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EC number: 201-321-0 | CAS number: 81-07-2
- 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Link to relevant study records
- Endpoint:
- two-generation reproductive toxicity
- Remarks:
- based on test type (migrated information)
- 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:
- Two-Generation reproduction toxicity study of Saccharin orally in Charles Rivers (CD)-derived Sprague-Dawley Rats
- GLP compliance:
- not specified
- Limit test:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles Rivers, Margate, Kent, United Kingdom.
- Age at study initiation: (P) x wks: No data available
(F1) x wks: 22 days old
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g: No data available
- Fasting period before study: No data available
- Housing: Animals were housed in groups of three to five per cage for a period of 4 weeks prior to mating, after mating female were housed singly in wire cages for the first 19 days of gestation and then transferred to Perspex boxes with wood shavings. Offspring were housed separately.
- Diet (e.g. ad libitum): Normal diet, ad libitum
- Water (e.g. ad libitum): No data available
- 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 - Route of administration:
- oral: feed
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- other: Normal diet
- Details on mating procedure:
- Details on study schedule:The offspring were sexed when 22 days old, and the males and females from each litter were housed in separate cages and fed the appropriate diet until killed.
- M/F ratio per cage:1: 1
- After successful mating each pregnant female was caged (how):Singly - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- Daily
- Remarks:
- Doses / Concentrations:
0 or 5% (2500 mg/kg/day)
Basis:
no data - No. of animals per sex per dose:
- No data available
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- No data available
- Positive control:
- No data available
- Parental animals: Observations and examinations:
- No data available
- Oestrous cyclicity (parental animals):
- No data available
- Sperm parameters (parental animals):
- No data available
- Litter observations:
- No data available
- Postmortem examinations (parental animals):
- Tissue concentrations of saccharin were examined in liver, kidnye, bladder wall, plaema and amnoitic fluid.
- Postmortem examinations (offspring):
- Tissue concentrations of saccharin were examined in liver, kidney, bladder wall, plaema and amnoitic fluid.
- Statistics:
- Determined by unpaired Student’s t test
- Reproductive indices:
- No data available
- Offspring viability indices:
- No data available
- Clinical signs:
- not specified
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Other effects:
- not specified
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- not specified
- Dose descriptor:
- NOAEL
- Effect level:
- 2 500 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: No Effect on organ tissue concentration
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 2 500 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No Effect on organ tissue concentration
- Reproductive effects observed:
- not specified
- Conclusions:
- NOAEL was considered to be 5% (2500 mg/kg/day) in the F0 and F1 generation when male and female Sprague-Dawley rats were treated with saccharin.
- Executive summary:
In a two-generation repeated dose toxicity study, male and female Sprague-Dawley rats were treated orally in diet with saccharin in concentration of 0 or 5% (2500 mg/kg/day). In the F0 generation, tissue saccharin concentrations were decreased in female rats and no evidence of excessive accumulation were shown in the bladder wall or other tissues of female rats during in utero exposure or during lactation. The results showed decreased tissue saccharin concentrations in fetal liver, kidney and bladder wall when compared to maternal level.
Therefore, NOAEL was considered to be 2500 mg/kg/day (5%) in the F0 and F1 generation when male and female Sprague-Dawley rats were treated with saccharin
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 2 500 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
- Quality of whole database:
- Data is from peer-reviewed journal obtained from two generation experimental study
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
From the data available for experimental studies that have been reported in peer reviewed journals, it is possible to use a weight of evidence appraoch and conclude that in most of the experimental studies no adverse effects on the reproductive organs due to administration of saccharin have been observed as compared to control. Thus, it can be cncluded that saccarin is not expected to cause reproductive toxicity effects at the dose levels reported in the various studies.
