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Carcinogenicity

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Description of key information

An NTP carcinogenicity study (NTP 1990) is available with rats and mice. In rats no treatment related tumours were found after oral dosing of 200 and 400 mg/kg bw (5 days/week). In the mice study an increased incidence of hyperplasia of the forestomach as well as forestomach squamous cell papillomas at 300 mg/kg bw and above was observed.

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
Study period:
From 19 January 1982 to 01 March 1984
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Reliable study summary (NTP), similar to OECD 451 (no haematology and clinical chemistry)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
GLP compliance:
yes
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Frederick Cancer Research Facility
- Age at study initiation: male: 8 weeks, female: 9 weeks
- Weight at study initiation:
- Fasting period before study:
- Housing: Polycarbonate cages with reemay spun-bonded polyester filters, five per cage
- Diet (e.g. ad libitum): NIH 07 Rat and Mouse Ration; available ad libitum
- Water (e.g. ad libitum): available ad libitum
- Acclimation period: 19 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16.7-31.7
- Humidity (%): 25%-86%
- Air changes (per hr): 15 room air changes/h
- Photoperiod (hrs dark / hrs light): fluorescent light 12 h/d

IN-LIFE DATES:
Male mice: From: 19 January 1982 To: 26 January 1984;
Female mice: From: 2 March 1982 To: 1 March 1984
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Dose volume: 10 mL/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of the test substance dissolved in corn oil at approximately 80 mg/mL was determined at the analytical laboratory. The chemical was found to be stable at room temperature in the dark for 14 days when stored in sealed vials. A small (approximately 5%) loss occurred when the test substance in corn oil was exposed to air and light for 3 hours at room temperature under simulated dosing conditions. Dose formulations were prepared once per week and were stored in the dark at room temperature under nitrogen for a maximum of 14 days throughout the studies.

Periodic ultraviolet analysis of the dose formulations was conducted at the study laboratory and at the analytical chemistry laboratory.

During the 2-year studies, the dose formulations were analyzed at approximately 8-week intervals.
For the test substance studies, it was estimated that the formulations were prepared within ± 10% of the target concentrations approximately 96% (77/80) of the time throughout the studies. Results of periodic referee analysis performed by the analytical chemistry laboratory indicated generally good agreement with the results from the study laboratory.
Duration of treatment / exposure:
103 weeks for female mice, 104 weeks for male mice
Frequency of treatment:
5 days/week
Post exposure period:
No recovery period.
Remarks:
Doses / Concentrations:
0, 200 or 400 mg/kg for male mice; 0, 300 or 600 mg/kg for female mice
Basis:
actual ingested
No. of animals per sex per dose:
50 males and 50 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses of the test substance selected for male mice for the 2-year studies were 200 and 400 mg/kg, based on renal lesions in one male mouse given 600 mg/kg and in all of the male mice given 1200 mg/kg for 13 weeks. Doses selected for female mice for the 2-year studies were 300 and 600 mg/kg because of the steep dose-response curve for mortality demonstrated in the 16-day and 13-week studies (survival-16-day study: 1600 mg/kg, 0/5; 13-week study: 1200 mg/kg, 9/10).

No additional data
Positive control:
None stated
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice per day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice per day

BODY WEIGHT: Yes
- Time schedule for examinations: on day 1, once a week for 13 weeks and once a month thereafter

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Number of animals receiving complete necropsy examination; all gross lesions including masses examined microscopically.

HISTOPATHOLOGY: Yes
Necropsy performed on all animals; the following tissues examined histologically for all vehicle control and high dose animals, and all animals dying before the end of the studies: adrenal glands, brain, cecum, colon, duodenum, epididymis/prostate/testes or ovaries/uterus, esophagus, femur including marrow, gallbladder, gross lesions and tissue masses, heart, ileum, jejunum, kidneys, liver, lungs and mainstem bronchi, mammary gland, mandibular or mesenteric lymph nodes, nasal cavity and turbinates, pancreas, parathyroid glands, pituitary gland, rectum, salivary glands, sciatic nerve, skin, spleen, stomach, thymus, thyroid gland, trachea, and urinary bladder. Tissues examined for low dose groups include adrenal glands, bone, brain, clitoral gland, eyes, gross lesions, heart, kidneys, liver, lungs, pituitary gland, spinal cord, spleen, stomach and gross lesions.
Other examinations:
None stated
Statistics:
The following analysis were performed: survival analyses, calculation of incidences and analysis of tumor incidence. In addition, historical control data were included for those tumors appearing.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
Clinical signs and mortality:
No significant differences were observed between any groups of either sex in mortality. No compound-related clinical signs were observed in clnical signs.

