1,2-benzisothiazol-3(2H)-one 1,1-dioxide

Endpoint summary

Description of key information

The substance 1,2-benzisothiazol-3(2H)-one 1,1-dioxide does not exhibit repeated dose toxicity by the oral ,inhalation and dermal route.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from peer reviewed journal

Qualifier:

according to guideline

Guideline:

other: refer below principle

Principles of method if other than guideline:

Subacute repeated dose toxicity study of orally administered saccharin in male rat.

GLP compliance:

not specified

Limit test:

yes

Species:

rat

Strain:

other: Charles Rivers CD

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles Rivers (Margate, Kent, U.K.)
- Age at study initiation: No data available
- Weight at study initiation: 250 g
- Fasting period before study: No data available
- Housing: Housing: After 1 month of treatment, animals were transferred for 24 h to individual plastic metabolism cages prior to collection of urine and faeces.
- Diet (e.g. ad libitum): CRMX Expanded Feed, ad libitum
- Water (e.g. ad libitum): Water, ad libitum
- Acclimation period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: No data available

Route of administration:

oral: feed

Vehicle:

other: CRMX Expanded Feed

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: Saccharin incorporated in CRMX Expanded Feed giving of 7.5 % in diet.

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): CRMX Expanded Feed
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): CRMX Expanded Feed
- Concentration in vehicle: 0 and 7.5 % (0 and 7500 mg/kg/day)
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

1 month i.e. 30 days

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
0 and 7.5 % (0 and 7500 mg/kg/day)
Basis:
no data

No. of animals per sex per dose:

Total: 10 males
Control (0%; 0 mg/kg/day): 5 males
7.5% (7500 mg/kg/day): 5 males

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data available
- Time schedule: No data available
- Cage side observations checked included. No data available

DETAILED CLINICAL OBSERVATIONS: No data available
- Time schedule: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: No data available

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data available
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data available

FOOD EFFICIENCY: No data available
- 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: No data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: No data available

OPHTHALMOSCOPIC EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available

HAEMATOLOGY: No data available
- Time schedule for collection of blood: No data available
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked: No data available

CLINICAL CHEMISTRY: No data available
- Time schedule for collection of blood: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked . No data available

URINALYSIS: Yes
- Time schedule for collection of urine: At the end of 1 month treatment
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No
- Parameters checked in table examined: Parameters examined: Total urine volume, average volume per 15 min, number of fractions containing >0.1, >0.5 or >1.0 ml, and maximum volume in 15 min were examined.

NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data available

OTHER: No data available

Sacrifice and pathology:

GROSS PATHOLOGY: No data available
HISTOPATHOLOGY: No data available

Statistics:

Statistical analysis was performed by used Student’s t-teat for unpaired data.

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Significant decrease in body weight was observed in treated rats as compared to control.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Significant increase in food consumption was observed in treated rats as compared to control.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

Significant increase in water consumption was observed in treated rats as compared to control.

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Significant increase in total urine volume, Average volume per 15 min, Number of fractions containing and Maximum volume in 15 min were observed in treated rats as compared to control.

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

The increased urine volume was associated with both an increased average volume per fraction and also an increased frequency of urination.

Dose descriptor:

NOAEL

Effect level:

7 500 other: mg/kg/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Effect on body weight, food consumption, water consumption and urination

Critical effects observed:

not specified

Conclusions:

NOAEL was considered to be 7.5 % (7500 mg/kg/day) when male CD rats were treated with saccharin.

Executive summary:

In a subacute repeated dose toxicity study, male CD rats were orally exposed to saccharin in diet in the concentration of 0 or 7500 mg/kg/day (7.5 %). A significant decrease in body weight and increase in food consumption were observed in treated rats as compared to control. In addition, significant increase in water consumption and increase in total urine volume, average volume per 15 min, number of fractions containing and maximum volume in 15 min were observed in the saccharin-treated rats. Therefore, NOAEL was considered to be 7500 mg/kg/day (7.5 %) when male CD rats were treated with saccharin orally in diet for one month prior to urinanalysis.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

7 500 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The data is K2 level as the data has been obtained from the experimental study from the reliable journal ‘Cancer Letters’.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

WoE Summary of 81-07-2 for repeated dose toxicity

The substance sodium saccharin has been investigated for the repeated dose toxicity of the substance in various studies and the details are presented below

In a chronic repeated dose toxicity study conducted by Prasad et al (1987), male and females ICR Swiss mice were orally exposed to saccharin by gavage at a dosage of 0, 0.5, 1.0 or 1.5 g/kg body weight/day (0, 500, 1000 or 1500 mg/kg/day).No mortality was observed but mice treated with 1000 or 1500 mg/kg/day showed evidence of weight loss. Significant differences were observed in mice after feeding 1000 or 1500 mg saccharin for 1 year, as compared to controls. TEC, Hb and PCV had significantly decreased, and a statistically insignificant increase was observed in TLC whereas DLC showed a marked increase in polymorphonuclear neutrophils. However, MCV, MCH and MCHC of the experimental mice did not show any difference from control. Histological examinations showed evidence of tumors in the neck region of 5 male and 3 female mice fed with 1500 mg/kg/day. Therefore, LOEL was considered to be 1000 mg/kg/day when male and female ICR Swiss mice were exposed to saccharin for 1 year.

