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EC number: 223-810-8 | CAS number: 4083-64-1
- 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
Description of key information
90-day oral toxicity in rats: NOAEL 231 mg/kg bw/day
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 2006 October 25 - 2007 January 30
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study performed according to EC and OECD guidelines and according to GLP principles.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- See below.
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- See below.
- Principles of method if other than guideline:
- Deviations:
1. One adrenal from animal no. 67 and from animal no. 4 was not available for histopathology. Reasons for this included that these tissues were not discernable at necropsy or trimming, or were erroneously not collected at necropsy. Tissues are listed in raw data and pathology report. Evaluation: Sufficient tissues were available for evaluation.
2. No terminal body weight was determined from animal no. 55, and no adrenal weight was recorded for animal no. 4. Evaluation: Sufficient data were available for evaluation. - GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Wistar Han, Crl:WI(Han)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Approximately 6 weeks
- Housing: 5 animals/sex in Macrolon cages with sterilised saw dust as bedding material and paper as cage-enrichment.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.0-23.2
- Humidity (%): 35-87
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): diets were prepared for weeks 1-4, 5-8 and 9-13.
- Mixing appropriate amounts with (Type of food): Standard powder rodent diet
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The concentrations analysed in the diets were between 83 and 113% of target. In the control diet, no test substance was detected.
- Duration of treatment / exposure:
- At least 90 days.
- Frequency of treatment:
- Ad libitum
- Remarks:
- Doses / Concentrations:
1000 ppm
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
3000 ppm
Basis:
nominal in diet - Remarks:
- Doses / Concentrations:
10000 ppm
Basis:
nominal in diet - No. of animals per sex per dose:
- 10
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: Based on results of a 28-day range finding study
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes, mortality
- Time schedule: at least twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily
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
- 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: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations:
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pre-test and week 13
- Dose groups that were examined: all animals, animals from groups 1 and 4, respectively
HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 13
- Anaesthetic used for blood collection: Yes, iso-flurane
- Animals fasted: Yes
- How many animals: all animals
- Parameters examined: Erythrocytes count, haemoglobin, Haematocrit, Mean corpuscular volume, Mean corpuscular haemoglobin, Mean corpuscular haemoglobin concentration, Platelet count, Red cell distribution width, Total leucocytes count, Differential leucocyte count, Prothrombin time, Partial thromboplastin time.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 13
- Animals fasted: Yes
- How many animals: all animals
- Parameters examined: Alanine aminotransferase, Alkaline phosphatase, Aspartate aminotransferase, Bilirubin, total, Chloride, Cholesterol, total, Creatinine, Glucose, Phosphorus, Protein, total, Protein, albumin, Urea, Calcium, Potassium, Sodium.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: week 12-13
- Dose groups that were examined: all
- Battery of functions tested: grip strength / motor activity / other: hearing ability, pupillary reflex, static righting reflex. - Sacrifice and pathology:
- Organ weights: Adrenal glands, Ovaries, Brain, Spleen, Epididymides, Testes, Heart, Thymus, Kidneys, Uterus, Liver.
GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table) - Other examinations:
- None.
- Statistics:
- None.
- 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):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- BODY WEIGHT AND WEIGHT GAIN
Body weights and body weight gain were reduced in males and females at 10.000 ppm, achieving a level of statistical significance on most occasions. Total weight gain deficit over the treatment period compared to controls was 21% and 11% for males and females, respectively.
Body weights and body weight gain of animals at 1000 or 3000 ppm remained in the same range as controls over the study period.
HISTOPATHOLOGY: NON-NEOPLASTIC
In 2/10 males at 10.000 ppm, a minimal degree of hyperplasia of the urothelium of the urinary bladder was recorded.
- Dose descriptor:
- NOAEL
- Effect level:
- 3 000 ppm
- Basis for effect level:
- other: Reduced body weight gain, histopathology (minimal urethelial hyperplasia in two animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 214 mg/kg bw/day (actual dose received)
- Sex:
- male
- Dose descriptor:
- NOAEL
- Effect level:
- 248 mg/kg bw/day (actual dose received)
- Sex:
- female
- Dose descriptor:
- LOAEL
- Effect level:
- 10 000 ppm
- Dose descriptor:
- LOAEL
- Effect level:
- 738 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: Reduced body weight gain, histopathology (minimal urethelial hyperplasia in two animals)
- Dose descriptor:
- LOAEL
- Effect level:
- 795 mg/kg bw/day (actual dose received)
- Sex:
- female
- Basis for effect level:
- other: Reduced body weight gain.
- Critical effects observed:
- not specified
- Conclusions:
- LOAEL: 10.000 ppm (738 mg/kg/day for males, or 795 mg/kg/day for females).
NOAEL: 3000 ppm (214 mg/kg/day for males, or 248 mg/kg/day for females). - Executive summary:
The study was based on the following guidelines.
