Registration Dossier

Diss Factsheets

Administrative data

Description of key information

The HYDROTOPES Category comprises the following 6 substances:
STS - Sodium toluene 4-sulphonate (CAS 657-84-1, EC 211-522-5)
SXS - Sodium (xylenes and 4-ethylbenzene) sulfonates (EC 701-037-1)
NH4XS - Ammonium (xylenes and 4-ethylbenzene) sulfonates (EC 943-024-5)
SCS - Sodium p-cumenesulphonate (CAS 15763-76-5, EC 239-854-6)
KCS - Potassium p-cumenesulphonate (CAS 164524-02-1, EC 629-764-9)
NH4CS - Ammonium p-cumenesulphonate (CAS 680972-33-2, EC 811-484-5) 
In addition CaXS (Calcium Xylenesulphonate, CAS 28088-63-3, EC 248-829-9) was evaluated for complete the assessment despite it is not registered under REACH.


There are many oral repeated dose toxicity studies on the three subgroups of hydrotrope category (toluene, xylene and cumene). Most of these studies were conducted on Sodium (xylenes and 4-ethylbenzene) sulphonate however there are reliable subacute studies on Sodium toluene 4-sulphonate and a sub-chronic study on Sodium p-cumene sulphonate.


The key oral study is the 90 day sub-chronic study, conducted in 1968 on Sodium (xylenes and 4-ethylbenzene) sulphonate, 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 other available 90 day sub-chronic study on rat and mouse. There is also a 28 days oral exposure study on sodium toluene 4-sulphonate which does not show any effect with a NOAEL of 1000 mg/kg bw (highest dose tested).


 


The key dermal studies are the two sub-chronic studies in rat and mouse performed as part of chronic carcinogenicity study (2 -years) performed on Sodium (xylenes and 4-ethylbenzene) sulfonates.


No animals died in these studies, minimal hyperplasia of the epidermis at the site of application occurred in male and female rats from the control groups as well as most dosed groups. The incidence of epidermal hyperplasia in 400 mg/mL males was considered to be possibly chemical-related.


For mice, hyperplasia of the epidermis at the site of application occurred in male and female mice from the highest dose tested group. The incidence of epidermal hyperplasia in 400 mg/mL in males and females was considered to be chemical-related.


In the 14 weeks exposure study, the NOAEL for rats is 500 mg a.i./kg/day based on epidermal hyperplasia and the NOAEL for mice is 440 mg/kg bw. The NOAEL for local dermal effects was set considering also the two years carcinogenicity study on dermal application 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.


The repeated dose toxicity for inhalation exposure does not to be investigated because exposure of humans via inhalation in production and/or use is not likely as based on the thorough and rigorous exposure assessment.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
other: Read across from another member of the category
Adequacy of study:
key study
Study period:
1968
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
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:
no
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 data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 degrees centigrade
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 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 temperature

VEHICLE
- 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
Dose / conc.:
0 other: %
Dose / conc.:
0.2 other: %
Remarks:
Basis: nominal in diet
Dose / conc.:
1 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
5 other: %
Remarks:
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:
- Observations: general appearance and behaviour
- Time schedule: no data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT:
Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg
body weight/day: Compound intake calculated as time-weighted averages from the consumption and body weight

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study):
- Time schedule for examinations: weekly for the first week only

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY:
- 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:
- Time schedule for collection of blood: terminally
- Animals fasted: No data
- Number of aninals: 10 males and 10 females from each dose group
- Parameters checked

URINALYSIS:
- 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

NEUROBEHAVIOURAL EXAMINATION: No

OTHER EXAMINATIONS
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
HISTOPATHOLOGY: Yes
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:
NOAEL > 763 mg/kg < 3534 mg/kg bw day
Executive summary:

The repeated oral toxicity of Sodium (xylenes and 4-ethylbenzene) sulfonates was assessed following official guideline OECD 408, Repeated Dose 90-Day Oral Toxicity Study in Rodents. The tested substance showed a very low order of toxicity. No toxic effects were seen in the dose group that received 1% of the substance in the diet (corresponding to a daily intake of 763 mg a.i./kg bw). In the dose group treated with 5% of the substance 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:
other: Read across from another member of the category
Adequacy of study:
supporting study
Study period:
May 17-30, 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
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:
no
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 data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +/- 1
- Humidity (%): no data
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12 / 12
IN-LIFE DATES: From: May 17 To: May 30
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): no data
- Mixing appropriate amounts with
(Type of food): Purina Mash
- Storage temperature of food: no data

VEHICLE
- 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
Dose / conc.:
0 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
0.25 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
0.5 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
1 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
2 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
4 other: %
Remarks:
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:
DETAILED CLINICAL OBSERVATIONS:
- Time schedule: twice daily

BODY WEIGHT:
- Time schedule for examinations: prior to dosing and then weekly

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

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
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

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%.

