Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
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:
2017
Report date:
2017

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: U.S. EPA Health Effects Test Guidelines OPPTS 870.3550 (2000)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: MAFF Japan Test Guidelines for Agricultural Chemicals 12-Nousan-8147 (2000)
Deviations:
no
GLP compliance:
yes

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
Batch No.: SG0312574
Purity: 98.2%

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
Details on species / strain selection:
The rat was selected for this study because it is a preferred species for reproductive toxicity testing and recommended by regulatory guidelines. The Crl:CD(SD) strain was chosen because extensive background data are available from the literature, the supplier, and previous studies at the test facility. This strain is also considered suitable relative to longevity, hardiness, and incidence of spontaneous disease.
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:
The analysis results show that the test substance was homogeneously mixed at the target concentrations for all diet samples analyzed.
The test substance was not detected in the control diet.
Duration of treatment / exposure:
Dietary administration of the test substance for P1 animals began on test day 1 (premating) and continued until the day of sacrifice.
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:
12
Control animals:
yes, plain diet

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
All clinical signs that were reported were unremarkable, observed in single animals in a group, and of a nature commonly seen in rats of this age.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
During the lactation period, mean body weights were significantly reduced in P1 females (8% lower than control) at 12,000 ppm on LD 4. Overall (LD 0-4) mean body weight gains were 77% lower (not statistically significant) than control group values at this level.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Mean food consumption was generally lower than control group values in P1 females during the premating phase at 12,000 ppm. Overall (TD 1-15) mean food consumption was 7% (not statistically significant) lower than control group values. During the gestation period, mean food consumption was generally lower (not statistically significant) than control values at 12,000 ppm. During the lacation period (LD 0-4), mean food consumption values were statistically significantly lower (30% lower than control) at 12,000 ppm.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
Mean food efficiency at 12,000 ppm was statistically significantly lower (16% lower than control) during the first week of test substance administration in P1 males. For the period that food consumption was evaluated in P1 males (TD 1-15), mean food efficiency was 15% (statistically significant) lower than control values at 12,000 ppm. These changes correlate with the minimal effects observed on body weight gain parameters in P1 males at this level. Mean food efficiency in p1 females during lactation was -0.036 at 12,000 ppm, compared to 0.102 for the control group.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Test substance-related changes were present in the kidney and urinary bladder at 12,000 ppm. In the kidneys, microscopic changes included: degeneration/regeneration of tubules; dilatation of the tubules and pelvis; hyperplasia of transitional and collecting duct epithelium; papillary necrosis; leukocytosis; and concretions. These microscopic changes were associated with increased kidney weights and, in males, low incidences of gross lesions in the kidneys. Changes in the urinary bladder included: inflammation; mast cell infiltrate; hyperplasia of transitional epithelium; hemorrhage; and concretions. In addition, transmural degeneration/necrosis of the urinary bladder was present in one 12,000 ppm male. Microscopic findings considered secondary to the kidney and urinary bladder changes were noted in the prostate/seminal vesicles/coagulating glands of one male. In addition, in the 12,000 ppm female group, decreased thymus weights and lymphoid depletion in the thymus were considered secondary stress-related findings. The tissue changes in the kidneys and urinary bladder at 12,000 ppm were considered adverse for rats; no test substance related terminal body weight, gross or microscopic findings were observed at ≤3000 ppm.

Reproductive function / performance (P0)

Reproductive performance:
no effects observed

Details on results (P0)

There was no evidence of reproductive toxicity at any concentration tested.

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
12 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:
Key result
Dose descriptor:
NOAEL
Remarks:
systemic and offspring toxicity
Effect level:
3 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was a slight test substance-related reduction in mean pup weight at 12,000 ppm. Mean pup weight at birth was 7% lower than control. This reduction was not statistically significant. Mean pup weight on lactation day 4 was statistically significantly lower than the control and was 13% lower than control. These reductions are consistent with the reductions in maternal body weight parameters during gestation and lactation that were seen at this level and were considered treatment-related, and potentially adverse.
There were no test substance-related or statistically significant effects on mean pup weight at 3000 ppm or lower.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Remarks:
offspring toxicity
Generation:
F1
Effect level:
3 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
NOAEL for systemic and offspring toxicity: 3000 ppm (equivalent to 228 mg/kg body weight/day for P1 males and 223, 212, and 316 mg/kg body weight/day for P1 females during premating, gestation, and lactation, respectively)
NOAEL for reproductive toxicity: 12000 ppm, the highest level tested (equivalent to 864 mg/kg body weight/day for P1 males and 838, 812, and 979 mg/kg body weight/day for P1 females during premating, gestation, and lactation, respectively)
Executive summary:

A repeated dose reproduction/developmental toxicity screening test was conducted with the test item according to the guidelines OECD 421 and US EPA OPPTS 870.3550. Crl:CD(SD) rats (12/sex/dose level) were administered the test substance via diets that contained 0, 150, 750, 3000, or 12,000 ppm of test item. Results from the analysis of the test diets show that the test item was homogeneously mixed at targeted concentrations. Test substance was not detected in the control diet.


