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Diss Factsheets

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: HJ/T 154-2004, 408 Sub-Chronic (90-Day) Oral Toxicity Test in Rodents
Version / remarks:
Second edition, 2013
GLP compliance:
yes
Remarks:
The test complied with the Principles of Good Laboratory Practices (GLP) of the Certification and Accreditation Administration of the People’s Republic of China (2013 revised edition).
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-nitro-4-(trifluoromethyl)benzonitrile
EC Number:
212-298-1
EC Name:
2-nitro-4-(trifluoromethyl)benzonitrile
Cas Number:
778-94-9
Molecular formula:
C8H3F3N2O2
IUPAC Name:
2-nitro-4-(trifluoromethyl)benzonitrile

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
SPF grade
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
10 mg/kg bw/day (actual dose received)
Dose / conc.:
27 mg/kg bw/day (actual dose received)
Dose / conc.:
70 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
control and high-dose groups: 16 (additional 6 animals each for recovery group examinations)
low- and mid-dose groups: 10
Control animals:
yes, concurrent vehicle
Positive control:
no

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
In the exposure period at days 3, 24, 31, 38, 45, 52, 59, 66, 73, 80, and 87, mean body weights for male rats in the high-dose group were reduced compared to the control group and presented a significant or extremely significant statistical difference (P ≤ 0.05, P ≤ 0.01, P ≤ 0.001). In the exposure period at day 80, mean body weight for male rats in the medium-dose group was reduced compared to the control group and the difference was significant (P ≤ 0.05). In the exposure period at days 3, 24, 31, and 66, weight gain for male rats in the high-dose group was reduced compared to the control group, and presented an extremely significant or significant statistical difference (P ≤ 0.001, P ≤ 0.01). In the exposure period at day 3, weight gain for male rats in the medium-dose group was reduced compared to the control group, and the difference was extremely significant (P ≤ 0.001). In the exposure period at day 45, weight gain for female rats in the high-dose group was elevated compared to the control group, and the difference was significant (P ≤ 0.05, P ≤ 0.01).
In the exposure period and the recovery period, for the remaining male and female animals in all dose groups, body weights and weight gain in all weeks did not present statistical differences compared to the control group.
The above changes did not present an obvious dose-response relationship and it can be concluded that they were not toxicologically significant.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
In the exposure period at days 3, 45, 59, 73, 80, and 87, mean change in food intake for male rats in the high-dose group was lower than in the control group and presented an extremely significant or significant statistical difference (P ≤ 0.001, P ≤ 0.01, P ≤ 0.05). In the exposure period at days 45, 59, 66, 73, 80, and 87 mean change in food intake for male rats in the medium-dose group was lower than in the control group and presented an extremely significant or significant statistical difference (P ≤ 0.001, P ≤ 0.01, P ≤ 0.05). In the exposure period at days 59 and 87 mean change in food intake for male rats in the low-dose group was lower than in the control group and presented a significant or extremely significant statistical difference (P ≤ 0.01, P ≤ 0.001). In the exposure period at days 3, 45, and 73, mean change in food intake for female rats in the high-dose group was lower than in the control group and the difference was significant (P ≤ 0.05). In the exposure period at day 10 mean change in food intake for female rats in the high-dose group was higher than in the control group and the difference was extremely significant (P ≤ 0.001). In the exposure period at days 10 and 66, mean change in food intake for female rats in the medium-dose group was higher than in the control group and the difference was significant (P ≤ 0.01, P ≤ 0.05). In the exposure period at days 10, 17, and 66 mean change in food intake for female rats in the low-dose group was higher than in the control group and the difference was significant (P ≤ 0.05, P ≤ 0.01).
In the exposure period and the recovery period, food intake quantities for male and female animals of all other dose groups did not present a statistical difference compared to the control group.
The above changes did not present an obvious dose-response relationship and it can be concluded that they were not toxicologically significant.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
At the end of the exposure period, haemoglobin concentration, total white blood cells, and lymphocytes in male rats in the high-dose group were reduced compared to the control group and the differences were significant (P ≤ 0.01, P ≤ 0.05). At the end of the exposure period, haemoglobin concentration in male rats in the medium-dose group was reduced compared to the control group, and the difference was significant (P ≤ 0.01). At the end of the exposure period total red blood cells, haemoglobin concentration, and haematocrit in female rats in the high-dose group were reduced compared to the control group and the difference was significant (P ≤ 0.05).
At the end of the recovery period, total red blood cells in male rats in the high-dose group were reduced compared to the control group and the difference was significant (P ≤ 0.05). At the end of the recovery period, mean corpuscular volume and mean corpuscular haemoglobin in male rats in the high-dose group were elevated compared to the control group, and the differences were significant (P ≤ 0.01, P ≤ 0.05). At the end of the exposure period, prothrombin time in female rats in the high-dose group and the low-dose group were reduced compared to the control group and the differences were significant (P ≤ 0.01, P ≤ 0.05). There was no obvious clinical significance.
At the end of the recovery period, prothrombin time in male rats in the high-dose group was elevated compared to the control group, and the difference was significant (P ≤ 0.05).
The above changes exhibited no obvious dose-response relationship and it can be concluded that they were not toxicologically significant.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
