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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
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 authoritative database

Data source

Reference
Reference Type:
review article or handbook
Title:
Toxicological Evaluations of the test chemical
Author:
FAO
Year:
2015
Bibliographic source:
Toxicological Evaluations of the test chemical, 2015

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
90 days repeated dose oral toxicity study was performed to evaluate the toxicological profile of the test chemical
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
3,7-dichloroquinoline-8-carboxylic acid
EC Number:
402-780-1
EC Name:
3,7-dichloroquinoline-8-carboxylic acid
Cas Number:
84087-01-4
Molecular formula:
C10H5Cl2NO2
IUPAC Name:
3,7-Dichloroquinoline-8-carboxylic acid
Test material form:
solid
Details on test material:
Name of the test chemical: 3,7-Dichloroquinoline-8-carboxylic acid
Common Name: Quinclorac
Molecular Weight: 242.0605 g/mol
Molecular Formula: C10H5Cl2NO2
Substance Type: Organic
Physical State: Solid

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Wistar (Chbb=Thom) rats
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: diet
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
0, 1000, 4000 or 12 000 ppm for 3 months. Achieved test chemical intakes were 0, 77, 302 and 930 mg/kg bw per day for males and 0, 87, 358 and 1035 mg/kg bw per day for females, respectively.
Duration of treatment / exposure:
3 months
Frequency of treatment:
daily
Doses / concentrations
Remarks:
0, 1000, 4000 or 12 000 ppm for 3 months. Achieved test chemical intakes were 0, 77, 302 and 930 mg/kg bw per day for males and 0, 87, 358 and 1035 mg/kg bw per day for females, respectively.
No. of animals per sex per dose:
Groups of 10 male and 10 female Wistar (Chbb=Thom) rats
Control animals:
yes, concurrent no treatment
Details on study design:
no data available

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes / No / Not specified :
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes / No / Not specified : yes
- Time schedule: Clinical signs were observed regularly

BODY WEIGHT: Yes / No / Not specified : yes
- Time schedule for examinations: body weight were observed regularly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / Not specified : food consumption were observed reegularly
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / Not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / Not specified : yes
- Time schedule for examinations: water consumption were observed regularly

OPHTHALMOSCOPIC EXAMINATION: Yes / No / Not specified : yes
- Time schedule for examinations: Ophthalmoscopy was performed on animals in the control and top-dose groups, pretest and prior to sacrifice.
- Dose groups that were examined:

HAEMATOLOGY: Yes / No / Not specified : yes
- Time schedule for collection of blood: Samples for clinical chemistry and haematology were takenon day 86.
- Anaesthetic used for blood collection: Yes (identity) / No / Not specified
- Animals fasted: Yes / No / Not specified
- How many animals:
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: Yes / No / Not specified : yes
- Time schedule for collection of blood: Samples for clinical chemistry and haematology were taken on day 86.
- Animals fasted: Yes / No / Not specified
- How many animals:
- Parameters checked in table [No.?] were examined.

URINALYSIS: Yes / No / Not specified : yes
- Time schedule for collection of urine: Urine analysis samples were obtained on day 80.
- Metabolism cages used for collection of urine: Yes / No / Not specified
- Animals fasted: Yes / No / Not specified
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes / No / Not specified
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

IMMUNOLOGY: Yes / No / Not specified
- Time schedule for examinations:
- How many animals:
- Dose groups that were examined:
- Parameters checked in table [No.?] were examined.

OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table) / No / Not specified : All animals were subjected to a gross pathological examination followed by a microscopic examination.

HISTOPATHOLOGY: Yes (see table) / No / Not specified: Control and top-dose animals received a full microscopic examination; for the low- and intermediate-dose groups, only lungs, liver, kidneys and gross lesions were examined.

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
A initial deficit in body weight in top-dose males was associated with reduced feed consumption and, although statistically significant, was less than 10%. There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no treatment-related adverse effects in the animals of the low dose and mid dose groups. There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
A number of water consumption were altered in top-dose animals indicative of potential liver and kidney toxicity. There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
Ophthalmological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Erythrocyte parameters were reduced in top-dose females. There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
A number of clinical chemistry parameters were altered in top-dose animals indicative of potential liver and kidney toxicity. Plasma bilirubin was decreased dose relatedly in all male groups (Table 8), but
this is not considered to be adverse in isolation.There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
Urinalysis findings:
no effects observed
Description (incidence and severity):
There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
The only pathological findings of note were chronic interstitial nephritis and focal urothelial hyperplasia in top-dose males. There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
The only pathological findings of note were chronic interstitial nephritis and focal urothelial hyperplasia in top-dose males.There were no treatment-related adverse effects in the animals of the low dose and mid dose groups
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Effect levels

Dose descriptor:
NOAEL
Effect level:
302 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
gross pathology
haematology
histopathology: non-neoplastic
mortality

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
The NOAEL was 4000 ppm (equal to 302 mg/kg bw per day), based on a range of clinical chemistry and haematological changes in both sexes and interstitial nephritis and urothelial hyperplasia in males at 12 000 ppm (equal to 930 mg/kg bw per day
Executive summary:

90 days repeated dose oral toxicity study was performed to evaluate the toxicological profile of the test chemical.

Groups of 10 male and 10 female Wistar (Chbb=Thom) rats were given diets containing the test chemical dose of 0, 1000, 4000 or 12 000 ppm for 3 months. Achieved test article intakes were 0, 77, 302 and 930 mg/kg bw per day for males and 0, 87, 358 and 1035 mg/kg bw per day for females, respectively. Clinical signs, body weight, and feed and water consumption were monitored regularly. Samples for clinical chemistry and haematology were taken on day 86. Urine analysis samples were obtained on day 80. Ophthalmoscopy was performed on animals in the control and top-dose groups, pretest and prior to sacrifice. All animals were subjected to a gross pathological examination followed by a microscopic examination. Control and top-dose animals received a full microscopic examination; for the low- and intermediate-dose groups, only lungs, liver, kidneys and gross lesions were examined. and mid-dose groups. Plasma bilirubin was decreased dose relatedly in all male groups (Table 8), but this is not considered to be adverse in isolation. The NOAEL was 4000 ppm (equal to 302 mg/kg bw per day), based on a range of clinical chemistry and haematological changes in both sexes and interstitial nephritis and urothelial hyperplasia in males at 12 000 ppm (equal to 930 mg/kg bw per day