Conclusions:
NOAEL > 1 < 2% in diet (male/female)
Executive summary:

The repeated oral toxicity of Sodium (xylenes and 4-ethylbenzene) sulfonates was assessed with a 14-day range finding with male and female mice treated with the tested substance in diet. The results showed no mortality, body weight lossand no effects in grosspathology.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
other: Read across from another member of the category
Adequacy of study:
supporting study
Study period:
May 17-30, 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
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:
no
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 data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 1
- Humidity (%): no data
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-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 percent

DIET PREPARATION
- Rate of preparation of diet (frequency): no data
- Mixing appropriate amounts with (Type of food): Purina Mash
- Storage temperature of food: no data

VEHICLE
- 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
Dose / conc.:
0 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
0.25 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
0.5 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
1 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
2 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
4 other: %
Remarks:
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:
DETAILED CLINICAL OBSERVATIONS:
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: at dosing and weekly thereafter

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

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
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
- 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

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%.

Conclusions:
NOAEL > 1 < 2% in diet
Executive summary:

The repeated oral toxicity of Sodium (xylenes and 4-ethylbenzene) sulfonates was assessed with a 14-day range finding with male and female mice treated with the tested substance in diet. The test results showed no mortality, no clinical signs, no lesions in the grosspathology but some effects on the body weight.

Endpoint:
sub-chronic toxicity: oral
Type of information:
other: Read across from another member of the category
Adequacy of study:
supporting study
Study period:
October 8, 1979 to January 7, 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
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:
no
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 data

ENVIRONMENTAL 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:
DIET PREPARATION
- Rate of preparation of diet (frequency): biweekly
- Mixing appropriate amounts with (Type of food): Purina Mash
- Storage temperature of food: no data

VEHICLE
- 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
Dose / conc.:
152 mg/kg bw/day (nominal)
Remarks:
in diet, males
Dose / conc.:
305 mg/kg bw/day (nominal)
Remarks:
in diet, males
Dose / conc.:
610 mg/kg bw/day (nominal)
Remarks:
in diet, males
Dose / conc.:
1 220 mg/kg bw/day (nominal)
Remarks:
in diet, males
Dose / conc.:
2 439 mg/kg bw/day (nominal)
Remarks:
in diet, males
Dose / conc.:
154 mg/kg bw/day (nominal)
Remarks:
in diet, females
Dose / conc.:
308 mg/kg bw/day (nominal)
Remarks:
in diet, females
Dose / conc.:
617 mg/kg bw/day (nominal)
Remarks:
in diet, females
Dose / conc.:
1 234 mg/kg bw/day (nominal)
Remarks:
in diet, females
Dose / conc.:
2 467 mg/kg bw/day (nominal)
Remarks:
in diet, females
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:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
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 treatment

HISTOPATHOLOGY NON-NEOPLASTIC - no lesions that could be attributed to treatment

OTHER 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

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).

Conclusions:
NOAEL > 2439 mg/kg bw day
Executive summary:

The repeated oral toxicity of Sodium (xylenes and 4-ethylbenzene) sulfonates was assessed following official guideline OECD 408, Repeated Dose 90-Day Oral Toxicity Study in Rodents. The test results showed no mortality, no clinical signs and no lesions in the gross pathology and histopathology.

Endpoint:
sub-chronic toxicity: oral
Type of information:
other: Read across from another member of the category
Adequacy of study:
key study
Study period:
October 8, 1979 to January 7, 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
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:
no
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 data

ENVIRONMENTAL 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 blender

DIET PREPARATION
- Rate of preparation of diet (frequency): biweekly
- Mixing appropriate amounts with (Type of food): Purina mash
- Storage temperature of food: no data

VEHICLE
- 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
Dose / conc.:
0.125 mg/kg bw/day (nominal)
Remarks:
Basis:nominal in diet
Dose / conc.:
0.25 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
0.5 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
1 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
2 other: %
Remarks:
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:
DETAILED CLINICAL OBSERVATIONS: Yes
Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: at test initiation and then weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL 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 level

BODY 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 lesions

HISTOPATHOLOGY: NON-NEOPLASTIC - no microscopic lesions

OTHER 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

This study was conducted to establish doses for a chronic study. The recommendation is MTD = 4% and MTD/2 = 2% for the chronic study.