At the end of the exposure period, creatinine in male rats in the high-dose group was reduced compared to the control group and the difference was significant (P ≤ 0.05). At the end of the exposure period, albumin in male rats in the high-dose group was elevated compared to the control group and the difference was significant (P ≤ 0.05). At the end of the exposure period, total protein and globulin in female rats in the high-dose group were elevated compared to the control group, and the differences were significant (P ≤ 0.05, P ≤ 0.01). At the end of the exposure period total protein and globulin in female rats in the medium-dose group were elevated compared to the control group, and the difference was significant (P ≤ 0.05). At the end of the exposure period urea in female rats in the low-dose group was reduced compared to the control group, and the difference was significant (P ≤ 0.05). At the end of the recovery period, urea and creatinine in male rats in the high-dose group were reduced compared to the control group, and the differences were significant (P ≤ 0.01, P ≤ 0.05). At the end of the recovery period, potassium in male rats in the high-dose group was elevated compared to the control group, and the difference was significant (P ≤ 0.05).
The above changes exhibited no obvious dose-response relationship and it can be concluded that they were not toxicologically significant.
Endocrine findings:
not examined
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
At the end of the exposure period and the recovery period, pH in female rats in the high-dose group was elevated compared to the control group, and the difference was significant (P ≤ 0.05).
Other test results at the end of the exposure period and the end of the recovery period did not present statistical differences compared to the control group.
The above changes did not present an obvious dose-response relationship and it can be concluded that they were not toxicologically significant.
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
At the end of the exposure period, in male rats in the high-dose group absolute body weight was reduced compared to the control group, and the difference was extremely significant (P ≤ 0.001). At the end of the exposure period, in male rats in the high-dose group the liver weight was elevated compared to the control group, and the difference was significant (P ≤ 0.05). At the end of the exposure period, in male rats in the low-, medium-, and high-dose groups the thymus gland was reduced compared to the control group, which presented extremely significant or significant statistical differences (P ≤ 0.001, P ≤ 0.05). At the end of the exposure period, in male rats in the medium- and high-dose groups, liver-body ratios were elevated compared to the control group, and the difference was extremely significant (P ≤ 0.001). At the end of the exposure period, in male rats in the high-dose group heart- and kidney-body ratios were elevated compared to the control group, which presented significant or extremely significant statistical differences (P ≤ 0.05, P ≤ 0.001). At the end of the exposure period, in male rats in the low- and high-dose groups, thymus-body ratios were reduced compared to the control group, which presented extremely significant or significant statistical differences (P ≤ 0.001, P ≤ 0.01). At the end of the exposure period, in male rats in the high-dose group, the liver-brain ratio was elevated compared to the control group and the difference was extremely significant (P ≤ 0.001). At the end of the exposure period, in male rats in the low- and high-dose groups, thymus-brain ratios were reduced compared to the control group and the difference was extremely significant (P ≤ 0.001).
At the end of the exposure period, in female rats in the medium- and high-dose groups, the liver weight was elevated compared to the control group, and the difference was extremely significant (P ≤ 0.001). At the end of the exposure period, in female rats in the low-dose group, the ovaries were reduced compared to the control group and the difference was significant (P ≤ 0.01). At the end of the exposure period, in female rats in the medium- and high-dose groups, the liver-body ratios were elevated compared to the control group, presenting significant or extremely significant statistical differences (P ≤ 0.05, P ≤ 0.001). At the end of the exposure period, in female rats in the low-dose group, the ovary-body ratio was reduced compared to the control group, the difference was significant (P ≤ 0.01). At the end of the exposure period, in female rats in the medium- and high-dose groups, liver-brain ratios were elevated compared to the control group and the difference was extremely significant (P ≤ 0.001). At the end of the exposure period, in female rats in the low-dose group, the ovary-brain ratio was reduced compared to the control group, and the difference was extremely significant (P ≤ 0.001).
At the end of the recovery period, in male rats in the high-dose group, the heart was elevated compared to the control group, and the difference was significant (P ≤ 0.05). At the end of the recovery period, in male rats in the high-dose group, the thymus and adrenal glands were reduced compared to the control group, and the difference was significant (P ≤ 0.05). At the end of the recovery period, in male rats in the high-dose group, the heart-body and kidney-body ratios were elevated compared to the control group, and the difference was significant (P ≤ 0.05). At the end of the recovery period, in male rats in the high-dose group, the thymus-body ratio was reduced compared to the control group, and the difference was significant (P ≤ 0.05). At the end of the recovery period, in male rats in the high-dose group, the heart-brain ratio was elevated compared to the control group, and the difference was significant (P ≤ 0.05). At the end of the recovery period, in male rats in the high-dose group, the thymus-brain ratio was reduced compared to the control group, and the difference was significant (P ≤ 0.01).
At the end of the recovery period, in female rats in the high-dose group, the brain and the ovaries were reduced compared to the control group, and the difference was significant (P ≤ 0.05). At the end of the recovery period, in female rats in the high-dose group, the brain-body and the ovary-body ratios were reduced compared to the control group, and the differences were significant (P ≤ 0.05, P ≤ 0.01). At the end of the recovery period, in female rats in the high-dose group, the ovary-brain ratio was reduced compared to the control group, and the difference was significant (P ≤ 0.05).

