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Diss Factsheets

Administrative data

Endpoint:
neurotoxicity: sub-chronic oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2016

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: JMAFF 2-1-9 Notification 12 Nousan 8147 (2000)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

1
Chemical structure
Reference substance name:
8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid
Cas Number:
353258-35-2
Molecular formula:
C9H4ClF3N2O2
IUPAC Name:
8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid
Specific details on test material used for the study:
Test substance: IN-QEK31-011
Lot number: SG0312574
Purity: 98.2%

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: Feed
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were collected from the top, middle, and bottom of the initial diet preparation for each
diet concentration and were analyzed to verify the homogeneity and concentration (average of
homogeneity samples) of test substance in the diets. The stability of the test substance at the concentration range from 50 to 20,000 ppm in the diet stored at room temperature for up to 22 days has been established in a previously conducted study. Samples were taken from at least 2 more different
time points for each of the concentrations to verify concentrations. A sample of control diet was analyzed together with each set of samples to verify the absence of test substance in the diet.
At the time of the analysis, the samples were extracted with an appropriate solvent and the extracts were analyzed by ultra high-performance liquid chromatography (UHPLC) with ultraviolet (UV) detection.
Duration of treatment / exposure:
Approximately 90 days
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
150 ppm
Dose / conc.:
750 ppm
Dose / conc.:
3 000 ppm
Dose / conc.:
12 000 ppm
No. of animals per sex per dose:
10
Control animals:
yes, plain diet

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
All clinical signs observed were those typically observed in rats in this type of study, and did not
exhibit a dose response.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Potentially adverse effects on body weight and body weight gain were observed in the 12000 ppm
male group. At 12000 ppm, mean final body weight (test day 91) and mean overall (test day 1-91)
body weight gain in males were 10% and 15% below control, respectively. Both of these differences were statistically significant.
There were no test substance-related effects on body weight and body weight gain in females at any concentration. Mean final body weight (test day 91) and overall body weight gain (test days 1-91) in 12000 ppm females were 2% and 5% below control (neither statistically significant).
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Changes were not considered to be related to the test substance due to the lack of a dose response.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Overall mean food efficiency in male and female rats fed 12,000 ppm was 15% and 7% below the
control, respectively.
Ophthalmological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Retinal degeneration was noted in one male at 3000 ppm. This was not considered test substance
related, as it did not occur in a dose-related manner.
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Blood urea nitrogen (BUN) was higher in the 12000 ppm male group (12% above the control).
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
pH was lower in the 3000 ppm male group (5% below the control), however it was considered to be
unrelated to treatment and non-adverse because it did not occur in a dose-related pattern.
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
There were no organ weight effects directly related to the test substance in males or females. In males, most statistically significant organ weight changes were caused by the terminal body weight decrease (statistically significant) at 12000 ppm.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At 12000 ppm, test substance related gross findings were found in the kidney (dilation, discoloration and lesion) or urinary bladder (Calculus\calculi) of 5/10 males and in the kidney of 6/10 females; test substance related findings were not present at ≤3000 ppm.
Neuropathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no statistically significant differences or test substance-related effects on forelimb or hindlimb grip strength or manipulations or other FOB parameters in males or females at any dietary concentration. No test substance-related effects on duration of movement or number of ambulatory movements in males or females at any dietary concentration. Duration of movement and number of ambulatory movements were lower in females at 3000 ppm. But were not considered test-substance related, for the following reasons: there was no dose response relationship observed (i.e. there were no statistically or biologically significant differences at 12000 ppm), there were no corroborative differences in motor activity in males, and there were no corroborative findings in any other neurobehavioral parameter in either sex.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Adverse microscopic findings in the kidney and/or urinary bladder of both sexes were observed at 12000 ppm. Microscopic changes in the kidney included: degeneration/regeneration of tubules; dilation of the tubules and pelvis; and hyperplasia of the transitional epithelium. Microscopic changes in the urinary bladder included: inflammation; concretions; and hyperplasia of the transitional epithelium.

Effect levels

open allclose all
Key result
Remarks on result:
other: there were no test substance-related effects on any neurobehavioral parameter evaluated in males or females at any dietary concentration
Dose descriptor:
NOAEL
Effect level:
3 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food efficiency
urinalysis

Applicant's summary and conclusion

Conclusions:
Under the conditions of the study, there were no test substance-related effects on any neurobehavioral parameter evaluated in males or females at any dietary concentration.
Executive summary:

The objective of this study was to evaluate the potential subchronic toxicity of test substance when incorporated into nutritionally adequate diet and fed to male and female rats for 90 days according to guidelines OECD 408, US EPA OPPTS 870.3100, EC B.26 and JMAFF. Five groups of young adult male and female Crl:CD(SD) rats (10/sex/concentration) were administered diets that contained 0, 150, 750, 3000, or 12000 ppm test substnace for approximately 90 days. Test substance was demonstrated to be homogeneously mixed, at targeted concentrations, and stable in the diet. Body weights, food consumption, and detailed clinical observations were evaluated weekly and acute clinical observations were evaluated daily in all animals. Clinical pathology (hematology, coagulation, clinical chemistry, urinalysis), organ weights, and gross and microscopic pathology were evaluated at the end of the
exposure period.
Overall (test day 1-91) mean daily intake in the 150, 750, 3000, or 12000 ppm groups was 9, 46, 183, or 784 mg/kg bw/day, respectively, in males, and 10, 51, 204, or 820 mg/kg bw/day, respectively, in females.
All animals survived to scheduled sacrifice. No test substance-related clinical signs and, ophthalmological, or neurobehavioral effects were observed.
Potentially adverse effects on body weight, body weight gain and food efficiency were observed in the 12000 ppm male group. At 12000 ppm, mean final body weight and mean overall (test day 1-91) body weight gain in males were 10% and 15% below control, respectively, and food efficiency was 15% below the control. No test substance-related effects on in-life parameters were observed in males at 3000 ppm or below or in females at any concentration tested. In clinical pathology, increased urea nitrogen in males at 12000 ppm may have been test-substance related but was considered nonadverse.
Adverse microscopic findings in the kidney and/or urinary bladder of both sexes were observed at 12000 ppm. Microscopic changes in the kidney included: degeneration/regeneration of tubules; dilation of the tubules and pelvis; and hyperplasia of the transitional epithelium. Microscopic changes in the urinary bladder included: inflammation; concretions; and hyperplasia of the transitional epithelium.
Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for test substance was 3000 ppm for male and female rats. This is equivalent to 183 and 204 mg/kg bw/day, respectively, in male and female rats. The NOAEL was based on kidney and urinary tract changes at 12000 ppm in males and female rats.