Following a 14-day premating period, P1 males and females were cohoused for up to 2 weeks within their respective treatment groups to produce F1 litters. Dams were allowed to deliver and rear their offspring until postpartum day 4. General and careful clinical observations were recorded at specified intervals during the study. Body weights and food consumption were recorded weekly for P1 males and females during premating, on days 0, 7, 14, and 20 of gestation, and on days 0 and 4 of lactation. Food consumption was not measured during cohabitation or thereafter for males or for females with no evidence of copulation.


F1 litter examinations (pup viability, individual pup weights, clinical observations) were performed at birth and on lactation day 4. Pups were euthanized (by decapitation) on lactation day 4 and discarded without anatomic pathology evaluation.


All P1 rats were given a gross pathological examination at terminal sacrifice. For P1 animals, selected tissues and gross lesions were weighed and/or retained for microscopic examination. Uterine implantation sites and ovarian corpora lutea were counted in cohabitated P1 females. All tissues collected from surviving P1 adult rats that produced a litter in the control and high-dose groups (Groups 1 and 5, respectively) were processed to slides and evaluated microscopically. Gross lesions from all rats (12 rats/sex/dose) were also processed and examined.


Mean daily intakes for P1 males during the premating period (days 1-15) were 0, 11.74, 57.77, 228.37, and 863.69 mg test substance/kg body weight/day at targeted concentrations of 0, 150, 750, 3000, and 12,000 ppm, respectively. Mean daily intakes for P1 females during the premating period (days 1-15) were 0, 11.43, 57.37, 222.57, and 837.53 mg test substance/kg body weight/day at targeted concentrations of 0, 150, 750, 3000, and 12,000 ppm, respectively. Throughout the gestation period (days 0-20G) mean daily intakes of the P1 females were 0, 10.71, 55.69, 212.08, and 812.12 mg test substance/kg body weight/day at targeted concentrations of 0, 150, 750, 3000, and 12,000 ppm, respectively. Mean daily intakes during lactation (days 0-4L) for these same respective concentrations were 0, 13.03, 79.97, 316.34, and 978.73 mg test substance/ kg body weight/day.


During the in-life phase of the study, there were no test substance-related clinical observations, nor were there any test substance-related deaths. Test substance-related, potentially adverse effects were limited to effects on body weight and food consumption parameters at 12,000 ppm in P1 females. There were no test substance-related effects during the in-life period at 3000 ppm or lower.


Test substance-related changes were present in the kidney and urinary bladder at 12,000 ppm. In the kidneys, microscopic changes included: degeneration/regeneration of tubules; dilatation of the tubules and pelvis; hyperplasia of transitional and collecting duct epithelium; papillary necrosis; leukocytosis; and concretions. These microscopic changes were associated with increased kidney weights and, in males, low incidences of gross lesions in the kidneys. Changes in the urinary bladder included: inflammation; mast cell infiltrate; hyperplasia of transitional epithelium; hemorrhage; and concretions. In addition, transmural degeneration/necrosis of the urinary bladder was present in one 12,000 ppm male. Microscopic findings considered secondary to the kidney and urinary bladder changes were noted in the prostate/seminal vesicles/coagulating glands of one male. In addition, in the 12,000 ppm female group, decreased thymus weights and lymphoid depletion in the thymus were considered secondary stress-related findings. The tissue changes in the kidneys and urinary bladder at 12,000 ppm were considered adverse for rats; no test substance related terminal body weight, gross or microscopic findings were observed at ≤3000 ppm. All mated pairs in each group littered successfully, and there were no test substance related findings in the F1 pups.


Test substance-related effects on offspring were limited to slight effects on offspring body weight at 12,000 ppm that were consistent with effects on parental body weight parameters at this concentration. These changes in offspring body weights were considered to be potentially adverse.


Under the current experimental conditions and based on adverse effects on the adult kidneys and urinary bladder and effects on P1 female body weight and food consumption parameters during lactation at 12,000 ppm, the no-observed-adverse-effect level (NOAEL) for systemic and offspring toxicity was 3000 ppm. This exposure was equivalent to 228 mg/kg body weight/day for P1 males and 223, 212, and 316 mg/kg body weight/day for P1 females during premating, gestation, and lactation, respectively. The NOAEL for offspring was also 3000 ppm, based on effects on pup weights during lactation at 12,000 ppm. Based on the lack of any evidence of reproductive toxicity at any concentration tested, the NOAEL for reproductive toxicity was 12,000 ppm, the highest level tested. This exposure was equivalent to 864 mg/kg body weight/day for P1 males and 838, 812, and 979 mg/kg body weight/day for P1 females during premating, gestation, and lactation, respectively.