Resorption of fetuses at 125 mg/kg was increased, although not significantly .

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical signs

body weight and weight gain

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

reproductive performance

Target system / organ toxicity (P0)

Critical effects observed:

no

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

no effects observed

Description (incidence and severity):

The incidence of anomalous fetuses in the 250 mg/kg group was borderline significant (p--0 .05). The was noted that this was most likely not significant in relation to the absence of significant findings in the 500mg/kg dose group

Other effects:

not specified

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

viability

gross pathology

histopathology: non-neoplastic

Overall reproductive toxicity

Reproductive effects observed:

no

Treatment related:

no

Applicant's summary and conclusion

Conclusions:

No signs of toxicity or any adverse effects were seen in the dams . Resorption of fetuses at 125 mg/kg was increased, although not significantly. The incidence of anomalous fetuses in the 250 mg/kg group was borderline significant (p--0 .05). It was noted that this was most likely not significant in relation to the absence of significant findings in the 500 mg/kg dose group. Hence, the NOAEL can be considered to be 500 mg/kg/day for maternal rats and fetus.

Executive summary:

Teratogenicity studies were conducted in rats treated orally from days 6-15 of gestation with single daily doses of the test chemical. Pregnant female Wistar rats (20 per group) received the following test doses of the test chemical suspended in com oil once per day by esophageal intubation: 0, 125, 250, or 500 mg/kg from day 6 to 15 of gestation. On the 22nd day of gestation, dams were killed and uterine contents were removed and analyzed . Females were weighed at frequent intervals during gestation. On the 22nd day of gestation, each dam was killed, its uterine contents removed, its number of corpora lutea determined, and was then necropsied. The fetuses were weighed and examined for viability nd external malformations. Early resorptions or implantation sites and fetuses dying at a late stage in their development, were recorded. Two-thirds of the live fetuses from each litter were examined for skeletal development after alizarin red staining. The remainder, fixed in Bouin's fluid, were dissected to study visceral anomalies. No signs of toxicity or any adverse effects were seen in the dams . Resorption of fetuses at 125 mg/kg was increased, although not significantly. The incidence of anomalous fetuses in the 250 mg/kg group was borderline significant (p--0 .05). It was noted that this was most likely not significant in relation to the absence of significant findings in the 500 mg/kg dose group. Hence, the NOAEL can be considered to be 500 mg/kg/day for maternal rats and fetus.