The organ weight results illustrated that, at the end of the exposure period, in male rats in the high-dose group, the liver’s absolute organ weight, organ-body ratio, and organ-brain ratio were higher than in the control group, presenting a statistical difference and showing an upward trend as dose increased. It was judged that this was possibly related to the test sample. At the end of the exposure period, in female rats in the medium- and high-dose groups, the liver’s absolute organ weight, organ-body ratio, and organ-brain ratio were higher than in the control group, presenting a statistical difference and showing an upward trend as dose increased. It was judged that this was possibly related to the test sample. At the end of the recovery period, in male and female rats in the high-dose group, the liver’s absolute organ weight, organ-body ratio, and organ-brain ratio recovered and did not present statistical significances.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
End of exposure period: One male rat in the control group exhibited enlarged submandibular lymph nodes; another male rat in the control group exhibited missing right testis and missing right epididymis; a third male rat in the control group exhibited small left testis and small left epididymis; one male rat in the medium-dose group exhibited small left testis and small left epididymis; another male rat in the medium-dose group exhibited centrilobular nodules of the liver; one female rat in the low-dose group exhibited enlarged uterus. There were no abnormalities in the remaining animals.
End of recovery period: No abnormalities were seen in any of the animals.
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
At the end of both the exposure and recovery period, there were no statistical significance in lesions occurring in all organs and they were spontaneous or occasional changes in SD rats at this age.
Histopathological findings: neoplastic:
no effects observed

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
food consumption and compound intake
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:
yes
Lowest effective dose / conc.:
25 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
no

Applicant's summary and conclusion

Conclusions:
Based on the results of the 2-nitro-4-(trifluoromethyl)benzonitrile 90-day repeated oral exposure test in rats, it can be concluded that, based on statistical results of mean change in food intake for male rats, the NOAEL in male rats was 10 mg/kg bw/day. Based on statistical results of liver weight in female rats, it was determined that NOAEL in female rats was 10 mg/kg bw/day.