Benzenesulfonic acid, 4-(1-methylethyl)-, potassium salt (1:1)

Endpoint summary

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

Reference

Reference 1

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.

Dose descriptor:

NOAEL

Effect level:

> 500 - < 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other:

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 corresponding to > 500 < 1000 mg/kg bw day

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.

Reference 2

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

Dose descriptor:

NOAEL

Effect level:

> 250 - <= 500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other:

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 > 0.5 ≤ 1% in diet corresponding to > 250 ≤ 500 mg/kg bw

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.

Reference 3

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.

Reference 4

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.

Reference 5

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

Dose descriptor:

NOAEL

Effect level:

> 500 - < 1 000 mg/kg bw (total dose)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other:

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 corresponding to > 500 ≤ 1000 mg/kg bw day

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.

Reference 6

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

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

Reference

Reference 1

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.

Reference 2

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.

Reference 3

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.

Reference 4

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

Reference

Reference 1

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.

Reference 2

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.

Reference 3

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.

Reference 4

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.

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.