Conclusions:
NOAEL > 1 < 2% in diet
Executive summary:

The repeated oral toxicity of Sodium (xylenes and 4-ethylbenzene) sulfonates was assessed following official guideline OECD 408, Repeated Dose 90-Day Oral Toxicity Study in Rodents. The test results showed mortality, effects on body weight, no lesions in gross pathology and histopathology.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
other: Read across from another member of the category
Adequacy of study:
supporting study
Study period:
April 23 - May 8, 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
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:
no
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 data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 1
- Humidity (%): no data
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12 / 12
IN-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 blender
DIET PREPARATION
- Rate of preparation of diet (frequency): biweekly
- Mixing appropriate amounts with (Type of food): NIH 07 open formula diet
- Storage temperature of food: refrigerated

VEHICLE- 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
Dose / conc.:
0 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
1 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
2 other: %
Remarks:
Basis:nominal in diet
Dose / conc.:
4 other: %
Remarks:
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:
DETAILED CLINICAL OBSERVATIONS:
- Time schedule: twice daily

BODY WEIGHT:
- Time schedule for examinations: weekly

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

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
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% diets
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- scratching the feed from their dishes indicating a possible taste acceptance problem

GROSS 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

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.

Conclusions:
NOAEL < 1 < 2 % in diet
Executive summary:

The repeated oral toxicity of Sodium (xylenes and 4-ethylbenzene) sulfonates was assessed with a 14-day range finding test with male and female mice treated with the tested substance in diet. The test results showed no mortality, no lesions in gross pathology but effects on body weight.

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
other: Read across from another member of the category
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
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
Limit test:
no
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 lib

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 specified
BODY WEIGHT: Yes
FOOD CONSUPTION: Yes
HAEMATOLOGY: Yes
CLINICAL CHEMISTRY: Yes
URINALYSIS: Yes
Gross pathology and histopathology was also undertaken on a number of tissues.
Sacrifice and pathology:
GROSS PATHOLOGY:
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 epididymides

HISTOPATHOLOGY: 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
Description (incidence and severity):
See attached tables for details.
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:
NOAEL = 1000 mg/kg bw/day (highest dose tested)
Executive summary:

The repeated oral toxicity of Sodium Toluene 4-sulphonate was assessed following guideline similar to the OECD Guideline 407, Repeated Dose 28 -Day Oral Toxicity in Rodents. In this study 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.

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

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:
other: Read across from another member of the category
Adequacy of study:
supporting study
Study period:
July 20-August 6, 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
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.
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
Deviations:
yes
Remarks:
17 day exposure
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 days

ENVIRONMENTAL 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: once

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not washed

TEST 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 delivered average daily doses of approximately 10, 30, 90, 260 and 800 mg/kg bw for males and 13, 40, 120, 330, and 1,030 mg/kg to females.
- Constant volume or concentration used: yes

VEHICLE
- Justification for use and choice of vehicle (if other than water): distilled water

USE 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
Dose / conc.:
0 mg/kg bw/day
Remarks:
Control for males and females
Dose / conc.:
10 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
30 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
90 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
260 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
800 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
13 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
40 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
120 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
330 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
1 030 mg/kg bw/day
Remarks:
Based on active ingredient, females
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: random
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily
DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: days 1, 8 and 17

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

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: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes, A necropsy was performed on all animals. The heart, right kidney, liver, lungs, right testis, and thymus were weighed.
HISTOPATHOLOGY: Yes, Histopathologic examination was restricted to skin from the site of application, skin from an untreated site, and gross lesions.

Statistics:
Kaplan-Meier method
Clinical signs:
no effects observed
Description (incidence and severity):
Only tan or brown discoloration of the skin and crusty white deposits at the application site.
In males and females, the few skin lesions observed grossly and microscopically were generally attributed to repeated clipping and were not considered related to chemical administration.
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
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Details on results:
CLINICAL SIGNS: only tan or brown discoloration of the skin and crusty white deposits at the application site.
In males and females, the few skin lesions observed grossly and microscopically were generally attributed to repeated clipping and were not considered related to chemical administration.
MORTALITY - no mortality
BODY WEIGHT AND WEIGHT GAIN - no treatment effects
ORGAN WEIGHTS - increase in liver weights relative to body weight in males and females at two highest doses; considered not to be of toxicological relevance.
GROSS PATHOLOGY - no treatment related effects
HISTOPATHOLOGY:
NON-NEOPLASTIC - no treatment related effects

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 030 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
gross pathology
mortality
organ weights and organ / body weight ratios
Key result
Dose descriptor:
NOAEL
Effect level:
>= 800 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
body weight and weight gain
clinical signs
gross pathology
mortality
organ weights and organ / body weight ratios
Critical effects observed:
not specified

See attached tables for results details.

Conclusions:
NOAEL > 1030 mg active ingredient/kg bw female
NOAEL > 800 mg active ingredient/kg bw male
Executive summary:

The repeated dermal toxicity of Sodium (xylenes and 4-ethylbenzene) sulfonates was assessed following official guideline EPA OPP 82-2 (Repeated dose dermal toxicity -21/28 days). There was a deviation due to the reduced administration period which was of 17 days. The test was perfomed on rats and the results showed no mortality, clinical signs only revelaed tan or brown discoloration of the skin and crusty white deposits at the application site. In males and females, the few skin lesions observed grossly and microscopically were generally attributed to repeated clipping and were not considered related to chemical administration.

