Alcohols, C9-11, branched and linear, ethoxylated, sulfates, sodium salts

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study was conducted in methods comparable to OECD guideline 411 " Subchronic Dermal Toxicity: 90-day Study". 25 animals per sex per dose, only two dose levels evaluated. Not GLP.

Justification for type of information:

Refer to the Category Approach Justification document provided in IUCLID6 Section 13.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1978

Report date:

1978

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)

Deviations:

yes

Remarks:

25 animals per sex per dose, only two dose levels evaluated.

GLP compliance:

no

Remarks:

However, quality reviews of the study were performed and documented.

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Alcohols, C10-16, ethoxylated, sulfates, sodium salts

EC Number:

500-223-8

EC Name:

Alcohols, C10-16, ethoxylated, sulfates, sodium salts

Cas Number:

68585-34-2

Test animals

Species:

mouse

Strain:

other: ICR- Swiss CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Weight at study initiation: female mice: 21 to 31 g, male mice: 28-31 g
- Housing: individually housed in steel hanging wire cages
- Diet: Wayne rodent diet, ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-26
- Humidity (%): 36-61
- Air changes (per hr): 9.1 and 9

IN-LIFE DATES: From: 1977-08-31 To: 1977-11-30

Administration / exposure

Type of coverage:

not specified

Vehicle:

not specified

Details on exposure:

TEST SITE
- Area of exposure: Dorsal area (2 X 3 cm²)
- Time intervals for shavings or clipplings: clipped

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

91 days

Frequency of treatment:

5 per week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
2.38 mg/day
Basis:
other: total amount applied/day

Doses / concentrations 2

Remarks:

Doses / Concentrations:
6.91 mg/day
Basis:
other: total amount applied/day

No. of animals per sex per dose:

25

Control animals:

yes, sham-exposed

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked: general health, mortality, and gross skin irritation effects

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD EFFICIENCY: No

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: After termination of the study, 5 females from each group were submitted to the study sponsor for in vitro skin penetration studies. Group 3, 4, and 6 animals were submitted on Day 90, Group 5 and 7 animals were submitted on Day 91 and Group 2 and 4 animals were submitted on Day 92 after dose initiation.

Sacrifice and pathology:

GROSS PATHOLOGY: After 28 days (21 dermal applications) 10 male and 10 females from each group were sacrificed and necropsied. The remaining animals continued on the treatment until the termination of the study. At study termination 5 animals from each dose group were submitted to the sponsor for skin penetration studies the remaining animals were sacrificed and necropsied. Organs collected and examined: brain, pituitary, thyroid, thymus, large intestine, small intestine, heart, trachea, axillary lymph nodes, stomach, esophagus, uterus, skin from treated area and dorsal untreated area, mesenteric lymph nodes, lungs, liver, spleen, kidneys, adrenals, urinary bladder, ovary, testis, eyes, aorta, pancreas, and carcass.

HISTOPATHOLOGY: Yes - above organs examined histologically.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Dermal irritation:

effects observed, treatment-related

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
- 28 day interim gross skin observations.
2.38 mg/day dose group: No dermal effects with the exception of two animals which exhibited scaling and erythema in the dorsal area. These effects were not significantly different from control animals.
6.91 mg/day dose group: No dermal effects with the exception of two animals which exhibited scaling and erythema in the dorsal area. These effects were not significantly different from control animals.

-91 day gross skin observations.
Animals treated with 2.38 mg/day did not exhibit any gross compound related irritative effects after 91 days of treatment.
The skin of animals treated with 6.91 mg/day exhibited erythema and scaling in most animals compared to no significant effect at 28 days.

BODY WEIGHT AND WEIGHT GAIN
The weekly average body weights of the male and female mice in both dose groups were normal and comparable to the vehicle control group.

GROSS PATHOLOGY
- 28 day interim sacrifice: The organ and tissue lesions identified were few, equally distributed between the dose groups and were not of a consistent type. No effects were considered to be substance related.

- 91 day terminal sacrifice:
2.38 mg/day dose group: The dorsal skin was noted as vascular in two animals. However, the compound was noted as not caused any gross compound related irritative effects. No other treatment related organ or tissue related gross lesions were identified.
6.91 mg/day dose group: The dorsal skin was noted as vascular in two animals. No other treatment related organ or tissue related gross lesions were identified.

