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EC number: 201-808-8 | CAS number: 88-19-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Carcinogenicity
Administrative data
Description of key information
Key study. Two-generation lifetime feeding study (no TG, no GLP, study well documented, acceptable for assessment). No statistically significant or dose-related incidence of tumours was observed in any groups. Based on the available data, the test item was not carcinogenic to rats.
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1974
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Principle of test:
Two-generation lifetime feeding study
- Short description of test conditions: 50 male and 50 female weanling Sprague-Dawley rats were administered the test item at different doses in their diet. After 3 months on test, F0 rats were bred and 50 pups of each sex, from every group, were weaned onto the parental diets, which both generations received for their lifetime. - GLP compliance:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratory, Canadian Breeding Farms, Montréal, Québec, Canada.
- Age at study initiation: 32 days
- Housing: The animals were housed individually, except during mating, in stainless-steel cages with screened floors. Cages were steam disinfected every 2 weeks and the "pull-papers" under the cages were changed daily.
- Diet: the basal diet was Master Laboratory Cubes (Master Feeds, Toronto, Ontario, Canada) to which 4% (w/w) corn oil had been added after the cubes were ground. Weighed amounts of the appropriate feed were distributed to the animals on a weekly basis in stainless steel feed cups.
- Water: drinking water was supplied by the Municipality of Ottawa, ad libitum, provided in a clear glass bottle, with a rubber stopper and stainless-steel nipple, which had been previously sterilized. The water bottles were changed 3 times/week.
DETAILS OF FOOD AND WATER QUALITY: Four lots of feed cubes were analyzed for the following micronutrients: calcium (1.7%), phosphorus (0.99 - 1.0%), copper (9.1 - 10 mg/lb), cobalt (2.5 - 2.8 mg/lb), manganese (64 - 68 mg/lb), zinc (30 - 31 mg/lb), iron (431 - 499 mg/lb). Analysis of several batches of feed during the study identified background levels of heavy metals, an average of 20 ppb of nitrosamines, trace amounts of 10 halogenated hydrocarbons (12 ppb total content), but no detectable amounts of aflatoxin or aflatoxin-like compounds. The classification of the drinking water hardness was 'very good' (< 4.7 grains CaCO3/US gal).
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1°C
- Humidity (%): 50-55%
- Photoperiod (hrs dark / hrs light): 12 h light/dark cycle - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): the appropriate amount of test chemical was premixed with 500g of ground rat chow. This concentrate premix was added to an appropriate amount of basal diet plus corn oil and mixed thoroughly on the day prior to use.
- Storage temperature of food: room temperature, protected from light. - Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- F0: 142 weeks; F1: 127 weeks.
- Frequency of treatment:
- Daily
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 2.5 mg/kg bw/day (nominal)
- Dose / conc.:
- 25 mg/kg bw/day (nominal)
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Remarks:
- plus 1% NH4CI in drinking watter, which was added to prevent the formation of alkaline urine (associated with the production of bladder calculi and bladder tumors in a previous study).
- No. of animals per sex per dose:
- 50
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale:
the doses were selected to be equivalent to the levels resulting from the dietary additions of Remsen-Falberg-produced saccharin used in previous studies (WARF, FDA).
- Rationale for animal assignment: Random.
- Schedule: After 3 months on test, the F0 rats were mated on a one-to-one basis; all litters were culled to 8 pups (4 males and 4 females) 4 days post partum in a random manner. The pups were weaned onto their parents' diet, and 50 males and 50 females from each group were randomly selected to constitute the second generation (F1). Thus, the pups were exposed to the test item in utero, during lactation via the dam's milk, and for the remainder of their life. The two generations remained on test for 127 (F1) and 142(F0) weeks. - Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
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, weekly
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
WATER CONSUMPTION AND COMPOUND INTAKE: A limited water balance study was undertaken with the male and female F1 generation animals when they were 20 months of age. These consisted of determining the volume of water consumed and the volume of urine during a 24h period, by each of 10 males and 10 females from the following groups: control, 250 mg/kg o-TS and 250 mg/kg o-TS + 1% NH4Cl in water
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: 0.1 - 0.125 ml were obtained from the tail aorta at 0, 4.5, 21, 44.5, 57, 65, 69, 96 and 98 weeks for F0; and at 4.5, 18.5, 32.5 and 45.5 weeks of age.
- Anaesthetic used for blood collection: Yes (ether)
- How many animals: 10 per group
- Parameters checked: erythrocyte enumeration (RBC), hematocrit (HTC), hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentratoin (MCHC), total leukocyte enumeration (WBC), differential leukocyte count including absolute values, and occasionally hematopoietic organs (bone marrow, lymph node, and spleen imprints) were examined in cases where hematologic involvement was observed in moribund animals.
