Registration Dossier

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

Referenceopen allclose all

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:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity 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 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 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 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 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 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 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:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity 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 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:
clinical signs
mortality
body weight and weight gain
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
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.
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

Referenceopen allclose all

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:
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 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:
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 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:
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 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:
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 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
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.