Body weight and weight again:
Mean body weights of dosed and vehicle control mice were similar throughout the studies. No compound-related clinical signs were observed.

Gross pathology:
Forestomach: Focal hyperplasia and squamous cell papillomas were increased in dosed male and female mice; the incidences of squamous cell papillomas in low and high dose female mice were significantly greater than that in vehicle controls.
Focal hyperplasia of the forestomach was characterized by a localized region of increased thickness of the stratified squamous epithelium. In the less severe lesions the surface of the epithelium was irregular or slightly folded, whereas in the more advanced lesions the epithelium was more extensively folded, producing short papillary projections with a narrow core of connective tissue. The squamous cell papillomas exhibited greater complexity of the papillae and the formation of a stalk.
A squamous cell carcinoma was diagnosed in a single high dose female mouse by the pathologist at the study laboratory.

Histopathology: non-neoplastic
Forestomach hyperplasia in mouse.

Histopathology: non-neoplastic
The only effects of the test substance were those seen in the forestomach of mice. The incidences of uncommonly occurring squamous cell papillomas of the forestomach in both exposure groups were significantly greater than those in vehicle controls (male: vehicle control, 1/50; low dose, 2/50; high dose, 5/50; female: 0/50; 5/50; 6/50). The increased incidences of papillomas were accompanied by dose-related increases in the incidences in forestomach hyperplasia (male: 7/50; 8/50; 16/50; female: 12/50; 23/50; 39/50).
Relevance of carcinogenic effects / potential:
Mean body weights of dosed mice were similar to their respective vehicle controls throughout the studies. No significant differences in survival were observed between any groups of mice (survival-male mice: 32/50; 33/50; 31/50; female mice: 30/50; 27/50; 35/50).
The only effects of the test substance were those seen in the forestomach of mice. The incidences of uncommonly occurring squamous cell
papillomas of the forestomach in both exposure groups were significantly greater than those in vehicle controls (male: vehicle control, 1/50; low dose, 2/50; high dose, 5/50; female: 0/50; 5/50; 6/50). The increased incidences of papillomas were accompanied by dose-related increases in the incidences in forestomach hyperplasia (male: 7/50; 8/50; 16/50; female: 12/50; 23/50; 39/50).
Dose descriptor:
NOAEL
Sex:
male/female
Basis for effect level:
other: In males an increased incidence of forestomach hyperplasia was noted at 400 mg/kg bw/day. In females an increased incidence of squamous cell papillomas and forestomach hyperplasia was noted at doses of 300 and 600 mg/kg bw/day.
Remarks on result:
not determinable
Remarks:
no NOAEL identified. Effect type:carcinogenicity (migrated information)
Dose descriptor:
LOAEL
Effect level:
> 300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: In the mice study an increased incidence of hyperplasia of the forestomach as well as forestomach squamous cell papillomas at 300 mg/kg bw and above was observed.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Conclusions:
There was some evidence of carcinogenic activity of the test substance for male or female B6C3Fi mice, as indicated by increased incidences of squamous cell papillomas and hyperplasia of the forestomach.
Executive summary:

B6C3F1 mice were used in this study. Groups of 50 male mice were administered 0, 200, or 400 mg/kg the test substance in corn oil by gavage, 5 days per week for 104 weeks. Groups of 50 female mice were administered 0, 300, or 600 mg/kg, 5 days per week for 103 weeks with the measurement of mortality, body weight, gross pathology and histopathology.

There was some evidence of carcinogenic activity of the test substance for male or female B6C3Fi mice, as indicated by increased incidences of squamous cell papillomas and hyperplasia of the forestomach.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LOAEL
300 mg/kg bw/day
Study duration:
chronic
Species:
mouse
Quality of whole database:
1 (reliable without restriction)

Justification for classification or non-classification

There is not sufficient evidence for a carcinogenic effect of the test substance. The indications cannot even be defined as limited according to Annex I of GLP. Therefore the test substance does not to be classified for this endpoint (DSD and CLP).

Additional information

The test substance was not carcinogenic in an oral 2-year carcinogenicity study in rats.

In a 103-week oral study in mice, there was some evidence of carcinogenic activity of the test substance, as indicated by increased incidences of squamous cell papillomas (benign) and hyperplasia of the forestomach. No carcinomas were observed. It cannot be excluded that the observed effects on the forestomach are related to irritant properies of the test substance (a conclusion that is in line with the conclusion of the German MAC-Committee, Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2010, Jun; 53(6):636-40).


Justification for selection of carcinogenicity via oral route endpoint:
This study was carried out according to a reliable method which similar to OECD Guideline 451 using mice.

Carcinogenicity: via oral route (target organ): digestive: stomach