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Repeated dose toxicity: dermal

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Administrative data

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.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1998
Report date:
1998

Materials and methods

Test guidelineopen allclose all
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

Test material

Constituent 1
Reference substance name:
Sodium (xylenes and 4-ethylbenzene) sulfonate
EC Number:
701-037-1
Molecular formula:
-
IUPAC Name:
Sodium (xylenes and 4-ethylbenzene) sulfonate

Test animals

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

Administration / exposure

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
Doses / concentrationsopen allclose all
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

Examinations

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

Results and discussion

Results of examinations

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

Effect levels

open allclose all
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

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.