Registration Dossier
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EC number: 211-522-5 | CAS number: 657-84-1
- 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
There are a total of 7 oral and 6 dermal repeated dose toxicity studies on the hydrotrope category substances. Most of these studies were conducted on Sodium xylene sulphonate however there is a reliable subacute study on Sodium toluene sulphonate.
The key oral study is the 90 day sub-chronic study, conducted in 1968, which is generally comparable to the OECD 408 guideline study. In that study, the highest dose for female rats - 4092 mg active ingredient (a.i.) per kilogram body weight - resulted in a loss in relative weight of the spleen. The 2nd highest dose for females - 763 mg a.i. per kilogram body weight - had no measureable adverse effects and therefore establishes the repeat dose oral NOAEL for the substance. The highest oral dose for male rats - 3534 mg a.i. per kilogram body weight - had no measurable adverse effects. No adverse effects were reported in the 90 day sub-chronic mouse study.
The key dermal study is the two year chronic/carcinogenicity study in the rat, which was generally comparable to the OECD 453 guideline study. There were no treatment related incidences of mononuclear cell leukaemia, neoplasms, or non-neoplastic lesions of the skin and other organs. In that study the NOAEL for females is 60 mg a.i./kg/day based on epidermal hyperplasia. This value was then used for the NOAEL for local dermal effects.No systemic toxicity was observed in this or any of the other repeat dose dermal studies.
There is no need for repeat dose data by the inhalation route since the two important routes of exposure have been addressed.
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:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1968
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Guideline not specified, but with detailed documentation
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- no functional observations or ophthalmoscopy
- Principles of method if other than guideline:
- Groups of 30 young rats (15 males and 15 females) were exposed by diet for 90 days to three concentrations. A control group was included. Observations were made of behavior, appearance, growth, food and water intake and a number of haematological factors. At the end of the experiment (during week 14) ten organs of each surviving rat were weighed and examined histologically for pathological changes. Liver enxyme activities were also determined.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: CIVO-colony- Age at study initiation: newly weaned - Weight at study initiation: 41-60 g- Fasting period before study: no data- Housing: metal wire screen cages (5 to a cage)- Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: no dataENVIRONMENTAL CONDITIONS- Temperature (°C): 24 degrees centigrade- Humidity (%): no data- Air changes (per hr): no data - Photoperiod (hrs dark / hrs light): no dataIN-LIFE DATES: From: To: no data
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: test chemical mixed directly with stock diet DIET PREPARATION- Rate of preparation of diet (frequency): once a fortnight- Mixing appropriate amounts with (Type of food): stock diet consisting of 28% yellow maize, 26% whole wheat, 10% rolled oats, 10% soybean oil meal, 8% fish meal and <5% each of meat scraps, dried whey, soybean oil, grass meal, minerals, sodium chloride and vitamin preparation.- Storage temperature of food: room temperatureVEHICLE- Justification for use and choice of vehicle (if other than water): no vehicle
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 13 weeks / 90 days
- Frequency of treatment:
- in ad libitum diet
- Remarks:
- Doses / Concentrations:0.2%, 1.0% and 5.0%Basis:nominal in diet
- No. of animals per sex per dose:
- 15
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: previous range finding test- Rationale for animal assignment (if not random): according to body weight
- Positive control:
- none
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes- Observations: general appearance and behaviour- Time schedule: no dataDETAILED CLINICAL OBSERVATIONS: No dataBODY WEIGHT: Yes- Time schedule for examinations: weeklyFOOD 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: NoFOOD 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: YesWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes - Time schedule for examinations: weekly for the first week onlyOPHTHALMOSCOPIC EXAMINATION: NoHAEMATOLOGY: Yes- Time schedule for collection of blood: week 6 and week 12- Anaesthetic used for blood collection: No data- Animals fasted: No- How many animals: 10 males and 10 females from each dose group- Parameters checked in table [No.4] were examined.CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: terminally- Animals fasted: No data- How many animals: 10 males and 10 females from each dose group- Parameters checked in table [No.5 and No.6] were examined.URINALYSIS: Yes - Time schedule for collection of urine: urinalysis from pooled samples from 10 males and 10 females from each dose group in 7th week.- Metabolism cages used for collection of urine: No data- Animals fasted: No data- Parameters checked in table [No.7 and No.8] were examined.NEUROBEHAVIOURAL EXAMINATION: NoOTHER: kidney funcion from samples of 10 males and 10 females in 13th week. Serum protein electrophoresis of 10 males and 10 females of control and high dose groups at 13 weeks. Liver enzyme activity at termination.
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table No.10) HISTOPATHOLOGY: Yes (see table No.11)
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- effects observed, treatment-related
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not specified
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 763 - < 3 534 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
- Critical effects observed:
- not specified
- Conclusions:
- Test compound possesses a very low order of toxicity. 1% in the diet (corrresponding to a daily intake of 763 mg a.i./kg bw) was a no toxic effect level. At 5% in the diet (corresponding to 4092 mg a.i./kg bw) there were slight indications of deleterious effecs.