Justification for selection of Effect on fertility via oral route:
In a Two-Generation repeapted dose toxicity study, Charles Rivers (CD)-derived Sprague-Dawley male and female rats treated with Saccharin in concentration of 0 and 2500 mg/kg/day (5%) orally in diet. In F0 generation,Tissue Saccharin Concentrations were decreased in female and no evidence of excessive accumulation in the bladder wall or other tissues of male rats during in utero exposure or during lactationas were observed compared to maternal level and steady-state concentrations of saccharin in the liver and kidneys of fetuses from mothers were observed.
Effects on developmental toxicity
Description of key information
From the various data available and adopting the weight of evidence approach, it has been concluded that 1,2-benzisothiazol-3(2H)-one 1,1-dioxide is not likely to have developmental/teratogenic effects.
Link to relevant study records
- Endpoint:
- developmental toxicity
- 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:
- Principles of method if other than guideline:
- Teratogenic effects of Saccharin in mouse
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- mouse
- Strain:
- other: ICR albino
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source:(Camm Research Institute, Wayne, NJ) - Route of administration:
- oral: drinking water
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- water
- Details on exposure:
- Details on exposure
PREPARATION OF DOSING SOLUTIONS: No data available
DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Water
- Concentration in vehicle: 0, 5, 10 or 20% solution
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available
Details on exposure
PREPARATION OF DOSING SOLUTIONS: No data available
DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Water
- Concentration in vehicle: 0, 5, 10 or 20% solution
- 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
- Details on mating procedure:
- - M/F ratio per cage: No data available
- Length of cohabitation: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: No data available
- After … days of unsuccessful pairing replacement of first male by another male with proven fertility: No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)]: No data available
- After successful mating each pregnant female was caged (how): No data available
- Any other deviations from standard protocol: No data available - Frequency of treatment:
- Daily
- Duration of test:
- 18 days, i.e. from day 0 through day 17 of pregnancy
- Remarks:
- Doses / Concentrations:
0, 5, 10 or 20% (0, 500, 1000, 2000 mg/Kg bw)
Basis: - No. of animals per sex per dose:
- Total: 25 females
Control: 10 females
5%: 5 females
10%: 5 females
20%: 5 females - Control animals:
- yes, concurrent vehicle
- Details on study design:
- No data available
- Maternal examinations:
- All dams were killed by cervical dislocation on day 17 and fetuses removed and examined.
- Ovaries and uterine content:
- The number of resorptions was observed.
- Fetal examinations:
- Fetuses were removed from maternal uteri and were examined for gross internal and external malformations. Externally, limbs, back, facies, and head were inspected for gross malformations. Internally, the palate, brain, heart, lungs, kidneys, bladder, gut, and gonads were examined for gross anomalies.
- Statistics:
- No data available
- Indices:
- No data available
- Historical control data:
- No data available
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
Maternal uteri examined for fetal resorption showed no significant increase compared with dams who received no saccharin. - Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
None of the fetuses from dams treated with saccharin showed significant increases in either external or internal malformations when compared to controls. - Dose descriptor:
- NOAEL
- Effect level:
- 2 000 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: teratogenicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- NOAEL was considered to be 2000 mg/kg bw in female ICR albino mice and their offspring when they the pregnant females were exposed to saccharin
- Executive summary:
In a teratogenicity study, the toxic effects of saccharin was evaluated in pregnant female ICR albino mice. The dams received saccharin in drinking water at a dosage of 0, 500, 1000 or 2000 mg/kg bw from day 0 to day 17 of gestation. The results showed no significant increase for fetal resorption in the maternal uteri as compared with dams who received no saccharin. None of the fetuses from dams treated with saccharin in drinking water showed significant increases in either external or internal malformations when compared to control. Therefore, NOAEL was considered to be 2000 mg/kg bw in the maternal F0 generation and in the F1 generation after administration of saccharin in drinking water from day 0 to day 17 of gestation.
Reference
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 2 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- mouse
- Quality of whole database:
- The data is K2 level as the data has been obtained from the experimental study from the reliable journal ‘Arch. Toxicol.’.
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Weight of evidence summary for reproductive and developmental toxicity
In different studies, saccharin has been investigated to a greater or lesser extent for the reproductive and developmental effects. Often are the studies based on in vivo experiments in rodents, i.e. most commonly in mice or rats.