- EC Directive 67/548/EEC, B Repeated Dose (90 days) Toxicity (oral), 2001.
- OECD 408, Repeated Dose 90-day Oral Toxicity Study in Rodents, 1998.
- EPA 712-C-98-199, 90-Day Oral Toxicity, 1998.
Based on a 28-day dietary range finding study (NOTOX Project 474053) and in consultation with the sponsor, the dose levels for this 90-day dietary study were selected to be 0, 1000, 3000 and 10.000 ppm. SPF-bred Wistar Han rats received the test substance by dietary intake for at least 90 days. One control group and three treated groups were tested, each consisting of 10 males and 10 females.
Chemical analyses of diet preparations were conducted to assess accuracy and homogeneity of diet preparations.
RESULTS
Homogeneity and accuracy of diet preparations were demonstrated by analyses.
Dietary inclusion levels of 0, 1000, 3000 and 10.000 ppm were equivalent to an average test article intake of 0, 70, 214 and 738 mg/kg body weight/day for males, and 0, 80, 248 and 795 mg/kg body weight/day for females.
At 10.000 ppm, a significant and consistent reduction of body weight gain was recorded (up to 21% compared to control animals).
Histopathology revealed a minimal degree of hyperplasia of the urothelium of the urinary bladder in two males at 10.000 ppm.
No other treatment-related toxicologically significant changes were noted in any of the remaining parameters examined/determined in this study (i.e. clinical appearance, functional observations, food consumption, clinical laboratory investigations, macroscopic examination and organ weights).
The observed minimal urethelial hyperplasia in two animals seems to be caused by local irritation by the chronic availability of p-TSA metabolite (p-sulphamonylbenzoic acid) in the urine, following the rapid and complete excretion of p-TSA. Such effect is local and fully reversible when exposure ends. As the hyperplasia is observed in only two animals, is minimal and likely a fully reversible temporal effect upon exposure, is not an adverse effect persé, the reduction of the body weight gain of 21% in males is considered serious enough to assign the 10000 ppm a LOAEL. Especially as a relation to palatability is not completely clear.
LOAEL: 10.000 ppm (738 mg/kg/day for males, or 795 mg/kg/day for females).
NOAEL: 3000 ppm (214 mg/kg/day for males, or 248 mg/kg/day for females).
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 231 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- NOAEL derived from a reliable OECD 408 study
Repeated dose toxicity: inhalation - systemic effects
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
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
The result of PTSA is read across to PTSI. This is considered justified because PTSI is extremely reactive with water and reacts instantaneously into the source substance PTSA.
A 90 -day oral repeated dose toxicity study was performed in accordance with OECD 408 and under GLP-conditions. The dose levels were 0, 1000, 3000, and 10000 ppm and were based on a 28-day dose range finding study. SPF-bred Wistar Han rats received PTSA by dietary intake for at least 90 days. One control group and three treated groups were tested, each consisting of 10 males and 10 females. Chemical analyses of diet preparations were conducted to assess accuracy and homogeneity of diet preparations. Clinical signs, functional observations, body weight, food consumption, ophthalmoscopy, clinical pathology, macroscopy, organ weights and histopathology were investigated.
Dietary inclusion levels of 0, 1000, 3000 and 10.000 ppm were equivalent to an average test article intake of 0, 70, 214 and 738 mg/kg body weight/day for males, and 0, 80, 248 and 795 mg/kg body weight/day for females. At the highest dose level, a significant and consistent reduction of body weight gain was recorded (up to 21% compared to control animals). Histopathology revealed a minimal degree of hyperplasia of the urothelium of the urinary bladder in two males at the highest dose, which seems to be caused by local irritation by the chronic availability of p-TSA metabolite (p-sulphamonylbenzoic acid) in the urine, following the rapid and complete excretion of p-TSA. Such effect is local and fully reversible when exposure ends. No other treatment-related toxicologically significant changes were noted in any of the remaining parameters examined. A LOAEL of 10.000 ppm (738 mg/kg/day for males, or 795 mg/kg/day for females) and a NOAEL of 3000 ppm (214 mg/kg/day for males, or 248 mg/kg/day for females) were established based on minimal urethelial hyperplasia and reduction of body weight gain observed in the highest dose.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
A reliable GLP 90-day oral toxicity study with PTSA according to OECD Guideline 408 was used. The result for PTSA was read across to PTSI
Justification for classification or non-classification
Based on the key value of 231 mg/kg bw/day (read across from PTSA) and the guidance value (Annex I of 1272/2008/EC) and guide value (Annex VI of 67/548/EEC) for classification, PTSI does not need to be classified for "Specific Target Organ Toxicity (STOT) - Repeated Exposure (RE)" or "Danger of serious damage to health by prolonged exposure - R48".
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