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- May 17-30, 1979
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Guideline not specified, but with detailed documentation
- Principles of method if other than guideline:
- 14-day range finding with male and female mice. 5 male and 5 female mice in each of 5 doses plus control. Exposed in diet. Endpoints include weight, feed consumption, clinical observations, and gross pathology.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- mouse
- Strain:
- B6C3F1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: Harlan Industries- Age at study initiation: no data- Weight at study initiation: males 22-27g and females 17-23g- Fasting period before study: no data- Housing: 5 per cage in polypropylene cages with stainless steel wire-bar lids and polyester filter bonnets. - Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: no dataENVIRONMENTAL CONDITIONS- Temperature (°C): 24 +/- 1- Humidity (%): no data- Air changes (per hr): 12- Photoperiod (hrs dark / hrs light): 12 / 12IN-LIFE DATES: From: May 17 To: May 30
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: no dataDIET PREPARATION- Rate of preparation of diet (frequency): no data- Mixing appropriate amounts with (Type of food): Purina Mash- Storage temperature of food: no dataVEHICLE- Justification for use and choice of vehicle (if other than water): no vehicle
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 14 days
- Frequency of treatment:
- ad libitum diet
- Remarks:
- Doses / Concentrations:0.0%, 0.25%, 0.50%, 1.0%, 2.0% and 4.0%Basis:nominal in diet
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: this is a range finding study- Rationale for animal assignment (if not random): random- Rationale for selecting satellite groups: none
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: NoDETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: twice dailyBODY WEIGHT: Yes- Time schedule for examinations: prior to dosing and then weeklyFOOD 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: NoFOOD 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: NoWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): NoOPHTHALMOSCOPIC EXAMINATION: NoHAEMATOLOGY: NoCLINICAL CHEMISTRY: NoURINALYSIS: NoNEUROBEHAVIOURAL EXAMINATION: No OTHER:
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes HISTOPATHOLOGY: No
- 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:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- BODY WEIGHT AND WEIGHT GAIN - Males exposed at 1%, 2% and 4% in diet had group average body weight losses of 50%, 75% and 100%, respectively, versus controls. Females exposed at 1%, 2% and 4% in diet had group average body weight losses of 100%, 150% and 250%, respectively, versus controls.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 - < 2 other: % in diet
- Sex:
- male/female
- Basis for effect level:
- other: overall effectsbody weight in both sexes
- Critical effects observed:
- not specified
- Conclusions:
- Based on body weight loss in this 14-day range finding study, it was recommended that the subchronic test level be established as 0.125% to 2.0%.
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- May 17-30, 1979
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Guideline not specified, but with detailed documentation
- Principles of method if other than guideline:
- 14-day range finding with male and female rats. 5 male and 5 female mice in each of 5 doses plus control. Exposed in diet. Endpoints include weight, feed consumption, clinical observations, and gross pathology.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: Harlon Industries- Age at study initiation: no data- Weight at study initiation: 92-138 g- Fasting period before study: no data- Housing: individually in hanging wire-mesh (galvanized steel) cages. - Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: no dataENVIRONMENTAL CONDITIONS- Temperature (°C): 23 +/- 1- Humidity (%): no data- Air changes (per hr): 12- Photoperiod (hrs dark / hrs light): 12 / 12IN-LIFE DATES: From: May 17 To: May 30, 1979
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: blended with food to achieve target percentDIET PREPARATION- Rate of preparation of diet (frequency): no data- Mixing appropriate amounts with (Type of food): Purina Mash- Storage temperature of food: no dataVEHICLE- Justification for use and choice of vehicle (if other than water): no vehicle
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 14 days
- Frequency of treatment:
- ad libitum in feed
- Remarks:
- Doses / Concentrations:0.25%, 0.50%, 1.0%, 2.0% and 4.0%Basis:nominal in diet
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: this was a range finding study- Rationale for animal assignment (if not random): random
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: NoDETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: twice dailyBODY WEIGHT: Yes - Time schedule for examinations: at dosing and weekly thereafterFOOD 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: NoFOOD 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: NoWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): NoOPHTHALMOSCOPIC EXAMINATION: No HAEMATOLOGY: No CLINICAL CHEMISTRY: No URINALYSIS: No NEUROBEHAVIOURAL EXAMINATION: NoOTHER:
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table) HISTOPATHOLOGY: No
- 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):
- effects observed, treatment-related
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY - no clinical signs of toxicity. 4 male deaths at 4% and 2 male deaths at 2%. 4 female deaths; one each at 4%, 2%, 0.5% and 0.25%. BODY WEIGHT AND WEIGHT GAIN - Group average body weight changes showed the males of the 1% and 2% levels gaining 16% and 66% less than the controls. The females of the 4% level gained 37% less than the controls.FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) - Appeared to be a problem with pallatability, many of the animlas were observed scratching feed out of the dish. The food consumption to body weight ratio indicate it took more feed to maintain animal body weights at the higher dose levels. GROSS PATHOLOGY - no compound related lesions at any dose
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 0.5 - <= 1 other: % in diet
- Sex:
- male/female
- Basis for effect level:
- other: overall effectsmortality; body weight; food consumption;
- Critical effects observed:
- not specified
- Conclusions:
- Based on mortality and body weight loss in this 14-day range finding study, it was recommended that the subchronic test level be established as 0.125% to 2.0%.
