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Carcinogenicity

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Description of key information

o-TSA is not carcinogenic.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Publication including proficient information; Study has been assigned 'valid with restriction' following OECD SIDS evalauation with peer review.
Principles of method if other than guideline:
two generation lifetime feeding study
GLP compliance:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
The animals were housed individually, except during mating, in stainless-steel cages with screened floors. The cages were kept in air-conditioned (22 ± 1°C), humidity controlled (50-55%) rooms with artificial lighting (12 hI' light/dark cycle). Cages were steam disinfected every 2 weeks and the "pull-papers" under the cages were changed daily.
Route of administration:
oral: feed
Details on exposure:
0, 2.5, 25, 250 mg/kg/day, or 250 mg/kg/day with 1% NH4Cl in drinking water.
NH4CI was added to the drinking water of one o-TSA-treated group, to prevent the formation of an alkaline urine,
No. of animals per sex per dose:
a) 0, 2.5, 25, 250 mg/kg/day: 50 males and 50 females per group
b) 250 mg/kg/day o-Toluenesulfonamide with 1% NH4Cl in drinking water: 40 males and 38 females
Details on study design:
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).
The two generations remained on test for 127 (F1) and 142(F0) weeks.
Sacrifice and pathology:
Histological examination was conducted for all organs including the bladder and tumors, all grossly abnormal areas of dermal, supportive, or skeletal tissues.
Statistics:
Statistical methods: Bonferrini's or t-tests for continuous data and Fisher's test for quantal data.
Relevance of carcinogenic effects / potential:
Not carcinogenic

1. 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 otoluenesulfonamide 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.

2. The growth curve for the F0 and F1 males and females receiving otoluenesulfonamide at 250 mg/kg or 250 mg/kg with 1% NH4Cl in the drinking water were significantly different (p < 0.05) from control animals.

3. 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 -toluenesulfonamide was observed for either sex.

4. 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.

5. There were no significant increased in the incidence of tumours. The incidence of bladder tumors in both generations is shown in 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.

Incidence of bladder tumors for rats fed diets containing o-toluenesulfonamide:

   F0 generation   F1 generation 
 o-Toluenesulfonamide  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

6. Some non-neoplastic lesion showed significant dose-response as shown in following table.

 

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 

*: by Bartholomew's test

a: Significantly different from controls (p<0.05)

b: Significantly different from 250 mg o-toluenesulfonamide group (p<0.05)

Conclusions:
No other dose-related tumours were observed in any groups.
Executive summary:

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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Only data available for o-TSA. There is no data on carcinogenicity of p-TSA

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The following evaluation is from OECD SIDS Initial Assessment Report on o-Toluenesulfonamide (o-TSA), 2002:

 

Four carcinogenic studies were reported in rats, as shown in the table below. The incidence of urinary bladder tumour was slightly increased in one lifetime feeding study [Schmähl: 1978], while no carcinogenic effects were observed in the other three studies. Hooson et al. (1980) reported two 2- year studies, in which female Wistar rats were given this chemical at 0 or 0.1 % (70 mg/kg b.w./day) in the drinking water, or 0 or 79 mg/kg b.w./day in the diet. These 2-year studies were conducted in only females and in only one dosed group. Arnold et al. (1980) conducted a two generation lifetime feeding study, which is identified as a key study because this study was well conducted and reported. Details of the studies by Schmähl (1978) and by Arnold et al. (1980) are as follows:

 

In the study by Schmähl (1978), o-toluenesulfonamide was fed to male and female SD rats at 0, 20 and 200 mg/kg b.w. for lifetime. A treatment-related effect on the survival time was not observed. In the urinary bladder, carcinoma (1/76 animals at 200 mg/kg b.w.) and papillomas (3/75 at 20 mg/kg b.w.and 4/76 at 200 mg/kg b.w.) were observed but no tumours occurred in the control group (71 animals). However, there was no sufficient information on historical data, the purity of the test chemical, statistical analysis, the sexes of animals with bladder tumours and the presence or absence of bladder parasites. Based on this lack of information and the low incidence of bladder tumour, the reliability of the carcinogenic potential of this chemical is considered to be low.

 

In a two generation lifetime feeding study, SD rats (32 days old) were given o-toluenesulfonamide in the diet at 0 (control), 2.5, 25, 250 mg/kg b.w./day (50 animals/sex/group) or 250 mg/kg b.w./day with 1 % NH4Cl in the drinking water (40 males and 38 females) [Arnold et al.: 1980]. 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 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.

 

Animals (the number)

Exposure periods

Exposure routes

Doses (mg/kg bw/day)

Results

Reference

SD Rat Male & female (71-76/group) 

Lifetime

Oral (feed)

0, 20, 200 

Urinary bladder tumours

Schmähl: 1978 

SD Rat Male & female (50/ group) 

Lifetime (two generations)

Oral (feed)

0, 2.5, 25, 250 

No change in tumour incidence

Arnold et al.: 1980 

Wistar Rat Female (63/group) 

2 years

Oral (drinking water)

0, 70

No change in tumour incidence

Hooson et al.: 1980 

Wistar Rat Female (50/group) 

2 years

Oral (feed)

0, 79

No change in tumour incidence

Hooson et al.: 1980 

-    Schmähl D, 1978, Experiments on the carcinogenic effect of ortho-toluol-sulfonamid (OTS). Z Krebsforsch Klin Onkol Cancer Res Clin Oncol.;91(1):19-22

-    Arnold DL et al., 1980, Long-term toxicity of ortho-toluenesulfonamide and sodium saccharin in the rat. Toxicol. Appl. Pharmacol. 52: 113-152

-    Hooson J et al., 1980, Ortho-toluene sulphonamide and saccharin in the promotion of bladder cancer in the rat. Br J Cancer.;42(1):129-47

 

There is no information available on humans.

No carcinogenicity studies were identified for p-TSA.


Justification for selection of carcinogenicity via oral route endpoint:
Well conducted and reported lifetime study.

Justification for classification or non-classification

There are no carcinogenicity studies available on o/p-TSA.

In a two generation lifetime feeding study on o-TSA, no increase in any tumour incidence was noted in rats of both generations at up to 250 mg/kg b.w./day. Two 2-year oral rat studies also demonstrated no carcinogenicity of this chemical. Only one lifetime feeding study showed a low incidence of urinary bladder tumors in rats but the reliability of this study is uncertain because of poor reporting. A cell transformation assay using mammalian cultured cells showed negative results. Based on a weight of evidence approach, the available data indicates that this chemical is not carcinogenic.

No carcinogenicity studies were identified for p-TSA, but since the substance shows no genotoxic hazards and is of general low toxicity, p-TSA is also considered to be not carcinogenic.