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
other: Read across from another member of the category
Adequacy of study:
supporting study
Study period:
July 27 - August 12, 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
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.
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
Deviations:
yes
Remarks:
17 days exposure
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 days

ENVIRONMENTAL 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 start

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 microliters
- Concentration (if solution): 0, 5, 15, 44, 133 and 400 mg/mL delivered average daily doses of approximately 20, 60, 190, 540, and 1,600 mg/kg bw to males and 26, 80, 220, 680, and 2,000 mg/kg to females.
- Constant volume or concentration used: yes

VEHICLE- Justification for use and choice of vehicle (if other than water): no vehicle

USE 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
Dose / conc.:
0 mg/kg bw/day
Remarks:
males and females
Dose / conc.:
20 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
60 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
190 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
540 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
1 600 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
26 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
80 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
220 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
680 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
2 000 mg/kg bw/day
Remarks:
Based on active ingredient, females
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: random
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: days 1, 8 and 17

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

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: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
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 doses

BODY WEIGHT AND WEIGHT GAIN
- to treatment related effects

ORGAN 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 not to be of toxicological relevance

GROSS PATHOLOGY - no treatment related effects

HISTOPATHOLOGY: NON-NEOPLASTIC - no treatment related effects
Key result
Dose descriptor:
NOAEL
Effect level:
>= 2 000 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
body weight and weight gain
clinical signs
gross pathology
mortality
organ weights and organ / body weight ratios
Dose descriptor:
NOAEL
Effect level:
>= 1 600 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
clinical signs
gross pathology
mortality
organ weights and organ / body weight ratios
Critical effects observed:
not specified
Conclusions:
NOAEL > 2000 mg a.i. /kg bw female
NOAEL > 1600 mg a.i. /kg bw male
Executive summary:

The repeated dermal toxicity of Sodium (xylenes and 4-ethylbenzene) sulfonates was assessed following official guideline EPA OPP 82-2 (Repeated dose dermal toxicity -21/28 days). There was a deviation due to the reduced administration period which was of 17 days. The test was performed on mouse and the results showed no mortality, clinical signs only revelaed tan or brown discoloration of the skin and crusty white deposits at the application site. In males and females, the few skin lesions observed grossly and microscopically were generally attributed to repeated clipping and were not considered related to chemical administration.

Endpoint:
sub-chronic toxicity: dermal
Type of information:
other: Read across from another member of the category
Adequacy of study:
key study
Study period:
February 16 - May 19, 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
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.
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPP 82-3 (Subchronic Dermal Toxicity 90 Days)
Deviations:
yes
Remarks:
clinical signs recorded weekly; no food consumption results; no ophthalmoscopy; clinical chemistry did not include sodium, potassium, chloride, phoshorus or glucose
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 days

ENVIRONMENTAL 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 study

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data

TEST 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: yes

VEHICLE
- 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 data

USE 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
Dose / conc.:
0 mg/kg bw/day
Remarks:
male and females
Dose / conc.:
6 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
20 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
60 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
170 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
500 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
10 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
30 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
90 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
260 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
800 mg/kg bw/day
Remarks:
Based on active ingredient, females
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: 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: random
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes but not included in tables
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
Clinical Chemistry: urea nitrogen, creatinine, total protein, albumin, alanine aminotransferase, alkaline phosphatase, creatine kinase, sorbitol dehydrogenase, and bile acids.

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

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: No

OPHTHALMOSCOPIC 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, Blood was collected from the retroorbital sinus.
- Anaesthetic used for blood collection: Yes / carbon dioxide
- Parameters: hematocrit, hemoglobin concentration, erythrocyte and reticulocyte counts, mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, platelet count, and leukocyte count and differentials.
- Animals fasted: No data
- How many animals: 10 per dose; males and females


LINICAL 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
HISTOPATHOLOGY: Yes
Complete histopathologic examinations were performedon control rats (core) and tested rats from the 400 mg/mL groups. In addition to gross lesions, tissue masses, and associated lymph nodes, the tissues examined included: adrenal gland, bone and marrow, brain, clitoral gland, esophagus, gallbladder (mice), heart, kidney, large intestine (cecum, colon, and rectum), small intestine (duodenum, jejunum, and ileum), liver, lung, lymph nodes (mandibular and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular stomach), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder, and uterus. Skin samples were examined in lower dose groups until a no-effect level was reached.
Statistics:
Kaplan-Meier
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Minimal hyperplasia of the epidermis at the site of application occurred in male and female rats from the control groups as well as most dosed groups. The incidence of epidermal hyperplasia in 400 mg/mL males was considered to be possibly chemical-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
Immunological 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 effects