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- October 8, 1979 to January 7, 1980
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Guideline not specified, but with detailed documentation
- Principles of method if other than guideline:
- Five groups of ten mice of each sex were exposed for 13 weeks to 5 doses in the diet. Concurrent controls fed same diet without test chemical. Survival, body weights, food consumption, clinical observations and gross pathology and histopathology were evaluated.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- mouse
- Strain:
- B6C3F1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: Charles River Breeding Labs - Age at study initiation: 57 days- Weight at study initiation: males 20-30 g; females 18-24 g- Fasting period before study: no data- Housing: 5 per cage in polycarbonate cages suspended in stainless steel racks covered with spun bonded fiberglass filter sheets. Cages were changed biweekly. Hardwood chip bedding. - Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: no dataENVIRONMENTAL CONDITIONS- Temperature (°C): 23 +/- 1 - Humidity (%): no data- Air changes (per hr): 12- Photoperiod (hrs dark / hrs light): 12 / 12IN-LIFE DATES: From: October 8, 1979 To: January 7, 1980
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: no dataDIET PREPARATION- Rate of preparation of diet (frequency): biweekly- Mixing appropriate amounts with (Type of food): Purina Mash- Storage temperature of food: no dataVEHICLE- Justification for use and choice of vehicle (if other than water): no vehicle
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Attachment 3 (analysis of the compound/feed mixture at all levels performed once during the study) is not included in the available report
- Duration of treatment / exposure:
- 13 weeks / 91 days
- Frequency of treatment:
- ad libitum in diet
- Remarks:
- Doses / Concentrations:males - 152, 305, 610, 1220 and 2439 mg/kg bw assuming 100% purity; Females - 154, 308, 617, 1234 and 2467 mg/kg bw assuming 100% purityBasis:nominal in diet
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: range finding study (0.125% to 2.0% in diet)- Rationale for animal assignment (if not random): random
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: NoDETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: twice dailyBODY WEIGHT: Yes - Time schedule for examinations: weeklyFOOD 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 HAEMATOLOGY: NoCLINICAL CHEMISTRY: No URINALYSIS: No NEUROBEHAVIOURAL EXAMINATION: No OTHER:
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table)HISTOPATHOLOGY: Yes (see table)
- Other examinations:
- Murine Virus determination of control mice at termination
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- 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:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY - No clinical evidence of toxicity in any group. Three males at 0.5% dose and one female at 0.125% dose died.BODY WEIGHT AND WEIGHT GAIN - Mean body weight gain of all male groups was 18% to 74% more than the controls. Mean body weight gain of 0.25% and 0.5% were slightly greater than controls; that of the 0.125% and 1.0% were slightly less than the controls; that of the 2.0% group was very slightly less than the controls.FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) - Mean food consumption fluctuated moderately from week to week but there was no apparent relationship between food consumption and dose or body weight fluctuation.GROSS PATHOLOGY - no lesions that could be attributed to treatmentHISTOPATHOLOGY: NON-NEOPLASTIC - no lesions that could be attributed to treatmentOTHER FINDINGS - Results of the Murine Virus test were negative
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- > 2 439 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: overall effects - no observed
- Critical effects observed:
- not specified
- Conclusions:
- The study was conducted to establish dosing for a chronic study. The bioassay protocol recommends that the high level dosage produce some effects, it is therefore recommended that the chronic study be conducted with both sexes at 4% (MTD) and 2% (MTD/2).
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- October 8, 1979 to January 7, 1980
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Guideline not specified, but with detailed documentation
- Principles of method if other than guideline:
- Resembles OECD 408; young male and female rats (10 per sex per dose) exposed by diet for 13 weeks; 5 exposure levels and a control; analytical verification of test substance in feed; ad libitum feed; survival, body weight, feed consumption, gross and histopathology examined.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: Charles River Breeding Labs- Age at study initiation: no data- Weight at study initiation: 144-177 g males, 115-144 g females- Fasting period before study: no data- Housing: five per cage in polycarbonate cages suspende in stainless steel racks covered with spun bonded fiberglass filter sheets which were vacumed daily and changed once a month.- Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period:no dataENVIRONMENTAL CONDITIONS- Temperature (°C): 23 +/- 1- Humidity (%): no data- Air changes (per hr): 12 - Photoperiod (hrs dark / hrs light): 12 / 12 IN-LIFE DATES: From: October 8, 1979 To: January 7, 1980
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: test substance mixed with feed bi-weekly using a 16 quart stainless steel PK blenderDIET PREPARATION- Rate of preparation of diet (frequency): biweekly- Mixing appropriate amounts with (Type of food): Purina mash - Storage temperature of food: no dataVEHICLE- Justification for use and choice of vehicle (if other than water): no vehicle
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of test substance in the feed was performed once during the study at all dosing levels
- Duration of treatment / exposure:
- 91 days
- Frequency of treatment:
- ad libitum in feed
- Remarks:
- Doses / Concentrations:0.125, 0.25, 0.50, 1.0 and 2.0 %Basis:nominal in diet
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: preliminary range finding study- Rationale for animal assignment (if not random): random
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No DETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: twice dailyBODY WEIGHT: Yes- Time schedule for examinations: at test initiation and then weeklyFOOD 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: YesFOOD 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: NoWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): NoOPHTHALMOSCOPIC EXAMINATION: NoHAEMATOLOGY: No CLINICAL CHEMISTRY: NoURINALYSIS: NoNEUROBEHAVIOURAL EXAMINATION: No
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (Attachment B "signed copy of Dr. Brown's pathology r eport" not reviewed)HISTOPATHOLOGY: Yes (Attachment B "signed copy of Dr. Brown's pathology report" not reviewed)
- Other examinations:
- Murine Virus determination for five control rats per sex upon completion of the test
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY - 5 of 10 animals died at 4% dose level, 1 of 10 died at 1% dose level; no clinical signs of toxicity at any dose levelBODY WEIGHT AND WEIGHT GAIN - limited at 2% and 4% FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) - animals refusing their food at 2% and 4%GROSS PATHOLOGY - no gross lesionsHISTOPATHOLOGY: NON-NEOPLASTIC - no microscopic lesionsOTHER FINDINGS - no murine virus titers
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 - < 2 other: % in diet
- Sex:
- male/female
- Basis for effect level:
- other: overall effectsmortality; body weight
- Critical effects observed:
- not specified
- Conclusions:
- This study was conducted to establish doses for a chronic study. The recommendation is MTD = 4% and MTD/2 = 2% for the chronic study.