Also in another chronic repeated dose toxicity study conducted by Althoff et al (1975), male and female Syrian Golden hamsters were orally exposed to saccharin through drinking water in the concentration of 0.0, 0.156, 0.312, 0.625 or 1.25%. Generalized amyloidosis and vascular calcinosis, common in animals over 40 weeks of age, were found in both untreated and treated hamsters. Tumor incidences were obtained both in controls and in animals given saccharin. However, the organ distribution and histologic types of neoplasms were within the range of spontaneously occurring tumors observed in these hamsters. Thus, NOAEL was considered to be 1.25% i.e. 353 mg/kg bw when male and female Syrian Golden hamsters were treated with saccharin for 50-60 weeks.

In a subacute repeated dose toxicity study by Renwick et al (1983), male CD rats were orally exposed to saccharin in diet in the concentration of 0 or 7500 mg/kg/day (7.5 %). A significant decrease in body weight and increase in food consumption were observed in treated rats as compared to control. In addition, significant increase in water consumption and increase in total urine volume, average volume per 15 min, number of fractions containing and maximum volume in 15 min were observed in the saccharin-treated rats. Therefore, NOAEL was considered to be 7500 mg/kg/day (7.5 %) when male CD rats were treated with saccharin orally in diet for one month prior to urinanalysis.

Also from the repeated dose toxicity study on the read across substance sodium saccharin by Luini et al (1981), CD-COBS male rats treated with sodium saccharin in the concentration of 0, 1000, 2500 and 5000 mg/kg/day orally in diet. Decrease in body weight was observed in treated male rats as compared to control. In addition, dose dependent suppression of primary humoral antibody production against SRBC, Blastogenesis were observed in 1000, 2500 and 5000 mg/kg/day dose groups as compared to control. no effect were observed on PHA responsiveness of 5000 mg/kg/day dose group as compared to control. therefore, LOAEL was considered to be 1000 mg/kg/day when CD-COBS male rats treated with Sodium saccharin orally in diet for 54 days

Thus based on above studies it can be concluded that saccharin is not a toxic chemical via repeated dose route below the dose level of 1000 mg/kg bw/d. .

Repeated dose toxicity : inhalation

The acute toxicity value for 1,2-benzisothiazol-3(2H)-one 1,1-dioxide (as provided in section 7.2.2) is 815.265 mg/L air. Thus, it is expected that 1,2-benzisothiazol-3(2H)-one 1,1-dioxide shall not exhibit 28 day repeated dose toxicity by the inhalation route. In addition, there is no data available that suggests that 1,2-benzisothiazol-3(2H)-one 1,1-dioxide shall exhibit repeated dose toxicity by the inhalative route.Hence this end point was considered for waiver.

Repeated dose toxicity :dermal

The acute toxicity value for 1,2-benzisothiazol-3(2H)-one 1,1-dioxide (as provided in section 7.2.3) is 4694 mg/kg body weight. Thus, it is expected that 1,2-benzisothiazol-3(2H)-one 1,1-dioxide shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that 1,2-benzisothiazol-3(2H)-one 1,1-dioxide shall exhibit repeated dose toxicity by the dermal route.Hence this end point was considered for waiver.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
NOAEL was considered to be 7.5 % (7500 mg/kg/day) when male CD rats were treated with saccharin.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The acute toxicity value for 1,2-benzisothiazol-3(2H)-one 1,1-dioxide (as provided in section 7.2.2) is 815.265 mg/L air. Thus, it is expected that 1,2-benzisothiazol-3(2H)-one 1,1-dioxide shall not exhibit 28 day repeated dose toxicity by the inhalation route. In addition, there is no data available that suggests that 1,2-benzisothiazol-3(2H)-one 1,1-dioxide shall exhibit repeated dose toxicity by the inhalative route.Hence this end point was considered for waiver. In addition, the vapour pressure of the chemcial is low as well as the possibility of inhalation of the particulates is also highly unlikely. Further, considering the use of the chemical as an artificial sweetner in food, medicines, etc. repeated exposure by the inhaltion route is highly unlikely.
Considering all of the above, this end point was considered for waiver.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
The acute toxicity value for 1,2-benzisothiazol-3(2H)-one 1,1-dioxide (as provided in section 7.2.3) is 4694 mg/kg body weight. Thus, it is expected that 1,2-benzisothiazol-3(2H)-one 1,1-dioxide shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that 1,2-benzisothiazol-3(2H)-one 1,1-dioxide shall exhibit repeated dose toxicity by the dermal route.Hence this end point was considered for waiver.
Considering the use of this chemical, the oral route is the most likely route of exposure. Repeated exposure to this chemical by the dermal route is highly unlikely. Thus, this end point was considered for waiver.

Justification for classification or non-classification

The substance 1,2-benzisothiazol-3(2H)-one 1,1-dioxide do not show repeated dose toxicity effect for oral,inhalation and dermal

route and thus will not be considered for further classification.