BODY WEIGHT AND WEIGHT GAIN
- no treatment related effects

FOOD CONSUMPTION
- protocol indicates measurements conducted, but not reported

HAEMATOLOGY
- no treatment related effects.
Hematology and clinical chemistry parameters of dosed groups of males and females were significantly different from those of the controls in several instances, but these differences were sporadic and did not demonstrate a treatment relationship

CLINICAL CHEMISTRY
- no treatment related effects

ORGAN 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 effects

HISTOPATHOLOGY: 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/day (actual dose received)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
clinical signs
gross pathology
mortality
organ weights and organ / body weight ratios
Dose descriptor:
NOAEL
Effect level:
>= 800 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
clinical signs
gross pathology
mortality
organ weights and organ / body weight ratios
Critical effects observed:
not specified

The incidence of epidermal hyperplasia in 400 mg/mL males was considered to be possibly chemical-related.

Conclusions:
NOAEL > 500 mg a.i./kg bw for males
NOAEL > 800 mg a.i./kg bw for females
Executive summary:

The repeated dermal toxicity of Sodium (xylenes and 4-ethylbenzene) sulfonates was assessed following official guideline EPA OPP 82-3 (Subchronic dermal toxicity - 90 days) similar to OECD 411. The test was performed on rats and the results showed no mortality and minimal hyperplasia of the epidermis at the site of application occurred in male and female rats from the control groups as well as most dosed groups.

Endpoint:
sub-chronic toxicity: dermal
Type of information:
other: Read across from another member of the category
Adequacy of study:
key study
Study period:
February 23 - May 26, 1988
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
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.
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPP 82-3 (Subchronic Dermal Toxicity 90 Days)
Deviations:
yes
Remarks:
clinical signs reported weekly; no food consumption; no ophthalmoscopy, no clinical chemisty; no haematology
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 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5 to 23.9
- Humidity (%): 15 to 63
- Air changes (per hr): 10 minimum
- Photoperiod (hrs dark / hrs light): 12 / 12
IN-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 study

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data

TEST 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: yes

VEHICLE
- 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 data

USE 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
Dose / conc.:
0 mg/kg bw/day
Remarks:
male and females
Dose / conc.:
17 mg/kg bw/day (actual dose received)
Remarks:
male
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Remarks:
male
Dose / conc.:
140 mg/kg bw/day (actual dose received)
Remarks:
male
Dose / conc.:
440 mg/kg bw/day (actual dose received)
Remarks:
male
Dose / conc.:
1 300 mg/kg bw/day (actual dose received)
Remarks:
male
Dose / conc.:
20 mg/kg bw/day (actual dose received)
Remarks:
female
Dose / conc.:
60 mg/kg bw/day (actual dose received)
Remarks:
female
Dose / conc.:
170 mg/kg bw/day (actual dose received)
Remarks:
female
Dose / conc.:
530 mg/kg bw/day (actual dose received)
Remarks:
female
Dose / conc.:
1 630 mg/kg bw/day (actual dose received)
Remarks:
female
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: 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: weekly

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

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: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Complete histopathologic examinations were performedon control mice (core) and tested mice from the 400 mg/mL groups. In addition to gross lesions, tissue masses, and associated lymph nodes, the tissues examined included: adrenal gland, bone and marrow, brain, clitoral gland, esophagus, gallbladder (mice), heart, kidney, large intestine (cecum, colon, and rectum), small intestine (duodenum, jejunum, and ileum), liver, lung, lymph nodes (mandibular and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular stomach), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder, and uterus. Skin samples were examined in lower dose groups until a no-effect level was reached.
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
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
- no treatment related effects

BODY WEIGHT AND WEIGHT GAIN
- slight increase in body weight of males at highest doseORGAN WEIGHTS - increase in kidney weight of males but not dose dependent

GROSS PATHOLOGY - no treatment related effects

OTHER FINDINGS - epidermal hyperplasia of application site in males and females at the highest dose.
Epidermal hyperplasia occurred in 44 mg/mL females, 133 mg/mL males, and 400 mg/mL males and females. Hyperplasia of the epidermis in 400 mg/mL males and females was considered related to chemical administration. Epidermal hyperplasia was most pronounced in male mice where it typically developed as a mild multifocal nodular to papillary thickening of the epidermis. The involved epidermis was somewhat disorganized, and cells tended to be elongated (oval or columnar) rather than normal cuboidal epidermal epithelium.
Chronic inflammation of the skin occurred primarily in three control and one dosed animal of each gender. These lesions consisted of mononuclear inflammatory cells in the dermis. Chronic inflammation was frequently accompanied by a minimal epidermal hyperplasia which was clearly a reaction to the inflammation and not diagnosed separately.
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

The incidence of epidermal hyperplasia in 400 mg/mL in males and females was considered to be chemical- related.