In a two-generation repeated dose toxicity study by Sweatman et al (1982), male and female Sprague-Dawley rats were treated orally in diet with saccharin in concentration of 0 or 5% (2500 mg/kg/day). In the F0 generation, tissue saccharin concentrations were decreased in female rats and no evidence of excessive accumulation were shown in the bladder wall or other tissues of female rats during in utero exposure or during lactation. The results showed decreased tissue saccharin concentrations in fetal liver, kidney and bladder wall when compared to maternal level. Therefore, NOAEL was considered to be 2500 mg/kg/day (5%) in the F0 and F1 generation when male and female Sprague-Dawley rats were treated with saccharin
In a multi generation toxicity study conducted by Kroes et al (1977), male and female Swiss SPF-derived outbred mice were treated orally in diet with saccharin in the concentration of 0, 0.2% (286 mg/kg/day) or 0.5% (714 mg/kg/day). No effect were observed on survival, clinical sign and body weight in the offspring of F0 and F1a, F1a’, F2a, F3a, F3b, F4a, F5a or F6a generation as compared to control. No effect were observed on number of implantation, living fetuses per implantation and number of resorption per total number of implantation, gross pathology and histopathology in the F0 generation after treatment with saccharin. There are few effects were observed in F3c, F2b, F4b and F5b compared to control. But the significances found for all investigates parameters were not consistent and are considered not to be due to the treatment at 286 mg/kg/day dose group. Therefore, NOAEL was considered to be 714 mg/kg/day for the F0 generation and 286 mg/kg/day for F1a, F1a’, F2a, F3a, F3b, F4a, F5a and F6a generations when male and female Swiss SPF-derived outbred mice treated with saccharin orally for 21 months. Also based on this study the lowest toxic dose was published to be 16800 mg/kg bw/d of saccharin.
Also from the studies conducted in read across substance sodium salt of saccharin the NOAEL values are found to be 200 mg/kg bw/d and LOAEL was found to be 2866 mg/kg bw/ in two different studies on mice.
Also In a teratogenicity study conducted by Dropkin et al (1984), the toxic effects of saccharin was evaluated in pregnant female ICR albino mice. The dams received saccharin in drinking water at a dosage of 0, 500, 1000 or 2000 mg/kg bw from day 0 to day 17 of gestation. The results showed no significant increase for fetal resorption in the maternal uteri as compared with dams who received no saccharin. None of the fetuses from dams treated with saccharin in drinking water showed significant increases in either external or internal malformations when compared to control. Therefore, NOAEL was considered to be 2000 mg/kg bw in the maternal F0 generation and in the F1 generation after administration of saccharin in drinking water from day 0 to day 17 of gestation.
In the same study the dams received a single i.p. injection of saccharin at a dosage of 0, 500, 1000 or 2000 mg/kg on the 10th day of gestation. The results showed no significant increase for fetal resorption in the maternal uteri as compared with dams who received no saccharin. None of the fetuses from dams treated with saccharin by i.p. injection showed significant increases in either external or internal malformations when compared to control. Therefore, NOAEL was considered to be 2000 mg/kg body weight/day in the maternal F0 generation and in the F1 generation after a single i.p. injection of saccharin on gestation day 10.
Also numbers of teratology studies have been performed in experimental animals using high doses of saccharin by Klotzsche C (1969) and negative results have been documented in rabbits.
Thus based on the above studies it can be conclude that substance saccharin does not have reproductive as well as developmental toxicity effects on higher dose levels as well and considered to be safe.
Justification for selection of Effect on developmental toxicity: via oral route:
NOAEL was considered to be 2000 mg/kg bw in female ICR albino mice and their offspring when they the pregnant females were exposed to saccharin
Justification for classification or non-classification
The chemical 1,2-benzisothiazol-3(2H)-one 1,1-dioxide does not exhibit toxicity to the reproductive system within the doses mentioned in the study end points.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.