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- April 23 - May 8, 1980
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Guideline not specified, but with detailed documentation
- Principles of method if other than guideline:
- 14 day range finding test of young male and female rats (5 per sex per dose); dosed in diet at 0, 1, 2 and 4%; fed adlibitum; survival, body weight, feed consumption, clinical observations, gross- and histo-pathology were evaluated.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: Marlan Industries- Age at study initiation: no data- Weight at study initiation: 134-163 g males, 110-126 g females- Fasting period before study: no data- Housing:individually in hanging wire mesh cages suspended in galvanized steel racks. Lined with absorbent pan liners that were changed biweekly. - Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: no dataENVIRONMENTAL CONDITIONS- Temperature (°C): 23 +/- 1- Humidity (%): no data- Air changes (per hr): 12- Photoperiod (hrs dark / hrs light): 12 / 12IN-LIFE DATES: From: April 23 To: May 8, 1980
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: test substance mixed directly with feed using 8 quart stainless steel PK blenderDIET PREPARATION- Rate of preparation of diet (frequency): biweekly- Mixing appropriate amounts with (Type of food): NIH 07 open formula diet- Storage temperature of food: refrigeratedVEHICLE- Justification for use and choice of vehicle (if other than water): no vehicle
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 14 days
- Frequency of treatment:
- ad libitum in diet
- Remarks:
- Doses / Concentrations:0, 1, 2 and 4%Basis:nominal in diet
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: repeat of range finding test- Rationale for animal assignment (if not random): random
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: twice dailyBODY WEIGHT: Yes- Time schedule for examinations: weeklyFOOD 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: NoFOOD 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: NoWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): NoOPHTHALMOSCOPIC EXAMINATION: NoHAEMATOLOGY: No CLINICAL CHEMISTRY: NoURINALYSIS: No NEUROBEHAVIOURAL EXAMINATION: NoOTHER:
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes HISTOPATHOLOGY: No
- 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):
- effects observed, treatment-related
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY - none BODY WEIGHT AND WEIGHT GAIN - weight loss in 1,2 and 4% dietsFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) - scratching the feed from their dishes indicating a possible taste acceptance problemGROSS PATHOLOGY - no lesions found at necropsy
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 - < 2 other: % in diet
- Sex:
- male/female
- Basis for effect level:
- other: overall effectsbody weight; food consumption
- Critical effects observed:
- not specified
- Conclusions:
- This study was conducted to establish doses for a chronic study. Based upon the severe body weight depressions at 4% in males and females the recommendation was MTD = 2% and MTD/2 = 1% in the diet.
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- not specified
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crj:CD(SD)IGS, SPF
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: Charles River Japan, Inc- Age at study initiation: 5 weeks of age- Weight at study initiation: 129 to 144 g (males) and 111 to 125g (females)- Housing: aluminum cage with wire-mesh floor and front side- Diet (e.g. ad libitum): ad lib- Water (e.g. ad libitum): ad libDETAILS OF FOOD AND WATER QUALITY: ENVIRONMENTAL CONDITIONS- Temperature (°C): 23 ± 3ºC- Humidity (%): 55 ± 20%- Air changes (per hr): 20 times/hour- Photoperiod (hrs dark / hrs light): 150 to 300 lux for 12 hours a day
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- In order to confirm that the dosing solutions for all dose groups were prepared appropriately, the concentration of the test article was confirmed for each dosing solution at the time of first preparation and the last preparation. No further details about the manner in which this analysis was undertaken was reported in the report.
- Duration of treatment / exposure:
- Twentyeight days.
- Frequency of treatment:
- Daily
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- Five/sex/dose
- Control animals:
- yes
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Not specifiedBODY WEIGHT: Yes FOOD EFFICIENCY: Not specifiedHAEMATOLOGY: Yes CLINICAL CHEMISTRY: Yes URINALYSIS: Yes Gross pathology and histopathology was also undertaken on a number of tissues.