Conclusions:
NOAEL > 440 mg a.i./kg bw male
NOAEL > 530 mg a.i. /kg bw female
Executive summary:

The repeated dermal toxicity of Sodium (xylenes and 4-ethylbenzene) sulfonates was assessed following official guideline EPA OPP 82-3 (Subchronic dermal toxicity - 90 days) similar to OECD 411. The test was perfomed on mouse and the results showed nomortality and no clinical findings related to tested substance administration. Hyperplasia of the epidermis at the site of application occurred in male and female mice from the highest dose tested group.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
other: Read across from another member of the category
Adequacy of study:
supporting study
Study period:
July 20-August 6, 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
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.
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
Deviations:
yes
Remarks:
17 day exposure
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 days

ENVIRONMENTAL 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: once

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not washed

TEST 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 delivered average daily doses of approximately 10, 30, 90, 260 and 800 mg/kg bw for males and 13, 40, 120, 330, and 1,030 mg/kg to females.
- Constant volume or concentration used: yes

VEHICLE
- Justification for use and choice of vehicle (if other than water): distilled water

USE 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
Dose / conc.:
0 mg/kg bw/day
Remarks:
Control for males and females
Dose / conc.:
10 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
30 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
90 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
260 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
800 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
13 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
40 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
120 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
330 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
1 030 mg/kg bw/day
Remarks:
Based on active ingredient, females
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: random
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily
DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: days 1, 8 and 17

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

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: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes, A necropsy was performed on all animals. The heart, right kidney, liver, lungs, right testis, and thymus were weighed.
HISTOPATHOLOGY: Yes, Histopathologic examination was restricted to skin from the site of application, skin from an untreated site, and gross lesions.

Statistics:
Kaplan-Meier method
Clinical signs:
no effects observed
Description (incidence and severity):
Only tan or brown discoloration of the skin and crusty white deposits at the application site.
In males and females, the few skin lesions observed grossly and microscopically were generally attributed to repeated clipping and were not considered related to chemical administration.
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
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Details on results:
CLINICAL SIGNS: only tan or brown discoloration of the skin and crusty white deposits at the application site.
In males and females, the few skin lesions observed grossly and microscopically were generally attributed to repeated clipping and were not considered related to chemical administration.
MORTALITY - no mortality
BODY WEIGHT AND WEIGHT GAIN - no treatment effects
ORGAN WEIGHTS - increase in liver weights relative to body weight in males and females at two highest doses; considered not to be of toxicological relevance.
GROSS PATHOLOGY - no treatment related effects
HISTOPATHOLOGY:
NON-NEOPLASTIC - no treatment related effects

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 030 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
gross pathology
mortality
organ weights and organ / body weight ratios
Key result
Dose descriptor:
NOAEL
Effect level:
>= 800 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
body weight and weight gain
clinical signs
gross pathology
mortality
organ weights and organ / body weight ratios
Critical effects observed:
not specified

See attached tables for results details.

Conclusions:
NOAEL > 1030 mg active ingredient/kg bw female
NOAEL > 800 mg active ingredient/kg bw male
Executive summary:

The repeated dermal toxicity of Sodium (xylenes and 4-ethylbenzene) sulfonates was assessed following official guideline EPA OPP 82-2 (Repeated dose dermal toxicity -21/28 days). There was a deviation due to the reduced administration period which was of 17 days. The test was perfomed on rats and the results showed no mortality, clinical signs only revelaed tan or brown discoloration of the skin and crusty white deposits at the application site. In males and females, the few skin lesions observed grossly and microscopically were generally attributed to repeated clipping and were not considered related to chemical administration.

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
other: Read across from another member of the category
Adequacy of study:
supporting study
Study period:
July 27 - August 12, 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
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.
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
Deviations:
yes
Remarks:
17 days exposure
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 days

ENVIRONMENTAL 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 start

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 microliters
- Concentration (if solution): 0, 5, 15, 44, 133 and 400 mg/mL delivered average daily doses of approximately 20, 60, 190, 540, and 1,600 mg/kg bw to males and 26, 80, 220, 680, and 2,000 mg/kg to females.
- Constant volume or concentration used: yes

VEHICLE- Justification for use and choice of vehicle (if other than water): no vehicle

USE 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
Dose / conc.:
0 mg/kg bw/day
Remarks:
males and females
Dose / conc.:
20 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
60 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
190 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
540 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
1 600 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
26 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
80 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
220 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
680 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
2 000 mg/kg bw/day
Remarks:
Based on active ingredient, females
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: random
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: days 1, 8 and 17

