Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study based on OECD guideline 410. Read across from SCI to SLMI

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report date:
1991

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
No ophthalmological observations were performed.
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Reference substance name:
Fatty acids, coco, 2-sulfoethyl esters, sodium salts
EC Number:
263-052-5
EC Name:
Fatty acids, coco, 2-sulfoethyl esters, sodium salts
Cas Number:
61789-32-0
Molecular formula:
C10H20O5S.Na-C20H40O5S.Na
IUPAC Name:
Fatty acids, coco, 2-sulfoethyl esters, sodium salts
Details on test material:
- Name of test material: Sodium cocoyl isethionate (SCI)
- Analytical purity: 72.45%
- Lot/batch No.: 1247
- Stability under test conditions: Stable for the duration of the study

Test animals

Species:
rat
Strain:
other: Charles River COBS CDR
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, MI, U.S.
- Age at study initiation: 5-7 weeks
- Weight at study initiation: 176-200g

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: Clipped dorsal area, 32 cm2 for body weights below 350 g, 36 cm2 for body weights of 350 to 400 g and 40 cm2 for body weights of 400 g
- Type of wrap if used: Gauze
- Time intervals for shavings or clipplings:


REMOVAL OF TEST SUBSTANCE
- Washing (if done):
- Time after start of exposure:


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.08 g a.i./kg (1.0% w/w), 0.91 g a.i./kg (14.0% w/w) and 2.07 g a.i./kg (36.0% w/w)


VEHICLE
- Millipore filtered water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Test substance concentrations and stability of the test substance in aqueous dose suspensions were verified each week
Duration of treatment / exposure:
6 hours /day
Frequency of treatment:
Daily for 6 hours/day
Doses / concentrations
Remarks:
Doses / Concentrations:
0.08 g a.i./kg (1.0% w/w), 0.91 g a.i./kg (14.0% w/w) and 2.07 g a.i./kg (36.0% w/w)
Basis:
nominal per unit body weight
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes, concurrent vehicle
Positive control:
Not performed

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes. Twice daily


DETAILED CLINICAL OBSERVATIONS: Yes. Twice daily


DERMAL IRRITATION (if dermal study): Yes.Twice daily observations, once in the morning, once in the afternoon. Signs of local irritation were recorded using the Draize method of scoring. Skin reactions at the test site were recorded prior to treatment.

BODY WEIGHT: Yes. At start of test, weekly and prior to sacrifice


FOOD CONSUMPTION: Recorded weekly


WATER CONSUMPTION: No


OPHTHALMOSCOPIC EXAMINATION: Not recorded


HAEMATOLOGY: Yes. All animals at sacrifice (18-20 hour fast prior to sampling).
Parameters: Haemoglobin, mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), mean corpuscular volume (MCV), packed cell volume (PCV), platelet count, prothrombin time, red blood cell (RBC) count, total and differential white blood cell (WBC) count.


CLINICAL CHEMISTRY: Yes. All animals at sacrifice (18-20 hour fast prior to sampling).
Parameters: A/G ratio, albumin, blood urea nitrogen, creatinine, 5¿-nucleotidase, globulin, glucose (fasted), lactate dehydrogenase, serum alanine aminotransferase, serum aspartate aminotransferase, serum calcium, serum chloride, serum phosphorus, serum potassium/sodium, sorbitol dehydrogenase, total bilirubin, total cholesterol, total serum protein and triglycerides.


URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS AND HISTOPATHOLOGY: Yes. Adrenal glands, aorta, brain, caecum, colon, duodenum, epididymis, oesophagus, eyes (2), femur, heart, ileum, jejunum, kidneys (2), liver, lungs, mammary gland, mesenteric lymph nodes, ovaries and fallopian tube, pancreas, peripheral nerve (sciatic), pituitary, prostate gland, rectum, salivary glands, seminal vesicles, skeletal muscles, skin and subcutis, spinal cord, spleen, sternum, stifle joint, stomach, testes, thymus, thyroid/parathyroid, tissue masses/abnormal tissue, trachea, urinary bladder, uterus and cervix.
Other examinations:
None
Statistics:
Dunn¿s Test, Jonckheere-Terpstra¿s Test, Dunnett¿s Test and Regression analysis were used as appropriate.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
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:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY
Very slight erythema (+1) was observed in two males during weeks 3 and 4. Dermal irritation in females was observed in each treatment group during week 1 of the study. Very slight erythema was observed in four females in the 1.0% (w/w) and 14.0% (w/w) treatment groups during the first week but no irritation was observed during the remainder of the study. Females in the 36.0% (w/w) group showed very slight and well-defined erythema (+2) which showed a significant difference from the control on days 4, 5, 6 and 7 of the study only Very slight oedema (+1) was also observed in females in this group but the difference was not significant.
Mortality: No treatment related effects. One male rat in the vehicle control group and one male rat in the 14.0% (w/w) group died during the study but these deaths were attributed to mechanical trauma due to struggling during the gauze wrapping procedure.

BODY WEIGHT AND WEIGHT GAIN
No significant difference between any group means during the test. Individual body weight data showed transient low weight gains and losses for males and females in all test groups, including the control.