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes Brain (including cerebrum, cerebellum and pons), spinal cord, pituitary, eyeballs, salivary glands (submandibular and sublingual), thyroid gland, epididymis, heart, thymus, lungs (including bronchus), trachea, liver, kidneys, spleen, adrenals, stomach, small intestines (including Peyer's patches), large intestine, testes, epididymides, seminal vesicles, prostate, ovaries, uterus, vagina, urinary bladder, peripheral nerves (sciatic nerve), lymph nodes (submandibular and mesenteric lymph nodes), bone marrow (femoral), aorta and the skin, testes and epididymidesHISTOPATHOLOGY: Yes Thymus, heart, liver, spleen, kidneys, adrenals, testes, epididymides, uterus, ovaries and bone marrow (femoral) of the animals in the control group and the high-dose group at the end of the administration period.
- Other examinations:
- Haematological examinations were conducted twice (once at the end of the administration period an d once at the end of the recovery period).Measurement of the following was undertaken: hematocrit, amount of haemoglobin, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, white blood cell count and white blood cell percentage, prothrombin time, activated partial thromboplastin time (APTT: Clot method) and fibrinogen.Blood biochemistry examinations included total protein, albumin, A/G ratio , blood glucose, triglyceride, total cholesterol, urea nitrogen, creatinine, total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, γ-glutamyl-transpeptidase, calcium and inorganic phosphorus. Sodium, potassium and chloride were also measured.Urinalysis was conducted twice (once in the final week of the administration period and once in the final week of the recovery period). Parameters measured were pH, occult blood, ketones, glucose, protein, bilirubin, urobilinogen. The 24-hour urine samples were subjected to analyses for urine volume, color, specific gravity of urine, and urinary sediment. The urine was also subjected to microscopic examination.
- Statistics:
- Body weight, food consumption, hematological examination, blood coagulation examination, blood biochemistry examination, urinalysis (urine volume and specific gravity), organ weight, and organ weight/body weight ratio measurements were subjected first to Bartlett's test for homogeneity of variance. Homogeneous data were subjected to Dunnett's multiple comparison test 1,2) to examine the significance of the difference between the control group and each dose group. The heterogeneous data in the Bartlett's test for homogeneity of variance were subjected to Steel's test for the significance of the difference between the control group and each dose group. The levels of significance were set at 5 and 1% bilaterally. The results of the pathological examinations were subjected to Fisher's exact test.
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food efficiency:
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not specified
- Immunological findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, non-treatment-related
- Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- gross pathology
- haematology
- histopathology: neoplastic
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- urinalysis
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Conclusions:
- All effects that were reported were reversible and were no longer present at the end of the recovery period or these effects were not treatment related. The NOAEL based on the findings from this study was 1000 mg/kg bw/day and this was the highest dose employed.
- Executive summary:
- In a subacute toxicity study (similar to the OECD Guideline 407 - Repeated Dose 28 -Day Oral Toxicity in Rodents) the substance was administered to 5 animals/sex/dose by oral gavage at dose levels of 0,100, 300 or 1000 mg/kg bw/day). There were no compound-related effects in mortality, clinical signs, body weight gain, haematology, clinical chemistry, organ weights, gross and histologic pathology. The NOAEL is 1000 mg/kg bw/day, the highest dose tested.
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 763 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Sufficient to meet requirements
- System:
- other: cardiovascular / hematological
- Organ:
- spleen
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
- Quality of whole database:
- The two important routes of exposure have been addressed. Hence no need for inhalation repeated dose.
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- July 20-August 6, 1987
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Protocols and resuls reviewed and accepted by the National Toxicology Program's Board of Scientific Counselor's Technical Reports Review Subcommittee, USA National Institutes of Health. The study was used as dose finding study for a carcinogenicity study and therefore the number of endpoints was limited.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
- Deviations:
- yes
- Remarks:
- 17 day only
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: Taconic Farms, Germantown, NY- Age at study initiation: 5 weeks- Weight at study initiation: no data- Fasting period before study: no data- Housing: 1 animal per cage; polycarbonate cage on stainless steel racks with heat-treated hardwood chips and spun-bonded polyester filters; changed once per week- Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: 12 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 22.5 to 25.6- Humidity (%): 51 to 68- Air changes (per hr): 10 minimum- Photoperiod (hrs dark / hrs light): 12 / 12IN-LIFE DATES: From: July 20 To: August 6, 1987
- Type of coverage:
- not specified
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- TEST SITE- Area of exposure: clipped interscapular skin- % coverage: no data- Type of wrap if used: no data - Time intervals for shavings or clipplings: onceREMOVAL OF TEST SUBSTANCE- Washing (if done): not washedTEST MATERIAL- Amount(s) applied (volume or weight with unit): 300 microliters applied five days per week- Concentration (if solution): 0, 5, 15, 44, 133 and 400 mg/mL- Constant volume or concentration used: yesVEHICLE- Justification for use and choice of vehicle (if other than water): distilled waterUSE OF RESTRAINERS FOR PREVENTING INGESTION: no data
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- doses analyzed by HPLC at the start of the 17 day period
- Duration of treatment / exposure:
- 17 days
- Frequency of treatment:
- 5 days per week
- Remarks:
- Doses / Concentrations:10, 30, 90, 260 and 800 mg active ingredient/kg bw for males, and 13, 40, 120, 330 and 1030 mg active ingredient/kg bw for femalesBasis:analytical per unit body weight
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: wide range for screening purposes- Rationale for animal assignment (if not random): random
- Positive control:
- no data
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: NoDETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: twice dailyDERMAL IRRITATION (if dermal study): Yes - Time schedule for examinations: twice dailyBODY WEIGHT: Yes- Time schedule for examinations: days 1, 8 and 17FOOD CONSUMPTION: - Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No dataFOOD 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: NoWATER CONSUMPTION: NoOPHTHALMOSCOPIC EXAMINATION: NoHAEMATOLOGY: NoCLINICAL CHEMISTRY: No URINALYSIS: NoNEUROBEHAVIOURAL EXAMINATION: NoOTHER:
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (Table F1)HISTOPATHOLOGY: Yes
- Statistics:
- Kaplan-Meier method
- Clinical signs:
- no effects observed
- Dermal irritation:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY - no mortality; only tan or brown discoloration of the skin and crusty white deposits at the application siteBODY WEIGHT AND WEIGHT GAIN - no treatment effectsORGAN WEIGHTS - increase in liver weights relative to body weight in males and females at two highest doses; considered to be of unknown toxicological relevanceGROSS PATHOLOGY - no treatment related effectsHISTOPATHOLOGY: NON-NEOPLASTIC - no treatment related effects
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 030 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: overall effectsclinical signs; mortality; body weight; gross pathology; organ weights; histopathology
- Critical effects observed:
- not specified
- Conclusions:
- NOAEL = highest dose (1030 mg active ingredient/kg bw).
