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Toxicological information

Carcinogenicity

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Description of key information

Under the conditions of these 2-year gavage studies, there wassome evidence of carcinogenic Activity of test chemical for male F344/N rats, as shown by increased incidences of renal cortical (tubular cell) adenomas. The incidences of renal tubular cell hyperplasia were also increased in male rats exposed to test chemical . The survival of male rats that received test chemical was reduced compared with survival of vehicle control male rats. There wasnoevidence ofcarcinogenic activityof test chemical for female F344/N rats or for male or female B6C3F1 mice that received 125 or 250 mg/kg per day.But acoording to NTP report, ̏ Positive results demonstrate that a chemical is carcinogenic for laboratory animals under the conditions of the study and indicate that exposure to the chemical has the potential for hazard to humans.”

Thus, comparing this value with the criteria of CLP regulation, Test chemical is suspected to induce a carcinogenic response and thus should be classified as toxic and be placed in Category 2.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data from NTP report
Qualifier:
equivalent or similar to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
The carcinogenic studies of test material was performed on F344/N Rats
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
Details on test animal and environmental conditions:
TEST ANIMALS
- Source: Harlan Industries
- Age at study initiation:45 days old
- Weight at study initiation:
- Fasting period before study:
- Housing: cages: Polycarbonate and bedding: Aspen wood chips, Animals were housed five per cage.
- Diet (e.g. ad libitum): NIH 07 feed ad libitum
- Water (e.g. ad libitum): Automatic watering system
(Edstrom Industries, Waterford, WI);
available ad libitum
- Acclimation period: 16 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.6°-26.7° C
- Humidity (%):30%•80%
- Air changes (per hr): 13 room air
Changes/h
- Photoperiod (hrs dark / hrs light): fluorescent light 12 hid;
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test chemical dissolved in corn oil




VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil
- Amount(s) applied (volume or weight with unit):5 ml/kg
- Concentration (if solution): 0.125. or 250 mg/kg
- Lot/batch no. (if required):
- Purity:
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
103 wk
Frequency of treatment:
5 days /week
Remarks:
0,125, or 250 mg/kg
No. of animals per sex per dose:
Total :300
0 mg/kg : 50 males and 50 females
125.0 mg/kg : 50 males and 50 females
250.0 mg/kg : 50 males and 50 females
Control animals:
yes
Observations and examinations performed and frequency:
Observation and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked in table [No.?] were included. Behaviour and physical appearance were observed.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: All animals were observed two times per day, and clinical signs were recorded at least once per month.


BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded once per week for the first 12 (rats) weeks of the studies and once per month thereafter.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data available

FOOD EFFICIENCY: No data available
OPHTHALMOSCOPIC EXAMINATION: No data available

HAEMATOLOGY: No data available

CLINICAL CHEMISTRY: No data available

URINALYSIS: No data available

NEUROBEHAVIOURAL EXAMINATION: No data available

OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Three statistical methods are used to analyze tumor incidence data: life table tests, incidental tumor analysis, and Fisher exact/Cochran-Armitage trend analyses. Tests of significance include pairwise comparisons of high dose and low dose groups with vehicle controls and tests for overall dose response trends.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Soft stools and occasional diarrhea were observed in chemically exposed rats starting 6 months after the beginning of exposure to test chemical
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
The survival of male rats exposed at 250 mg/kg was significantly lower than that of vehicle controls after week 89. Survival of chemically exposed female rats was comparable to survival of the vehicle controls throughout the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Mean body weights of male rats that received 250 mg/kg were never more than 10% lower than that of vehicle controls, and mean body
weights of male rats that received 125 rng/kgwere never more than 6% lower than that of vehicle controls Mean body weights of chemically exposed female rats were comparable to those of vehicle controls throughout the studies.
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:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Pigmentation of the small and large intestines was present in exposed rats but not in vehicle controls. Ulcers and erosive lesions of the digestive tract were observed in male rats that received 250 mglkg and to a lesser extent in male rats that received 125 mg/kg. A carcinoma of the colon occurred in one male rat that received 250 mg/kg; no other neoplasms were observed in the gastrointestinal tract of rats.
The severity of nephropathy was markedly greater in exposed male rats than in vehicle controls. Associated with the nephropathy were nonneoplastic lesions indicative of reduced renal function and secondary hyperparathyroidism, including parathyroid hyperplasia, mineralization of various organs, and fibrous osteodystrophy. Renal tubular cell hyperplasia (1150; 4/48; 5/50) and renal cortical (tubular cell) adenomas (0/50; 1148; 3/50) occurred in male rats. Renal cortical adenomas are infrequently observed in male F344/N rats (historical incidence, 0.5%).
More preputial gland adenomas or carcinomas (combined) were observed in low dose male rats than in vehicle controls (3/50; 10/48; 3/50), whereas the incidences of clitoral gland neoplasms were decreased in dosed female rats (9/50; 6/50; 1149).
Other effects:
not specified
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
clinical signs
mortality
body weight and weight gain
histopathology: neoplastic
Remarks on result:
other: There was some evidence of carcinogenic activity of for male F344/N rats was observed
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
histopathology: non-neoplastic
histopathology: neoplastic
Remarks on result:
other: No evidence of carcinogenic activity of for female F344/N rats was observed
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
There was some evidence of carcinogenic activity of for male F344/N rats, as increased incidences of renal cortical (tubular cell) adenomas and the incidences of renal tubular cell hyperplasia .The survival of male rats that received test chemical was reduced compared with survival of vehicle control male rats. There was no evidence of carcinogenic activity of test chemical for female F344/N rats in 2-year gavages studies.
Executive summary:

