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Toxicological information

Carcinogenicity

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Administrative data

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1978
Report Date:
1978

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Study was performed to determine whether selected chemicals have the capacity to produce cancer in animals. Mice were exposed to DETU in diet during 103 weeks.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River breeding Laboratories, Inc., Wilmington, Massachussets
- Age at study initiation: around 6 weeks-old
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: in polycarbonate cages suspended from aluminium racks.
- Diet (e.g. ad libitum): Wayne Lab-Blox (Allied Mills, Inc. Chicago, Ill.), ad libitum
- Water (e.g. ad libitum): aciduled water (pH 2.5) was suplied to animals in water bottles filled in an automated metering device, ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-26°C
- Humidity (%):45-55%
- Air changes (per hr):12-15
- Photoperiod (hrs dark / hrs light): fluorescent lighlting 8h/day (9.00 am to 5.00 pm)

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
- Concentration: 250 and 500 ppm.
- Positive control: non
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
daily
Post exposure period:
1 week
Doses / concentrationsopen allclose all
Dose / conc.:
500 ppm
Dose / conc.:
250 ppm
No. of animals per sex per dose:
- Number of animals per dose: 50 males + 50 females
- Control groups: 20 males + 19 females
Control animals:
yes, concurrent no treatment
Positive control:
no

Examinations

Observations and examinations performed and frequency:
- Body weight: immediately prior to initiation of the experiment and then once monthly throughout the bioassay
- Food consumption: collected at monthly intervals from 20 of the animals of the animals in each group.
- Mortality: inspected twice daily
Sacrifice and pathology:
- Animal sacrifice: by CO2 asphyxiation, at the end of the bioassay or when moribund or when animals developed large, palpable masses that jeopardize their health.
- Necropsy: as soon as death occured.
- Gross and microscopic examination of all major tissues, organs and gross lesions.
- Tissues were preserved in a 10 percent neutral buffered formalin solution, embedded in paraffin, sectioned, and stained with hematoxylin and eosin prior to microscopic examination. Slides were prepared from the following tissues: skin, subcutaneous tissue, lungs and bronchi, trachea, bone marrow, spleen, lymph nodes, thymus, heart, salivary gland, liver, pancreas, esophagus, stomach, small intestine, large intestine, kidney, urinary bladder, pituitary, adrenal, thyroid, parathyroid, testis, prostate, brain, tunica vaginalis, uterus, mammary gland and ovary. - A few tissues were not examined for some animals, particularly for those that died early. Besides, some animals were missing, cannibalized, or judged to be in such an advanced state of autolysis as to preclude histopathologic interpretation.
Statistics:
- A Tarone test was performed to evaluate association between dosage and mortality. - Statistical analyses for a possible dose-related effect on survival used the method of Cox (1972) when testing two groups for equality and used Tarone's (1975) extensions of Cox's methods when testing a dose-related trend.
- To determine whether animals receiving the test substance developed a significantly higher proportion of tumors than did the control animals, the one-tailed Fisher exact test was used to compare the tumor incidence of a control group to that of a group of treated animals at each dose level. In practice, the incidence of lesions was analyzed by a Cochran-Armitage test which was used when comparing the dosed groups to the control and which was supported by a Fisher exact test, comparing the high dose group to the control.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No abnormal clinical signs were recorded.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
There were no significant positive associations between the dosages of N,N'-diethylthiourea administered and mortality of either sex.
There were adequate numbers of animals in all dose groups survived sufficiently long to be at risk from late-developing tumors.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Dose related mean body weight depression was apparent in both male and female mice after week 30, indicating that the concentrations of N,N'-diethylthiourea administered to mice may have approximated the maximum tolerated dosages (250 and 500 ppm)..
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
The severity and incidence of non-neoplastic lesions were also not unusual (ex: pneumonia, spleen hyperplasia...).
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
In both sexes, the neoplasms observed were similar in type and distribution in dosed and control mice (ex: alveolar/bronchiolar adenoma, hepatocellular adenoma and carcinoma, leukemia or malignant lymphoma...). None of statistical tests for any site revealed a significant positive association between administration of compound and increased tumor incidence.
Other effects:
not examined
Relevance of carcinogenic effects / potential:
The test substance was considered as not carcinogenic in B6C3F1 mice.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
< 250 ppm
Sex:
male/female
Basis for effect level:
other: Decrease of body weight gain was observed at 250 and 500 ppm in mice.
Remarks on result:
other: Systemic toxicity
Dose descriptor:
NOAEL
Effect level:
> 500 ppm
Sex:
male/female
Basis for effect level:
other: No tumors was observed in mice after exposure of 250 and 500 ppm of DETU during 103 weeks.
Remarks on result:
other: carcinogenicity

Any other information on results incl. tables

Tables of results: Carcinogenicity study in mice with DETU

 

1/ Analyses of the incidence of primary tumors at specific sites in female mice treated with DETU

 

Topography: morphology

control

Low dose (250 ppm)

High dose

(500 ppm)

Hematopoietic system :

Leukemia or malignant lymphoma

weeks to first observed tumor

8/19 (42%)

 

93

15/48 (31%)

 

78

9/41 (22%)

 

92

Uterus: Endometrial stromal polyp

weeks to first observed tumor

0/17 (0%)

/

3/45 (7%)

62

2/38 (5%)

91

 

 

2/ Analyses of the incidence of primary tumors at specific sites in male mice treated with DETU

 

Topography: morphology

control

Low dose (250 ppm)

High dose

(500 ppm)

Lung: Alveolar/Bronchiloar adenoma or alveolar/bronchiolar carcinoma

weeks to first observed tumor

2/13 (15%)

 

 

99

4/46 (9%)

 

 

104

6/46 (13%)

 

 

99

Hematopoietic system :

Leukemia or malignant lymphoma

weeks to first observed tumor

3/15 (20%)

 

93

11/48 (23%)

 

90

12/49 (24%)

 

76

Circulatory system: Hemangioma or hemangiosarcoma

weeks to first observed tumor

1/15 (7%)

 

104

1/48 (2%)

 

104

3/49 (6%)

 

99

Liver: Hepatocellular carcinoma

weeks to first observed tumor

2/14 (14%)

104

5/48 (10%)

71

2/49 (4%)

104

Liver: Hepatocellular carcinoma or hepatocellular adenoma

weeks to first observed tumor

5/14 (36%)*

 

/

7/48 (15%)

 

104

3/49 (6%)*

 

91

 

* Significative difference between treated and control groups (cochran-Armitage est supported by a Fischer exact test)

 

Applicant's summary and conclusion

Executive summary:

Study was performed to determine whether DETU have the capacity to produce cancer in animals.

Mice were exposed to DETU in diet during 103 weeks at 250 and 500 ppm (12.5 and 25 mg/kg bw/d respectively).

No mortality, no clinical signs were observed during this study, but decrease of body weight gain was observed at each dose.

In both sexes, the neoplasms observed were similar in type and distribution in dosed and control mice (ex: alveolar/bronchiolar adenoma, hepatocellular adenoma and carcinoma, leukemia or malignant lymphoma...). None of statistical tests for any site revealed a significant positive association between administration of compound and increased tumor incidence.

The severity and incidence of non-neoplastic lesions were also not unusual (ex: pneumonia, spleen hyperplasia...).

The test substance was considered as not carcinogenic in B6C3F1 mice.