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

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: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
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 doses

BODY WEIGHT AND WEIGHT GAIN
- to treatment related effects

ORGAN 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 not to be of toxicological relevance

GROSS PATHOLOGY - no treatment related effects

HISTOPATHOLOGY: NON-NEOPLASTIC - no treatment related effects
Key result
Dose descriptor:
NOAEL
Effect level:
>= 2 000 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
body weight and weight gain
clinical signs
gross pathology
mortality
organ weights and organ / body weight ratios
Dose descriptor:
NOAEL
Effect level:
>= 1 600 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
clinical signs
gross pathology
mortality
organ weights and organ / body weight ratios
Critical effects observed:
not specified
Conclusions:
NOAEL > 2000 mg a.i. /kg bw female
NOAEL > 1600 mg a.i. /kg bw male
Executive summary:

The repeated dermal toxicity of Sodium (xylenes and 4-ethylbenzene) sulfonates was assessed following official guideline EPA OPP 82-2 (Repeated dose dermal toxicity -21/28 days). There was a deviation due to the reduced administration period which was of 17 days. The test was performed on mouse and the results showed no mortality, clinical signs only revelaed tan or brown discoloration of the skin and crusty white deposits at the application site. In males and females, the few skin lesions observed grossly and microscopically were generally attributed to repeated clipping and were not considered related to chemical administration.

Endpoint:
sub-chronic toxicity: dermal
Type of information:
other: Read across from another member of the category
Adequacy of study:
key study
Study period:
February 16 - May 19, 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
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.
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPP 82-3 (Subchronic Dermal Toxicity 90 Days)
Deviations:
yes
Remarks:
clinical signs recorded weekly; no food consumption results; no ophthalmoscopy; clinical chemistry did not include sodium, potassium, chloride, phoshorus or glucose
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 days

ENVIRONMENTAL 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 study

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data

TEST 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: yes

VEHICLE
- 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 data

USE 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
Dose / conc.:
0 mg/kg bw/day
Remarks:
male and females
Dose / conc.:
6 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
20 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
60 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
170 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
500 mg/kg bw/day
Remarks:
Based on active ingredient, males
Dose / conc.:
10 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
30 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
90 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
260 mg/kg bw/day
Remarks:
Based on active ingredient, females
Dose / conc.:
800 mg/kg bw/day
Remarks:
Based on active ingredient, females
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: 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: random
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes but not included in tables
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
Clinical Chemistry: urea nitrogen, creatinine, total protein, albumin, alanine aminotransferase, alkaline phosphatase, creatine kinase, sorbitol dehydrogenase, and bile acids.

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

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: No

OPHTHALMOSCOPIC 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, Blood was collected from the retroorbital sinus.
- Anaesthetic used for blood collection: Yes / carbon dioxide
- Parameters: hematocrit, hemoglobin concentration, erythrocyte and reticulocyte counts, mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, platelet count, and leukocyte count and differentials.
- Animals fasted: No data
- How many animals: 10 per dose; males and females


LINICAL 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
HISTOPATHOLOGY: Yes
Complete histopathologic examinations were performedon control rats (core) and tested rats from the 400 mg/mL groups. In addition to gross lesions, tissue masses, and associated lymph nodes, the tissues examined included: adrenal gland, bone and marrow, brain, clitoral gland, esophagus, gallbladder (mice), heart, kidney, large intestine (cecum, colon, and rectum), small intestine (duodenum, jejunum, and ileum), liver, lung, lymph nodes (mandibular and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular stomach), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder, and uterus. Skin samples were examined in lower dose groups until a no-effect level was reached.
Statistics:
Kaplan-Meier
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Minimal hyperplasia of the epidermis at the site of application occurred in male and female rats from the control groups as well as most dosed groups. The incidence of epidermal hyperplasia in 400 mg/mL males was considered to be possibly chemical-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
Immunological 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 effects

BODY WEIGHT AND WEIGHT GAIN
- no treatment related effects

FOOD CONSUMPTION
- protocol indicates measurements conducted, but not reported

HAEMATOLOGY
- no treatment related effects.
Hematology and clinical chemistry parameters of dosed groups of males and females were significantly different from those of the controls in several instances, but these differences were sporadic and did not demonstrate a treatment relationship

CLINICAL CHEMISTRY
- no treatment related effects

ORGAN 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 effects

HISTOPATHOLOGY: 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/day (actual dose received)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
clinical signs
gross pathology
mortality
organ weights and organ / body weight ratios
Dose descriptor:
NOAEL
Effect level:
>= 800 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
clinical signs
gross pathology
mortality
organ weights and organ / body weight ratios
Critical effects observed:
not specified

The incidence of epidermal hyperplasia in 400 mg/mL males was considered to be possibly chemical-related.

