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Carcinogenicity

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Description of key information

The substance was found to be non carcinogenic in two valid feeding studies in rats (Hunter 1981) and mice (Gfeller 1981).

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1972-02-24 to 1975-04-02
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
other: OECD guideline 452 (chronic toxicity study)
GLP compliance:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): TK 10047
- Physical state: pale yellow powder
Species:
rat
Strain:
CF-1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Carworth Europe, England
- Age at study initiation: 25 days old
- Weight at study initiation: individual body weights are reported.
- Fasting period before study: not reported
- Housing: the rats were housed five to a cage (unless the number was reduced by mortality), in suspended metal cages fitted with wlre-mesh floors
- Diet and water (e.g. ad libitum): free access to tap water and to quantities of powdered laboratory rat food, Spratt's Laboratory Animals Diet No. 2.
- Acclimation period: 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 55
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
REPARATION OF DOSING SOLUTIONS:
- A premix containing 20000 ppm was prepared each week, and from this the different dietary concentrations were obtained by direct dilution with further quantities of diet. Homogeneity was achieved by mixing for ten minutes in a rotary double-cone blender; all diets were stored until use in heat-sealed, opaque polythene bags.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of the diet fed to the rats have been analysed for their content of TK 10 047 by spectrophotometry. The estimated relative reproducibility of this method is - 10% or better. Within the limits of error of sampling technique and of the analytical method, there was good correspondence between the concentrations found in the diets and the nominal values.
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
daily
Post exposure period:
none
Remarks:
Doses / Concentrations:
4 and 6 mg/kg bw ; 14 and 17 mg/kg bw0; 47 and 58 mg/kg bw; 142 and 169 mg/kg bw for males and females, respectively
Basis:
actual ingested
Dose / conc.:
100 ppm (nominal)
Dose / conc.:
300 ppm (nominal)
Dose / conc.:
1 000 ppm (nominal)
Dose / conc.:
3 000 ppm (nominal)
No. of animals per sex per dose:
50
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: yes
All rats were examined daily; all signs of ill-health and toxicity, together with any behavioural changes, were recorded on the so-called Case History Sheet. Detailed descriptions were made of any skin lesions, cataracts or palpable growths, together with the progression or regression of such lesions.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: weekly for first 12 weeks, and at 4 week intervals thereafter


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: assessed in the first instance by inspection of the water bottles


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Before treatment commenced, and after 13, 26, 52, 75 and 102 weeks
- Dose groups that were examined: control and group 3


HAEMATOLOGY: Yes
- Time schedule for collection of blood:After 13, 26, 52, 78 and 102 weeks of treatment
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10 animals/sex from control group and group 5


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After 13, 26, 52, 78 and 102 weeks of treatment
- Animals fasted: No data
- How many animals: 10 animals/sex from control group and group 5


URINALYSIS: Yes
- Time schedule for collection of urine: After 13, 26, 52, 78 and 103 weeks of treatment
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data


NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
ROSS PATHOLOGY: Yes
All superficial tissues, including the urinogenital orifices and tail, each pinna, orbit and external auditory meatus, were examined visually and by palpation, for distortion, swelling, or other evidence of tumour formation; similar attention was given to the mammary tracts and the cervical subcutaneous structures. The nares, buccal cavity, tongue, pharynx and auditory region were then examined, and the cranial roof removed to allow observation of the brain, pituitary gland and cranial nerves . After ventral mid-line incision and skin reflection, all subcutaneous tissues were examined, including regional lymph nodes, mammary and salivary glands . The abdominal viscera were examined before and after removal. The urinary bladder, from all rats dying or killed after 52 weeks of treatment, was briefly distended with fixative in situ, then removed, opened and examined
under low-power magnification. Stomach and caecum were incised and the mucosae scrutinised. The condition of the thoracic viscera was noted, with due attention to the thymus and lymph nodes; the heart was incised and each chamber examined. The oesophagus, intestines, and uterus were incised to expose the mucosae and subjected to visual appraisal in toto. The lungs were remoyed and all pleural surfaces examined under
suitable illumination, while the liver and kidneys were sectioned at intervals of a few millimetres; any lesion suggestive of neoplasia was noted, including details of location, size and multiplicity. Any abnormalities in the appearance and size of the gonads, adrenals, thyroids, intra-abdominal lymph nodes and accessory reproductive organs were recorded. Any evidence of adhesion, invasion or other interaction between presumptive neoplasia and the adjacent structures was noted.

HISTOPATHOLOGY: Yes
(all macroscopically observed lesions suggestive of neoplasia, for every animal; all macroscopically abnormal tissues from decedents in an attempt to ascertain cause of death; 10 rats of each sex from control and 3000 ppm killed at 104 weeks). The following organs were fixed and preserved: adrenals, aorta, brain (cerebrum,cerebellum and pons), caecum, colon, duodenum, eyes, femur, heart, ileum, jejunum, kidneys, liver, lungs, lymph nodes (cervical and mesenteric), optic nerve, ovaries, pancreas, pituitary, prostate, rectum, sciatic nerve, skeletal muscle, skin, spinal cord, stomach (cardiac, fundus and pylorus), testes, thymus, thyroid, urinary bladder, uterus, spleen