FOOD CONSUMPTION
Males in the 14.0% (w/w) group showed a significant (p<0.05) increase in food consumption during weeks 1 and 4 of the test. There were no other significant differences in food consumption.

HAEMATOLOGY
Males showed a significant (p<0.05) decrease in average haemoglobin in the 36.0% (w/w) group. However, the effect was marginal and historical control data showed the haemoglobin concentration to be within the normal range for this species. All other results showed no treatment related effects.

CLINICAL CHEMISTRY
Average serum glucose concentration was significantly (p<0.05) lower in males in the 36.0% (w/w) group. Analysis showed that 3 of the ten rats showed values below that of the control. No indication of adverse treatment related effects were recorded for any other parameter tested. All other results showed no treatment related effects.

ORGAN WEIGHTS
A significant (p<0.05) increase in relative heart weight for males in the 36.0% (w/w) group was observed. However, historical control data showed the weights to be within the normal range. No other parameters were significantly different in males.
In females, the relative organ weight to final body weight showed a significant (p<0.05) increase in relative adrenal weight in the 36.0% (w/w) group. Again, historical control data showed the weights to be within the normal range. No other parameters were significantly different in females.

GROSS AND HISTOPATHOLOGY: Necropsy revealed red patchy areas on the lungs of rats occurring randomly throughout the control and test groups, with one rat showing pale lungs in the 1.0% (w/w) test group. None of these findings were considered to be treatment related.
Histopathology results showed no treatment related effects as all findings were considered to be incidental, except microscopic findings in the liver of one male in the 36.0% (w/w) treatment which showed fibrous trabeculae, increased Kupffer cell macrophages and lipofuscin pigment and one female in the vehicle control which showed coagulative necrosis of one liver lobe. These findings were determined to be due to mechanical trauma.
Excised skin sections showed slight microscopic differences in morphology between treated and untreated sites in each of the control and test groups. Skin from the treated sites showed a slight thickening of the epithelium and slightly increased cornification. The basal cell layer showed a slight increase in the mitotic rate in the treated skin sites compared to the untreated sites. These differences were attributed to the vehicle and semi-occlusive gauze dressing since there were no difference between the vehicle control and SCI treated groups. In addition, no inflammatory changes were observed.

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
2.07 other: g.a.i./kg
Sex:
male/female
Basis for effect level:
other: Local skin effects
Dose descriptor:
NOAEL
Effect level:
2.07 other: g a.i./kg (36.0% w/w)
Sex:
male/female
Basis for effect level:
other: Systemic toxicity
Dose descriptor:
NOAEL
Effect level:
0.91 other: g a.i./kg (14.0% w/w)
Sex:
male/female
Basis for effect level:
other: Local skin effects, based on transient irritation

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

There was no evidence of systemic toxicity in the treated animals during the test. Two animals died during the study, however, these deaths were attributed to mechanical trauma resulting from the semi-occlusive wrap procedure and not to test substance related effects. Observations revealed slight erythema and very slight oedma in 4/10 males at the highest test dose and in females in the highest test dose, respectively. Both findings were minimal and decreased towards the end of the study. Haematology and clinical chemistry results did not show treatment related effects during the test. Necropsy did not reveal any abnormal morphologic changes attributable to the test substance.

Clinical observation results of repeated dose toxicity (dermal) 28 days

Observation

Vehicle control

SCI, 0.08 g/kg

SCI, 0.91 g/kg

SCI, 2.07 g/kg

 

M

F

M

F

M

F

M

F

Number of animals examined

10

10

10

10

10

10

10

10

Clinical observations

Mortality

0

0

0

0

1

0

0

0

Swollen snout/broken incisor

1

0

0

0

0

0

0

0

Alopecia on forepaws

0

0

0

0

0

1

0

0

Chomodacryorrhea

1

0

0

0

0

0

0

0

Scabs on skin

1

0

1

0

0

1

0

0

Hematuria

0

0

0

0

0

0

1

0

Mean body weight gain during test

52.8 ± 22.7

20.7 ± 14.3

48.3 ± 14.7

18.2 ± 13.5

64.8 ± 24.0

21.1 ± 7.9

36.8 ± 19.0

16.5 ±

9.4

Food consumption (g/rat/day)

23.2 ± 1.9

16.5 ± 1.3

23.8 ± 1.3

17.0 ± 1.1

25.4 ± 2.6a

16.9 ± 0.8

22.4 ±

1.2

17.4 ±

1.1

Clinical chemistry*

Glucose (mg/dL)

118.7 ± 16.5

115.7 ± 15.0

114.9 ± 12.1

116.4 ± 10.0

118.9 ± 15.3

123.3 ± 8.0

101.7 ± 8.8d

116.0 ± 21.7

Haematology*

Haemoglobin (g/dL)

16.6 ± 0.7

15.7 ± 0.7

16.5 ± 0.8

15.8 ± 0.5

15.8 ± 0.6

15.6 ± 0.5

15.8 ± 0.8b

15.6 ±

 0.5

Haematocrit (%)