- Endpoint:
- short-term repeated dose toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- July 27 - August 12, 1987
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Protocols and results reviewed and accepted by the National Toxicology Program's board of Scientific Counselor's Technical Reports Review Subcommittee, USA National Institutes of Health. The study was used as dose finding study for a carcinogenicity study and therefore the number of endpoints was limited.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
- Deviations:
- yes
- Remarks:
- 17 days exposure versus 21-28 days
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- mouse
- Strain:
- B6C3F1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: Taconic Farms, Germantown, NY- Age at study initiation: 6 weeks- Weight at study initiation: no data- Fasting period before study: no data- Housing: 1 animal per cage; polycarbonate cages with stainless steel racks; heat-treated hardwood chip bedding and spun-bonded polyester cage filters changed weekly- Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: 11 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 15.8 to 23.9- Humidity (%): 31 to 50- Air changes (per hr): 10 minimum- Photoperiod (hrs dark / hrs light): 12 / 12 IN-LIFE DATES: From: July 27 To: August 12, 1987
- Type of coverage:
- not specified
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- TEST SITE- Area of exposure: clipped interscapular skin- % coverage: no data- Type of wrap if used: no data- Time intervals for shavings or clipplings: once at the startREMOVAL OF TEST SUBSTANCE- Washing (if done): no dataTEST MATERIAL- Amount(s) applied (volume or weight with unit): 100 microliters- Concentration (if solution): 0, 5, 15, 44, 133 and 400 mg/mL- Constant volume or concentration used: yesVEHICLE- Justification for use and choice of vehicle (if other than water): no vehicleUSE OF RESTRAINERS FOR PREVENTING INGESTION: no data
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- HPLC at the beginning of the study
- Duration of treatment / exposure:
- 17 days
- Frequency of treatment:
- 5 days per week
- Remarks:
- Doses / Concentrations:20, 60, 190, 540 and 1600 mg active ingredient/kg bw for males and 26, 80, 220, 680 and 2000 mg active ingredient/kg bw for femalesBasis:analytical per unit body weight
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: wide range for screening study- Rationale for animal assignment (if not random): random
- Positive control:
- no data
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: NoDETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: twice dailyDERMAL IRRITATION (if dermal study): Yes- Time schedule for examinations: twice dailyBODY WEIGHT: Yes- Time schedule for examinations: days 1, 8 and 17FOOD CONSUMPTION: - Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: NoFOOD 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: NoWATER CONSUMPTION: NoOPHTHALMOSCOPIC EXAMINATION: NoHAEMATOLOGY: NoCLINICAL CHEMISTRY: NoURINALYSIS: NoNEUROBEHAVIOURAL EXAMINATION: NoOTHER:
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table F3)HISTOPATHOLOGY: Yes
- Statistics:
- Kaplan and Meier
- Clinical signs:
- no effects observed
- Dermal irritation:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY - no mortality; crusty white deposits at the application sites at two highest dosesBODY WEIGHT AND WEIGHT GAIN - to treatment related effectsORGAN WEIGHTS - significant increase in liver weight relative to body weight for females at all but the lowest dose and for males at the highest dose; the effects were considered to be of unknown toxicological relevanceGROSS PATHOLOGY - no treatment related effectsHISTOPATHOLOGY: NON-NEOPLASTIC - no treatment related effectsOTHER FINDINGS
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 2 000 mg/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: overall effectsclinical signs; mortality; body weight; gross pathology; organ weights, histopathology
- Critical effects observed:
- not specified
- Conclusions:
- Test substance not toxic at up to 2000 mg a.i. /kg bw.