The carcinogenicity study of test chemical was performed on male and female F344/N rats. The test chemical dissolved in corn oil in dose concentration 0,125.0, 250mg/kg and administered in dose volume 5ml/kg via oral gavages route for 5days/weeks for 2 years. Each dose group contained 50males and 50 females. All animals were observed two times per day, and clinical signs were recorded at least once per month. Body weights were recorded once per week for the first 12 (rats) weeks of the studies and once per month thereafter. Necropsy performed on all animals; histologic exams performed on all male rats. vehicle control and high dose female rats; liver examined in low dose female rats; The survival of male rats exposed at 250 mg/kg was significantly lower than that of vehicle controls after week 89. Survival of chemically exposed female rats was comparable to survival of the vehicle controls throughout the study. Soft stools and occasional diarrhea were observed in chemically exposed rats starting 6 months after the beginning of exposure to test chemical. Mean body weights of male rats that received 250 mg/kg were never more than 10% lower than that of vehicle controls, and mean body weights of male rats that received 125 mg/kg were never more than 6% lower than that of vehicle controls Mean body weights of chemically exposed female rats were comparable to those of vehicle controls throughout the studies. Pigmentation of the small and large intestines was present in exposed rats but not in vehicle controls. Ulcers and erosive lesions of the digestive tract were observed in male rats that received 250 mg/kg and to a lesser extent in male rats that received 125 mg/kg. A carcinoma of the colon occurred in one male rat that received 250 mg/kg; no other neoplasms were observed in the gastrointestinal tract of rats. The severity of nephropathy was markedly greater in exposed male rats than in vehicle controls. Associated with the nephropathy were nonneoplastic lesions indicative of reduced renal function and secondary hyperparathyroidism, including parathyroid hyperplasia, mineralization of various organs, and fibrous osteodystrophy. Renal tubular cell hyperplasia (1150; 4/48; 5/50) and renal cortical (tubular cell) adenomas (0/50; 1148; 3/50) occurred in male rats. Renal cortical adenomas are infrequently observed in male F344/N rats (historical incidence, 0.5%). More preputial gland adenomas or carcinomas (combined) were observed in low dose male rats than in vehicle controls (3/50; 10/48; 3/50), whereas the incidences of clitoral gland neoplasms were decreased in dosed female rats (9/50; 6/50; 1149). As there wassome evidence of carcinogenic activityof for male F344/N rats, as increased incidences ofrenal cortical (tubular cell) adenomas and the incidences of renal tubular cell hyperplasia .The survival of male rats that received test chemical was reduced compared with survival of vehicle control male rats. There wasno evidence of carcinogenic activityof test chemical for female F344/N rats in 2-year gavages studies,

 

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
250 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from authoritative database

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Carcinogenicity by oral route             

In given NTP study report, Test chemical has been investigated for Carcinogenicity, The studies are as mentioned below:

Study 1

The carcinogenicity study of test chemical was performed on male and femaleF344/N rats. The test chemical dissolved in corn oil in dose concentration 0,125.0, 250mg/kg and administered in dose volume 5ml/kg via oral gavages route for 5days/weeks for 2 years. Each dose group contained 50males and 50 females. All animals were observed two times per day, and clinical signs were recorded at least once per month. Body weights were recorded once per week for the first 12 (rats) weeks of the studies and once per month thereafter. Necropsy performed on all animals; histologic exams performed on all male rats. vehicle control and high dose female rats; liver examined in low dose female rats; The survival of male rats exposed at 250 mg/kg was significantly lower than that of vehicle controls after week 89. Survival of chemically exposed female rats was comparable to survival of the vehicle controls throughout the study. Soft stools and occasional diarrhea were observed in chemically exposed rats starting 6 months after the beginning of exposure to test chemical. Mean body weights of male rats that received 250 mg/kg were never more than 10% lower than that of vehicle controls, and mean body weights of male rats that received 125 mg/kg were never more than 6% lower than that of vehicle controls Mean body weights of chemically exposed female rats were comparable to those of vehicle controls throughout the studies. Pigmentation of the small and large intestines was present in exposed rats but not in vehicle controls. Ulcers and erosive lesions of the digestive tract were observed in male rats that received 250 mg/kg and to a lesser extent in male rats that received 125 mg/kg. A carcinoma of the colon occurred in one male rat that received 250 mg/kg; no other neoplasms were observed in the gastrointestinal tract of rats. The severity of nephropathy was markedly greater in exposed male rats than in vehicle controls. Associated with the nephropathy were nonneoplastic lesions indicative of reduced renal function and secondary hyperparathyroidism, including parathyroid hyperplasia, mineralization of various organs, and fibrous osteodystrophy. Renal tubular cell hyperplasia (1150; 4/48; 5/50) and renal cortical (tubular cell) adenomas (0/50; 1148; 3/50) occurred in male rats. Renal cortical adenomas are infrequently observed in male F344/N rats (historical incidence, 0.5%). More preputial gland adenomas or carcinomas (combined) were observed in low dose male rats than in vehicle controls (3/50; 10/48; 3/50), whereas the incidences of clitoral gland neoplasms were decreased in dosed female rats (9/50; 6/50; 1149). As there wassome evidence of carcinogenic activityof for male F344/N rats, as increased incidences ofrenal cortical (tubular cell) adenomas and the incidences of renal tubular cell hyperplasia .The survival of male rats that received test chemical was reduced compared with survival of vehicle control male rats. There wasno evidence of carcinogenic activityof test chemical for female F344/N rats in 2-year gavages studies.