CLINICAL CHEMISTRY: No data
URINALYSIS: Yes
- Time schedule for collection of urine: at 6 months intervals, at 9 AM and 2 PM (groups: for control, 250 mg/kg o-TS and 250 mg/kg o-TS + 1% NH4Cl in water)
- Metabolism cages used for collection of urine: No
- Parameters: pH, turbidity, Bililabstix determination (for presence of glucose, ketones, bilirubin, protein and blood), presence of sediment or exfoliated epithelial cells (microscopical examination), presence of parasites (Trichosomoides crassicauda).
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (all animals). Animals were anesthetized with ether and exsanguinated from the abdominal aorta.
- If the urinary bladder contained urine, it was drained with a syringe. If not, physiological saline (0.2 ml) was injected into the bladder and a sample was drawn out, to examine for bladder parasites, sediment and bladder epithelial cells. The bladder was then filled with up to 0.2 ml of 10% neutral buffered formalin prior to being placed in a container of buffered formaling along with all of the other organs, tissues, and tumors. On the next working day, all organs and tumours were opened, examined grossly, and prepared for histological examination.
HISTOPATHOLOGY: Yes. Representative portions from all organs and all grossly abnormal areas of dermal, supportive or skeletal tissues were embedded in paraffin and sectioned at a thickness of 4 µm, or directly by cryostat when appropriate. The tissues were stained with hemalum-phloxine-saffron (HPS, unless a special stain was indicated). In addition, slides of the bladder tumors were reviewed by a panel of pathologists not associated with the design/conduct of the study. - Statistics:
- Unless otherwise noted, the observed results for each test diet were compared to those for the control diet separately for each sex and time of observation, limiting the overall significance to 5% for each sex and time of observation, using the Bonferroni inequality. t-tests were used for continuous data and Fisher's test for quantal data.
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- The F0 generation animals were kept on test for 142 weeks, at which time less than 3 % of the initial animals were alive. The F1 portion of the study was terminated after 127 weeks; when approximately 20 % of the initial animals were still alive. The time-to-death was normally distributed in the F0 generation and was not affected by treatment. In the F1 generation, no significant increase in the probability of dying by time t as a result of exposure to o -TSA was observed for either sex.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The growth curves for the F0 and F1 males and females receiving o-TSA at 250 mg/kg or 250 mg/kg with 1% NH4Cl in the drinking water were significantly different (p < 0.05) from control animals.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Animals consuming o-TSA at 250 mg/kg or 250 mg/kg with 1% NH4Cl in the drinking water consumed less feed.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- For the seven hematological parameters (number of erythrocytes, hematocrit, hemoglobin, mean corpuscular volume, total number of leukocytes, neutrophils and lymphocytes), there were no patterns suggesting an effect due to treatment, sex, generation, or variable measured.
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Statistical analysis of urinary pH values for male rats during the 18th month on test revealed that only the urine from the group of males receiving o-TSA at 250 mg/kg with NH4Cl in the drinking water significantly different when compared to males in other treatment groups; it was more acidic. The effect of dietary treatment upon urinary pH values of female rats was not as extensively studied except for control where no statistically significant differences were observed.
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- At necropsy, the most common lesions found for both F0 and F1 animals were pituitary and subcutaneous tumors. Grossly visible bladder stones were observed in 3 animals during the study. Microscopic examination revealed the following: epithelial hyperplasia in an F0 control animals, diffuse papillomatosis involving most of the bladder wall in an F0 animal receiving 2.5 mg/kg o-TS, no pathological changes in an F1 animal receiving 2.5 mg/kg o-TS. 3 F0 females from the control, 2.5 mg/kg o-TS and 250 mg/kg o-TS groups had grossly visible kidney stones, but none had urinary bladder tumors.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- See table 2 below.
- Histopathological findings: neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no significant increased in the incidence of tumours (see table below). The bladder tumors were found at the apex or funds of the bladder, except for one F1 female from the 2.5 mg/kg group which had a benign papilloma arising from the base of the bladder. They arose from a narrow pedicle which measured approximately 1 mm in diameter and 2 mm in length. The benign tumors were primarily soft, papillary, edematous, masses which were not particularly hyperemic or hemorrhagic. The benign papillomata in F0 animals consisted primarily of somewhat edematous, vascular, stroma covered by a layer of transitional epithelium that appeared normal while those in F1 animals were covered by a thick hyperplastic epithelium.