44.8 ± 2.0

42.4 ± 1.8

44.4 ± 2.6

42.6 ± 1.9

41.6 ± 2.0c

42.8 ± 2.3

42.5 ±

 2.4

42.7 ±

 1.6

Organ weights relative to body weight*

Adrenals

0.024 ± 0.006

0.034 ±0.006

0.025 ± 0.005

0.039 ± 0.006

0.0024 ± 0.005

0.037 ± 0.004

0.025 ± 0.005

0.042 ± 0.008e

Heart

0.36 ± 0.02

0.40 ± 0.04

0.36 ± 0.03

0.41 ± 0.04

0.37 ± 0.03

0.39 ± 0.03

0.39 ± 0.03e

0.42 ± 0.04

* Significantly different from the control group, p<0.05 (Dunnett¿s test).

bSignificantly different from the control group, p<0.05 (Dunnett¿s test) and significantly decreased trend with dose observed at p=0.004 (Regression Analysis).

cSignificantly different from the control group, p<0.01 (Dunnett¿s test) and significantly decreased trend with dose observed at p=0.014 (Regression Analysis).

dSignificantly different from the control group, p<0.05 (Dunn¿s test).

eSignificantly different from the control group, p<0.05 (Dunnett¿s test). Significantly increased trend with dose observed at p=0.005 for male relative heart weight and at p=0.018 for female relative adrenal weight (Regression Analysis).

* Only data with significant differences shown.

Dermal irritancy results of repeated dose toxicity (dermal) 28 days ¿ male rats

Erythema

Oedema

 

0

+1

+2

+3

0

+1

+2

+3

Week 1

Vehicle control

10/10

-

-

-

10/10

-

-

-

SCI, 0.08 g/kg

10/10

-

-

-

10/10

-

-

-

SCI, 0.91 g/kg

10/10

-

-

-

10/10

-

-

-

SCI, 2.07 g/kg

10/10

-

-

-

10/10

-

-

-

Week 2

Vehicle control

10/10

-

-

-

10/10

-

-

-

SCI, 0.08 g/kg

10/10

-

-

-

10/10

-

-

-

SCI, 0.91 g/kg

10/10

-

-

-

10/10

-

-

-

SCI, 2.07 g/kg

10/10

-

-

-

10/10

-

-

-

Week 3

Vehicle control

10/10

-

-

-

10/10

-

-

-

SCI, 0.08 g/kg

10/10

-

-

-

10/10

-

-

-

SCI, 0.91 g/kg

9/9

-

-

-

9/9

-

-

-

SCI, 2.07 g/kg

8/10

2/10

-

-

10/10

-

-

-

Week 4

Vehicle control

10/10

-

-

-

10/10

-

-

-

SCI, 0.08 g/kg

10/10

-

-

-

10/10

-

-

-

SCI, 0.91 g/kg

9/9

-

-

-

9/9

-

-

-

SCI, 2.07 g/kg

8/10

2/10

-

-

10/10

-

-

-

Dermal irritancy results of repeated dose toxicity (dermal) 28 days ¿ female rats

 

Erythema

Oedema

 

0

+1

+2

+3

0

+1

+2

+3

Week 1

Vehicle control

10/10

-

-

-

10/10

-

-

-

SCI, 0.08 g/kg

6/10

4/10

-

-

10/10

-

-

-

SCI, 0.91 g/kg

6/10

4/10

-

-

10/10

-

-

-

SCI, 2.07 g/kg

3/10

2/10

5/10*

-

5/10

5/10

-

-

Week 2

Vehicle control

10/10

-

-

-

10/10

-

-

-

SCI, 0.08 g/kg

10/10

-

-

-

10/10

-

-

-

SCI, 0.91 g/kg

10/10

-

-

-

10/10

-

-

-

SCI, 2.07 g/kg

5/10

3/10

2/10

-

7/10

3/10

-

-

Week 3

Vehicle control

10/10

-

-

-

10/10

-

-

-

SCI, 0.08 g/kg

10/10

-

-

-

10/10

-

-

-

SCI, 0.91 g/kg

10/10

-

-

-

10/10

-

-

-

SCI, 2.07 g/kg

6/10

2/10

2/10

-

9/10

1/10

-

-

Week 4

Vehicle control

10/10

-

-

-

10/10

-

-

-

SCI, 0.08 g/kg

10/10

-

-

-

10/10

-

-

-

SCI, 0.91 g/kg

10/10

-

-

-

10/10

-

-

-

SCI, 2.07 g/kg

6/10

4/10

-

-

10/10

-

-

-

* Significantly different from the control group, at p<0.05 on days 4, 5, 6 and 7 (Dunnett¿s test).

  Significantly increased trend with dose observed (Jonckheere-Terpstra¿s test).

Applicant's summary and conclusion

Conclusions:
There was no evidence of systemic toxicity in the treated animals during the study up to the highest dose of 2.07 g/kg/day. Observations revealed very slight erythema in a few males at the highest dose and slight erythema and oedema in females at the highest dose. Both findings decreased in incidence and severity towards the end of the study.