Conclusions:
NOAEL > 500 mg a.i./kg bw for males
NOAEL > 800 mg a.i./kg bw for females
Executive summary:

The repeated dermal toxicity of Sodium (xylenes and 4-ethylbenzene) sulfonates was assessed following official guideline EPA OPP 82-3 (Subchronic dermal toxicity - 90 days) similar to OECD 411. The test was performed on rats and the results showed no mortality and minimal hyperplasia of the epidermis at the site of application occurred in male and female rats from the control groups as well as most dosed groups.

Endpoint:
sub-chronic toxicity: dermal
Type of information:
other: Read across from another member of the category
Adequacy of study:
key study
Study period:
February 23 - May 26, 1988
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
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.
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPP 82-3 (Subchronic Dermal Toxicity 90 Days)
Deviations:
yes
Remarks:
clinical signs reported weekly; no food consumption; no ophthalmoscopy, no clinical chemisty; no haematology
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 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5 to 23.9
- Humidity (%): 15 to 63
- Air changes (per hr): 10 minimum
- Photoperiod (hrs dark / hrs light): 12 / 12
IN-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 study

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data

TEST 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: yes

VEHICLE
- 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 data

USE 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
Dose / conc.:
0 mg/kg bw/day
Remarks:
male and females
Dose / conc.:
17 mg/kg bw/day (actual dose received)
Remarks:
male
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Remarks:
male
Dose / conc.:
140 mg/kg bw/day (actual dose received)
Remarks:
male
Dose / conc.:
440 mg/kg bw/day (actual dose received)
Remarks:
male
Dose / conc.:
1 300 mg/kg bw/day (actual dose received)
Remarks:
male
Dose / conc.:
20 mg/kg bw/day (actual dose received)
Remarks:
female
Dose / conc.:
60 mg/kg bw/day (actual dose received)
Remarks:
female
Dose / conc.:
170 mg/kg bw/day (actual dose received)
Remarks:
female
Dose / conc.:
530 mg/kg bw/day (actual dose received)
Remarks:
female
Dose / conc.:
1 630 mg/kg bw/day (actual dose received)
Remarks:
female
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: 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: weekly

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No

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: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Complete histopathologic examinations were performedon control mice (core) and tested mice from the 400 mg/mL groups. In addition to gross lesions, tissue masses, and associated lymph nodes, the tissues examined included: adrenal gland, bone and marrow, brain, clitoral gland, esophagus, gallbladder (mice), heart, kidney, large intestine (cecum, colon, and rectum), small intestine (duodenum, jejunum, and ileum), liver, lung, lymph nodes (mandibular and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach (forestomach and glandular stomach), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder, and uterus. Skin samples were examined in lower dose groups until a no-effect level was reached.
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
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
- no treatment related effects

BODY WEIGHT AND WEIGHT GAIN
- slight increase in body weight of males at highest doseORGAN WEIGHTS - increase in kidney weight of males but not dose dependent

GROSS PATHOLOGY - no treatment related effects

OTHER FINDINGS - epidermal hyperplasia of application site in males and females at the highest dose.
Epidermal hyperplasia occurred in 44 mg/mL females, 133 mg/mL males, and 400 mg/mL males and females. Hyperplasia of the epidermis in 400 mg/mL males and females was considered related to chemical administration. Epidermal hyperplasia was most pronounced in male mice where it typically developed as a mild multifocal nodular to papillary thickening of the epidermis. The involved epidermis was somewhat disorganized, and cells tended to be elongated (oval or columnar) rather than normal cuboidal epidermal epithelium.
Chronic inflammation of the skin occurred primarily in three control and one dosed animal of each gender. These lesions consisted of mononuclear inflammatory cells in the dermis. Chronic inflammation was frequently accompanied by a minimal epidermal hyperplasia which was clearly a reaction to the inflammation and not diagnosed separately.
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

The incidence of epidermal hyperplasia in 400 mg/mL in males and females was considered to be chemical- related.

Conclusions:
NOAEL > 440 mg a.i./kg bw male
NOAEL > 530 mg a.i. /kg bw female
Executive summary:

The repeated dermal toxicity of Sodium (xylenes and 4-ethylbenzene) sulfonates was assessed following official guideline EPA OPP 82-3 (Subchronic dermal toxicity - 90 days) similar to OECD 411. The test was perfomed on mouse and the results showed nomortality and no clinical findings related to tested substance administration. Hyperplasia of the epidermis at the site of application occurred in male and female mice from the highest dose tested group.

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

Justification for classification or non-classification

Based on the reported findings from a variety of repeat dose studies by both oral and dermal routes of exposure, there is no justification for hazard classification.