- Endpoint:
- sub-chronic toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- February 16 - May 19, 1987
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Protocols and results reviewed and accepted by the National Toxicology Program's Board of Scientific Counselor's Technical Reports Review Subcommittee, USA National Institutes of Health. The study was used as dose finding study for a carcinogenicity study and therefore the number of endpoints was limited.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
- Deviations:
- yes
- Remarks:
- clinical signs recorded weekly; no food consumption results; no ophthalmoscopy; clinical chemistry did not include sodium, potassium, chloride, phoshorus or glucose
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: Taconic Farms, Germantown, NY- Age at study initiation: 6 weeks- Weight at study initiation: no data- Fasting period before study: no data- Housing: 1 animal per cage; polycarbonate cage with stainless steel rack (rotated every 2 weeks); heat-treated hardwood chips and spun-bonded polyester cage filters changed weekly- Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: 12 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 20.1 to 24.5- Humidity (%): 20 to 67- Air changes (per hr): 10 minimum- Photoperiod (hrs dark / hrs light): 12 / 12 IN-LIFE DATES: From: February 16 To: May 19, 1988
- Type of coverage:
- not specified
- Vehicle:
- ethanol
- Details on exposure:
- TEST SITE- Area of exposure: clipped interscapular skin- % coverage: no data- Type of wrap if used: no data- Time intervals for shavings or clipplings: once at start of studyREMOVAL OF TEST SUBSTANCE- Washing (if done): no dataTEST MATERIAL- Amount(s) applied (volume or weight with unit): 300 microliters- Concentration (if solution): 0, 5, 15, 44, 133, 400 mg/mL- Constant volume or concentration used: yesVEHICLE- Justification for use and choice of vehicle (if other than water): ethanol because test material beads up rather than spreads out when applied neat- Amount(s) applied (volume or weight with unit): 300 microliters of combined test material and vehicle- Concentration (if solution): 50% solution of ethanol i water- Lot/batch no. (if required): no data - Purity: no dataUSE OF RESTRAINERS FOR PREVENTING INGESTION: no data
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- HPLC on each dose at beginning, middle and end of the study
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- 5 days per week
- Remarks:
- Doses / Concentrations:17, 50, 140, 440 and 1300 mg active ingredient/kg bw for males and 20, 60, 170, 540 and 1620 mg active ingredient/kg bw for femalesBasis:analytical per unit body weight
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: wide range of doses for screening- Rationale for animal assignment (if not random): random- Rationale for selecting satellite groups: 10 males and 10 females at each dose for special hematology and clinical chemistry study- Post-exposure recovery period in satellite groups: no data- Section schedule rationale (if not random): random
- Positive control:
- no data
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes- Time schedule: twice daily- Cage side observations checked in table were not included. DETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: weeklyDERMAL IRRITATION (if dermal study): Yes - Time schedule for examinations: weeklyBODY WEIGHT: Yes - Time schedule for examinations: weeklyFOOD CONSUMPTION: - Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: NoFOOD 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: NoWATER CONSUMPTION: NoOPHTHALMOSCOPIC EXAMINATION: No HAEMATOLOGY: Yes - Time schedule for collection of blood: day 5 and 21 (from satellite group) and at end of study for all animals- Anaesthetic used for blood collection: Yes / carbon dioxide- Animals fasted: No data- How many animals: 10 per dose; males and females- Parameters checked in table [No.1] were examined. CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: day 5 and 21 (from satellite group) and at end of study for all animals- Animals fasted: No data- How many animals: 10 per dose; males and females- Parameters checked in table [No.1] were examined.URINALYSIS: NoNEUROBEHAVIOURAL EXAMINATION: NoOTHER:
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 1)HISTOPATHOLOGY: Yes (see table 1)
- Statistics:
- Kaplan-Meier
- Clinical signs:
- no effects observed
- Dermal irritation:
- effects observed, treatment-related
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY - no treatment related effectsBODY WEIGHT AND WEIGHT GAIN - no treatment related effectsFOOD CONSUMPTION - protocol indicates measurements conducted, but not reportedHAEMATOLOGY - no treatment related effectsCLINICAL CHEMISTRY - no treatment related effectsORGAN WEIGHTS - decrease seen in liver weights of males but not accompanied by histopathology changes; a liver enzyme increase was observed in males at day 5 but not at a later time period.GROSS PATHOLOGY - no treatment related effectsHISTOPATHOLOGY: NON-NEOPLASTIC - protocol indicates examinations conducted, but not reported OTHER FINDINGS - epidermal hyperplasia of the application site in both males and females at the highest dose
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 500 mg/kg bw (total dose)
- Sex:
- male
- Basis for effect level:
- other: overall effects: other: epidermal hyperplasia at highest dose in males
- Critical effects observed:
- not specified
- Conclusions:
- NOAEL = 500 mg a.i./kg bw for males based on epidermal hyperplasia of the application site.