HISTOPATHOLOGY: NON-NEOPLASTIC
- 28 day interim sacrifice
Animals treated with 2.38 mg or 6.91 mg of the test substance exhibited comparable histological skin changes as controls at 28 days.

-91 day terminal sacrifice:
Microscopic evaluation revealed a comparable appearance of dermal effects in control mice and mice treated with 2.38 mg of the test substance. Mice treated with 6.91 mg test substance had minimal to slight acanthosis in 12/25 mice.

Effect levels

1

Dose descriptor:

NOEL

Remarks:

local

Effect level:

2.38 other: mg/day

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: No treatment-related effects observed.

2

Dose descriptor:

NOEL

Remarks:

local

Effect level:

68 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: No treatment-related effects observed.

3

Dose descriptor:

LOEL

Remarks:

local

Effect level:

6.91 other: mg/day

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: Minimal to slight acanthosis at site of application at study termination.

4

Dose descriptor:

NOEL

Remarks:

systemic

Effect level:

>= 6.91 other: mg/day

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: No treatment-related effects observed.

5

Dose descriptor:

NOEL

Remarks:

systemic

Effect level:

>= 195 mg/kg bw/day (nominal)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: No treatment-related effects observed.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Gonadal tissues were examined for both gross pathology and histopathology and no treatment-related effects were detected.

Applicant's summary and conclusion

Conclusions:

The test substance did not produce dermal irritation after 91 days of treatment at a dose of 2.38 mg/day. Increasing the dose to 6.91 mg/day over 91 days did induce some irritation effects. No systemic effects were identified at either dose level.

Executive summary:

The objective of the study was to obtain scientific data to determine the histopathological effects of the skin at treatment sites after repeated dermal exposure to the test substance over 91 days with a 28 day interim sacrifice.

Fifty ICR-Swiss CD-1 mice (25M, 25F) per group were assigned to each of the following treatment groups. The dose volume for each group was 0.1mL with the control group being sterile water, a 2.38 mg/day test group, and a 6.91 mg/day test group.

An area of 2 x 3 cm of the dorsal area of all animals was clipped and treated with the appropriate dose five times per week.

All animals were observed daily for signs of general health, mortality and gross skin irritation effects. Gross signs of toxicity and body weights were recorded on a weekly basis throughout the study.

After 28 days (21 dermal applications) 10 males and 10 females from each group were sacrificed and necropsied. The remaining animals continued on the treatment regimen until the termination of the study. At study termination (90-92 days from initiation of the study), 5 females from each group were sent to the sponsor for in-vitro skin penetration studies. The remainder of the animals, were sacrificed and necropsied.

At the 28 and 91 day necropsies, the following tissues were examined and preserved in formalin: brain, pituitary, thyroid, thymus, small and large intestine, heart, trachea, axillary and mesenteric lymph nodes, stomach, esophagus, uterus, skin from treated and dorsal non-treated areas, lungs, liver, spleen, kidneys, adrenals, urinary bladder, ovary, testis, eyes, aorta, pancreas, and carcass. The skin tissues from treated animals and dermal non-treated areas were examined histopathologically.

No mortalities were attributed to treatment and there were no significant differences in body weights in any animals throughout the study. Gross necropsies at interim or terminal sacrifice did not reveal any compounds related lesions with the exception of skin effects at the site of treatment.

At the 28 day interim evaluation, repeated dermal applications of 2.38 mg/day and 6.91 mg/day of the test substance did not result in any gross skin effects with exception of two animals per group, which exhibited scaling and erythema or scales in the dorsal area which were not deemed to be of significance. Histopathologic examinations of skin from animals treated with 2.38 mg/day and 6.91 mg/day of the test substance exhibited comparable skin effects as controls.

Furthermore, animals treated with 2.38 mg/day of the test substance did not exhibit any gross or microscopic compound related irritative effects after 91 days of treatment. However, mice treated with 6.91 mg of the test substance showed minimal or slight acanthosis in 12 of the 25 mice.

Gonadal tissues were examined for both gross pathology and histopathology and no treatment-related effects were detected.

The test substance did not produce dermal irritation after 91 days of treatment at a dose of 2.38 mg/day. Increasing the dose to 6.91 mg/day over 91 days did induce some irritation effects. No systemic effects were identified at either dose level.