The animals were free of urinary bladder parasites. There were no treatment-related effects associated with longevity. Urinary bladder tumours, all of which were benign, were observed in one male each of the 0, 2.5 and 250 mg/kg b.w. group and in one female of the 2.5 mg/kg b.w. group in the first generation, and 2 females of the 2.5 mg/kg b.w. group in the second generation. However, the incidence was neither statistically significant nor dose-related. No other dose-related tumours were observed in any groups. - Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No significant differences (p > 0.05) from the control group were observed for any of the reproductive parameters. However, there was a statistically significant decrease
in the litter size of the 250 mg o-TS/kg group. When the average pup body weight at 4 days postpartum was adjusted for litter size, there was a significantly lower average body weight at 4 days postpartum in both groups receiving 250 mg/kg o-TS. No other treatment-related effect was evident. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Critical effects observed:
- no
- Conclusions:
- The test item was not carcinogenic to rats under test conditions.
- Executive summary:
In a two generation lifetime feeding study (no TG, no GLP), SD rats (32 days old) were given o-TS in the diet at 0 (control), 2.5, 25, 250 mg/kg bw/day (50 animals/sex/group) or 250 mg/kg bw/day with 1% NH4Cl in the drinking water (40 males and 38 females). Rats were exposed to this chemical from 90 days before mating in the first generation (for 142 weeks) and after weaning in the second generation (for 127 weeks). The animals were free of urinary bladder parasites. There were no treatment-related effects associated with longevity. Urinary bladder tumours, all of which were benign, were observed in one male each of the 0, 2.5 and 250 mg/kg bw group and in one female of the 2.5 mg/kg bw group in the first generation, and 2 females of the 2.5 mg/kg b.w. group in the second generation. However, the incidence was neither statistically significant nor dose-related. No other dose-related tumours were observed in any groups. Based on the available data, the test item was not carcinogenic to rats under test conditions.
Reference
Table 1.Incidence of bladder tumors for rats fed diets containing o-TS:
F0 generation |
F1 generation |
|||
o-TS |
Benign |
Malignant |
Benign |
Malignant |
Males |
||||
Control |
1 |
0 |
0 |
0 |
2.5 mg/kg |
1 |
0 |
0 |
0 |
25 mg/kg |
0 |
0 |
0 |
0 |
250 mg/kg |
1 |
0 |
0 |
0 |
250 mg/kg + 1%NH4Cl |
0 |
0 |
0 |
0 |
Females |
||||
Control |
0 |
0 |
0 |
0 |
2.5 mg/kg |
1 |
0 |
2 |
0 |
25 mg/kg |
0 |
0 |
0 |
0 |
250 mg/kg |
0 |
0 |
0 |
0 |
250 mg/kg + 1%NH4Cl |
0 |
0 |
0 |
0 |
Table 2. Non-neoplastic lesion with significant dose response* in F0 male rats
Dose (mg/kg) |
0 |
2.5 |
25 |
250 |
250 + NH4Cl |
No.of Animals |
49 |
49 |
50 |
50 |
39 |
Lung |
|||||
-Chronic respiratory disease-slight |
13 |
17 |
26 |
20 |
28ab |
Liver |
|||||
-Peliosis |
4 |
9 |
18 |
13 |
8a |
Non-neoplastic lesion with significant dose response in F0 female rats
Dose (mg/kg) |
0 |
2.5 |
25 |
250 |
250 + NH4Cl |
No.of Animals |
50 |
50 |
50 |
50 |
38 |
Spleen |
|||||
-Dense hematosiderosis |
16 |
12 |
16 |
26 |
13 |
Kidneys |
|||||
-Pelvic subepithelial telangiectasia |
1 |
3 |
2 |
9 |
2 |
Non-neoplastic lesion with significant dose response in F1 male rats
Dose (mg/kg) |
0 |
2.5 |
25 |
250 |
250 + NH4Cl |
No.of Animals |
50 |
50 |
50 |
50 |
49 |
Liver |
|
|
|
|
|
-Peliosis |
10 |
9 |
5 |
20 |
14 |
Spleen |
|
|
|
|
|
-Dense hematosiderosis |
5 |
2 |
7 |
13 |
17a |
Pancreas |
|
|
|
|
|
-Focal chronic pancreatitis-slight |
19 |
18 |
16 |
27 |
22 |
Non-neoplastic lesion with significant dose response in F1 female rats
Dose (mg/kg) |
0 |
2.5 |
25 |
250 |
250 + NH4Cl |
No.of Animals |
50 |
50 |
50 |
50 |
50 |
Liver |
|
|
|
|
|
-Centrilobular basophil chromogenesis |
- |
1 |
1 |
7 |
13a |
-Peliosis |
1 |
3 |
9 |
10 |
6a |
Spleen |
|
|
|
|
|
-Dense hematosiderosis |
4 |
18 |
7 |
20 |
25a |
*: Bartholomew's test; a: Significantly different from control (p<0.05); b: Significantly different from 250 mg o-TSA group (p<0.05)
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 250 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
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
Based on the available data, the test item is not classified for carcinogenicity according to CLP, Regulation (EC) No. 1272/2008.
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