All nodules, tissue masses and otherwise macroscopically abnormal tissues were routinely preserved and processed along with samples of adjacent tissue where appropriate.
Other examinations:
none
Statistics:
Student's 't' test was employed to assess the significance of intergroup differences where the data suggested a treatment related response . Differences in tumour incidence were compared by a 2 x 2 contingency test used as a one tailed test, computing the exact probability of the observed tumour distribution occurring or one which is more extreme.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
See repeated-dose part.
Relevance of carcinogenic effects / potential:
No carcinogenic potential was observed in rats.
Dose descriptor:
NOEL
Effect level:
>= 3 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: 3000 ppm corresponds to 142 and 169 mg/kg bw/d for males and females, respectively.
Remarks on result:
other: absence of carcinogenicity
Dose descriptor:
NOEL
Effect level:
1 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Critical effects observed:
no
Conclusions:
No indication of carcinogenicity was observed upon chronic feed application.
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From Jul 27, 1978 to Sep 10, 1981
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
yes
Remarks:
hematology, urinalysis, and clinical chemistry paramters not examined
GLP compliance:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): TK 10047
- Physical state: solid
- Lot/Batch No.: EN 71000
Species:
mouse
Strain:
other: Tif MAGF (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Animal Production Stein, CIBA-GEIGY LTD.
- Age at study initiation: Approx. 4 weeks
- Weight at study initiation: 21.7 - 22.3, males; 20.4 - 21.0, females
- Housing: housed in groups of 5 in Macrolon cages type 3 with standardised granulated soft wood bedding
- Diet (e.g. ad libitum): pelleted, certified standard Nafag No. 890 tox diet ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 10
- Air changes (per hr): 15 - 17
- Photoperiod (hrs dark / hrs light): 14/10


IN-LIFE DATES: From: July 27, 1978 To: Aug 6, 1980
Route of administration:
oral: feed
Type of inhalation exposure (if applicable):
not specified
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
-TK 10047 was weighed on a calibrated mettler balance. The pulverised food was then homogeneously mixed with the appropriate concentrations of the compound and 30% water was added before pelleting to ensure the necessary pellet quality. The pellets were subsequently airdried.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Prior to the initiation of the study pretest feed samples were analysed for concentration and stability of the test material. The same was undertaken with the food batches applied during the test. These analyses were carried out in the Analytical Laboratories of the Plastics and Additives Division of CIBA-GEIGY LTD., Basle/Switzerland.
Duration of treatment / exposure:
24 months
Frequency of treatment:
daily
Post exposure period:
not reported
Dose / conc.:
5 ppm (nominal)
Dose / conc.:
50 ppm (nominal)
Dose / conc.:
500 ppm (nominal)
No. of animals per sex per dose:
50
Control animals:
yes, plain diet
Details on study design:
Animal allocation random
Positive control:
None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for 3 months, then monthly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No


OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
At the end of the test period all control and test animals which survived were bled under ether anaesthesia and subjected to detailed autopsy. Liver, adrenals, brain, heart, kidneys and gonads were weighed. These and the following organs and tissues were preserved in 10 % neutral
formalin:
brain (cerebrum, cerebellum, brainstem), eyes, pituitary, heart, thyroid, aorta, lung, spleen, lymph nodes, peripheral nerve, stomach, small and large intestine, adrenal glands, pancreas, liver, kidneys, urinary bladder, ovaries, testes, prostate, epididymis, uterus, skin (mammary area), organs and tisues showing macroscopical changes
Statistics:
For each time point and parameter a uni-variate statistical analysis was conducted. Due to the routine manner of the analysis system, parameter free methods were applied. Each treated group was compared to the control group in respect of dispersion and displacement. In addition a trend test was applied considering all groups. Survival analysis was performed by the generalised Wilcoxon Test (Breslow 1970) and the generalised Savage Test (Mantel-Cox 1966). The Mantel-Cox and Breslow Tests differ in the way they weight observations. The Breslow Test gives greater weight to early observations, and is less sensitive to late events which occur when few animals on the study remain alive. Both tests are valid in large samples whether the censoring patterns (moribund sacrifice of interim sacrifice) are equal or unequal.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
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
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Relevance of carcinogenic effects / potential:
The substance has no carcinogenic potential in mice.
Dose descriptor:
NOEL
Effect level:
500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: corresponds to 62- 64 mg/kg bw/d
Remarks on result:
other: absence of carcinogenic properties
Critical effects observed:
no
Conclusions:
The substance was not carcinogenic in mice upon feed application.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
mouse

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is considered to be not classified as a carcinogen under Regulation (EC) No. 1272/2008.

Additional information

The carcinogenic potential was investigated in two feeding studies. The study in mice (Gfeller, 1981) is chosen as key study as it was specifically designed as a carcinogenicity study. Its procedure is equivalent to the OECD testing guidline 451, which was published a few months prior to finalization of that study. Its performance was supervised by the internal quality assurance unit which is certified in the study report.

Specifically, 400 MAGf (SPF) mice (50 male and 50 female per dose group) were treated at dose level of 0, 5, 50 or 500 ppm per day for 24 months. No clinical symptoms and no substance-related mortality were observed. A mean daily intake of 500 ppm (corresponding to 62-64 mg/kg bw) did not produce inflammatory, degenerative, proliferative or neoplastic lesions and was considered to be the NOEL.

The study in rats (Hunter et al, 1981) was designed as a chronic feeding study in rats (OECD testing guideline 452), but in regard to the number of animals and mortality, it is similarly suitable to assess the endpoint of carcinogenicity. Due to the overall low toxicity of this substance, high doses were tested. No indication of an increased tumour incidence or preneoplastic lesions were recorded.

Specifically, a total of 500 CFY rats (50 male and 50 female per dose group) were treated with the test article in the diet, at dose levels of 0, 100, 300, 1000 and 3000 ppm in the diet per day for 104 weeks. No clinical symptoms and no substance-related mortality were observed. At 3000 ppm a small reduction of body weight gain during the second year of treatment and slightly reduced food intake among females during the period 53 to 80 weeks of treatment were observed.

The findings are consistent with a life-time feeding study in mice for which only limited details are reported (Neukomm,1961).