- Endpoint:
- sub-chronic toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- February 23 - May 26, 1988
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Protocols and results reviewed and accepted by the National Toxicology Program's Board of Scientific Counselor's Technical Reports Review Subcommittee, USA National Institutes of Health. The study was used as dose finding study for a carcinogenicity study and therefore the number of endpoints was limited.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
- Deviations:
- yes
- Remarks:
- clinical signs reported weekly; no food consumption; no ophthalmoscopy, no clinical chemisty; no haematology
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- mouse
- Strain:
- B6C3F1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: Taconic Farms, Germantown, NY- Age at study initiation: 7 weeks- Weight at study initiation: no data- Fasting period before study: no data- Housing: 1 animal per cage; polycarbonate cages and stainless steel racks (rotated every 2 weeks), with heat-treatted hardwood chip bedding and spun-bonded polyester cage filters changed every week.- Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: 19 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 21.5 to 23.9- Humidity (%): 15 to 63- Air changes (per hr): 10 minimum- Photoperiod (hrs dark / hrs light): 12 / 12IN-LIFE DATES: From: February 23 To: May 26, 1988
- Type of coverage:
- not specified
- Vehicle:
- ethanol
- Details on exposure:
- TEST SITE- Area of exposure: clipped interscapular skin- % coverage: no data- Type of wrap if used: no data- Time intervals for shavings or clipplings: once at start of studyREMOVAL OF TEST SUBSTANCE- Washing (if done): no dataTEST MATERIAL- Amount(s) applied (volume or weight with unit): 100 microliters- Concentration (if solution): 0, 5, 15, 44, 133 and 400 mg/mL- Constant volume or concentration used: yesVEHICLE- Justification for use and choice of vehicle (if other than water): ethanol, because in water alone the test substance beaded up- Amount(s) applied (volume or weight with unit): 100 microliters of 50% ethanol and 50% distilled water - Concentration (if solution): 50%- Lot/batch no. (if required): no data- Purity: no dataUSE OF RESTRAINERS FOR PREVENTING INGESTION: no data
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- HPLC verification of each dose at beginning, midpoint and end of study
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- 5 days per week
- Remarks:
- Doses / Concentrations:17, 50, 140, 440 and 1300 mg active ingredient/kg bw for males and 20, 60, 170, 540 and 1620 mg active ingredient/kg bw for femalesBasis:analytical per unit body weight
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: wide range for screening study- Rationale for animal assignment (if not random): random
- Positive control:
- no data
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes - Time schedule: twice daily- Cage side observations were not included in the report. DETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: weeklyDERMAL IRRITATION (if dermal study): Yes- Time schedule for examinations: weeklyBODY WEIGHT: Yes - Time schedule for examinations: weeklyFOOD CONSUMPTION: - Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: NoFOOD 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: NoWATER CONSUMPTION: NoOPHTHALMOSCOPIC EXAMINATION: No HAEMATOLOGY: NoCLINICAL CHEMISTRY: No URINALYSIS: NoNEUROBEHAVIOURAL EXAMINATION: NoOTHER:
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table No 1)HISTOPATHOLOGY: Yes (see table No 1)
- Statistics:
- Kaplan and Meier
- Clinical signs:
- no effects observed
- Dermal irritation:
- effects observed, treatment-related
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY - no treatment related effectsBODY WEIGHT AND WEIGHT GAIN - slight increase in body weight of males at highest doseORGAN WEIGHTS - increase in kidney weight of males but not dose dependentGROSS PATHOLOGY - no treatment related effectsOTHER FINDINGS - epidermal hyperplasia of application site in males and females at the highest dose
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 440 mg/kg bw (total dose)
- Sex:
- male
- Basis for effect level:
- other: overall effectsother: epidermal hyperplasia (also seen in females at highest dose)
- Critical effects observed:
- not specified
- Conclusions:
- NOAEL = 440 mg a.i./kg bw
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 60 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
- Quality of whole database:
- The database of available repeat dose dermal studies includes two sub-chronic 90 day studies as well as two chronic/carcinogenicity studies, conducted in both rats and mice. These studies were limited in design such that not all important endpoints were investigated. These studies found only local effects and no systemic toxicity. So for the purpose of calculating a DNEL value for systemic effects, the oral NOAEL has been used together with information on relative absorption by the oral and dermal routes.
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 0.48 mg/cm²
- Study duration:
- chronic
- Species:
- rat
- Quality of whole database:
- Sufficient to meet requirements. The study with the lowest NOAEL for local effects (hyperplasia of the epidermis) is the 2 year dermal carcinogenicity study in the rat, where the NOAEL for females was 60 mg/kg. Taking a mean body weight figure for the female rats in the 60 mg/kg dose group of 0.2kg (stated range = 0.107 to 0.288 kg) and assuming a surface area of dosing of 25 cm2, gives a NOAEL of 0.48 mg/cm2.
Additional information
A 28-day oral repeat dose toxicity study was conducted in male and female Wistar rats employing p-toluene sulphonic acid (Hoeschst, 1990). Whilst this is not a hydrotropes category member it does share the same organic anion as sodium toluene sulphonate. This study followed the OECD Guideline 407 with no reported deviations to the study plan and was conducted to GLP. Rats (10/sex/dose) were orally administered 0, 4, 20, 100 or 500 mg/kg bw/day of the substance. The top dose for this study was selected on the basis of a preliminary study in which a single dose of 1250 mg/kg bw resulted in 40% mortality in females. Some of the males displayed salivation at the top dose and urinalysis showed that the urine was acidic in both males and females. The salivation was considered to be a sign of irritation by the study authors and both effects were not considered to be toxicologically relevant (non-adverse). Thus, the NOEL is 100 mg/kg bw/day and the NOAEL is 500 mg/kg bw/day (nominal concentration) or >490 mg/kg bw/day (actual concentration).
Reference:
Hoeschst , A.G. (1990). Subakute orale toxizitat (29 Applikationen in 29 Tagen an SPF-Winstar-Ratten.
Justification for classification or non-classification
Based on the reported findings from a variety of repeat dose studies by both the oral and dermal routes, there is no justification for hazard classification.
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.

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