Study 2

The carcinogenicity study of test chemical was performed on male and femaleB6C3F1 mice. The test chemical dissolved in corn oil in dose concentration 0,125.0, 250mg/kg and administered in dose volume 10ml/kg via oral gavages route for 5days/weeks for 2 years. Each dose group contained 50males and 50 females. All animals were observed two times per day, and clinical signs were recorded at least once per month. Body weights were recorded once per week for the first 13 (mice ) weeks of the studies and once per month thereafter. Necropsy performed on all animals; histological exams performed on all male male and female mice; liver and pancreas examined in low dose mice.

No significant differences in survival were observed between chemically exposed and vehicle control animals. Three high dose female mice that died on the same day during week 19 exhibited chemical signs indicative of compound-related toxicity. The deaths of other female mice before week 60 did not appear to be compound related. No compound-related clinical signs were observed in mice during the 2-year studies. Mean body weights of chemically exposed males and mean body weights of females that received 250 mg/kg were comparable to those of vehicle controls; the mean body weight of females that received 125 mg/kg was up to 17% greater than that of vehicle controls.Circulatory System:The incidence of hemangiomas or hemangiosarcomas (combined) in 250mg/kg dose male mice was significantly greater than that in vehicle controls .Each tumor occurred at a different site (subcutaneous tissue, spleen, liver, lymph nodes, and pancreas). The historical control incidence is11%at the study laboratory and 6% in 2-year NTP studies.Lung:Chronic bronchopneumonia and hyperplasia of the alveolar epithelium were observed at increased incidences in dosed male mice (chronic bronchopneumonia--male: vehicle control, 2/50; low dose, 10/32; high dose, 8/50; female: 4/49; 3/18; 1/49; alveolar epithelium hyperplasia-male: 1/50; 11/32; 3/50; female: 3/49;3/18; 0/49). The lesions were focal, minimal to mild in severity, and morphologically similar in all animal groups. These lesions are indicative of a resolving viral infection and are consistent with the presence of positive titers for Sendai virus found in sentinel mice during the 2-year studies

Kidney:The incidence of renal tubule pigmentation in males that received 250 mglkg was markedly greater than that found in vehicle control males (male: vehicle control, 4/50; low dose, 0/18 [32 kidneys not examined microscopically]; high dose, 25/50; female: none observed). The pigment consisted of yellow to brown material and was located in the lumen of the tubule. It did not resemble the study chemical or material derived from the study chemical. Usually, only one or two tubules were involved, and there was no difference in degree of severity or involvement between chemically exposed and vehicle control animals. There were no histopathologic changes in the tubular epithelium associated with the presence of pigment.Anterior Pituitary Gland:The incidence of adenomas or adenocarcinomas (combined) in high dose female mice was significantly lower than that in vehicle controls. Under the conditions of these 2-year gavages studies There wasno evidence of carcinogenic activityof test chemical for male or femaleB6C3F1 mice that received 125 or 250 mg/kg per day.

Under the conditions of these 2-year gavage studies, there wassome evidence of carcinogenic Activity of test chemical for male F344/N rats, as shown by increased incidences of renal cortical (tubular cell) adenomas. The incidences of renal tubular cell hyperplasia were also increased in male rats exposed to test chemical . The survival of male rats that received test chemical was reduced compared with survival of vehicle control male rats. There wasnoevidence ofcarcinogenic activityof test chemical for female F344/N rats or for male or female B6C3F1 mice that received 125 or 250 mg/kg per day.But acoording to NTP report, ̏ Positive results demonstrate that a chemical is carcinogenic for laboratory animals under the conditions of the study and indicate that exposure to the chemical has the potential for hazard to humans.”Thus, Test chemical is suspected to induce a carcinogenic response and thus should be classified as toxic and be placed in Category 2.

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation,Test chemical is suspected to induce a carcinogenic response and thus should be classified as toxic and be placed in Category 2.