Registration Dossier

Administrative data

Description of key information

In a 90d oral study on rats (Braun, 2009) the read across material Sodium Isethionate acheived a NOAEL of 200mg/kg bw/d;  426mg/kg bw/d (converted to SLMI)
In a 28d oral study on rats (Lea, 1995) the read across material Sodium Coco Isethionate acheived a NOAEL of 1000mg/kg bw/d; 1092mg/kg bw/d (converted to SLMI)
In a 28d dermal study on rats (Greico, 1991) the read across material Sodium Coco Isethionate acheived a NOAEL of 2070mg/kg bw/d; 2260mg/kg bw/d (conerted to SLMI)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2008-08-14 till 2009-05-16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories Ltd., Füllinsdorf / Switzerland
- Age at study initiation: Ca. 7 weeks
- Weight at study initiation:
Males: 183 g to 202 g (mean 194 g)
Females: 138 g to 156 g (mean 146 g)
- Fasting period before study: for approximately 18 hours before blood sampling but allowed access to water ad libitum.
- Housing: In groups of five in Makrolon type-4 cages with wire mesh tops and standard softwood bedding
- Diet (e.g. ad libitum): Pelleted standard Kliba Nafag 3433 rat / mouse maintenance diet, ad libitum
- Water (e.g. ad libitum): Community tap-water from Itingen was available, ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70%).
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The dose formulations were prepared weekly. Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.


VEHICLE
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): 10 mL/kg body weight
- Purity: bidistilled water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
After experimental start, samples of the control group as well as three samples (top, middle and bottom) of about 2 g of each concentration were taken prior to dosing for analysis of homogeneity and concentration and stability. Samples of about 2 g of each concentration were taken during week 3, 8 and 13 after commencement of dosing to confirm homogeneity and concentration. The test item was used as analytical standard.
The test item concentrations were determined by IC coupled to a conductivity detector. The content was determined by external standard quantitation referring to the area under the test item peak.
Duration of treatment / exposure:
91/92 days
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
50 mg/kg bw
Basis:
actual ingested
Remarks:
Doses / Concentrations:
200 mg/kg bw
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
Group 1: 15 males and 15 females (control group, where 10 animals were satellite A and the other 5 animals formed satellite B)
Group 2: 10 males and 10 females
Group 3: 10 males and 10 females
Group 4: 15 males and 15 females ( 10 animals were satellite A and the other 5 animals formed satellite B)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were selected based on a previous dose range finding toxicity study in Wistar rats (Harlan Laboratories Study B96974).
- Rationale for selecting satellite groups: the animals were allowed to a 28-day treatment-free recovery period
- Post-exposure recovery period in satellite groups: 28 days
Positive control:
No
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once before commencement of administration as well as twice daily on days 1 to 3, once daily from on day 4 to the end of the treatment period, and once daily during days 1 to 28 (recovery period).
- Cage side observations checked: appearance (piloerection, salivation, hunched posture), motor (ataxia, tremor, prostration), behaviour (hyperactivity, somnolence), respiration (dyspnea, tachypnea, bradypnea)


BODY WEIGHT: Yes
- Time schedule for examinations: weekly during acclimatization, treatment and recovery periods and before necropsy


FOOD CONSUMPTION:
once during the acclimatization period and weekly thereafter


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: once in all animals during acclimatization period; once in animals of the control and high dose groups, as well as in animals of the middle dose groups if test item-related changes were seen in the high dose (treatment period); once in the remaining animals of the control and high dose groups during the recovery period.


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the dosing period, and after 17 weeks (satellite B animals)
- Anaesthetic used for blood collection: Yes (under light isoflurane anesthesia)
- Animals fasted: Yes (for approximately 18 hours before blood sampling but allowed access to water ad libitum)
- How many animals: all group animals at week 13, while 6 males and 6 females/group after 17 weeks, only groups 0 and 4
- Parameters checked in table No 1 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the dosing period, and after 17 weeks (satellite B animals)
- Animals fasted: Yes (for approximately 18 hours before blood sampling but allowed access to water ad libitum)
- How many animals: all group animals at week 13, while 6 males and 6 females/group after 17 weeks, only groups 0 and 4
- Parameters checked in table No. 2 were examined.


URINALYSIS: Yes
- Time schedule for collection of urine: during the 18 hours fasting period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table No. 3 were examined.


NEUROBEHAVIOURAL EXAMINATION: No

OTHER:
- functional observational battery (week 13)
- grip strength (week 13)
- locomotor activity (week 13)
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table No. 4)
HISTOPATHOLOGY: Yes (see table No. 4)

Statistics:
The following statistical methods were used to analyze body weight, locomotor activity, fore- and hindlimb grip strength, clinical laboratory data, organ weights and ratios as well as macroscopic findings:
- The Dunnett-test
- The Steel-test
- Fisher's exact-test
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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
no effects observed
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
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
All rats survived until scheduled necropsy.
No test item-related clinical signs of toxicological relevance were noted during daily observations or weekly observations (weeks 1 - 12) at any dose level.

BODY WEIGHT AND WEIGHT GAIN
A trend to slightly lower mean absolute and relative body weights values were ascertained in males treated with 1000 mg/kg/day when compared with controls. This was considered to be a mild test item-related change. All other animals were unaffected.

FOOD CONSUMPTION
No differences of toxicological relevance were noted in the mean daily food consumption.


OPHTHALMOSCOPIC EXAMINATION
None of the ophthalmoscopic findings noted after 13 weeks’ treatment in rats treated with 1000 mg/kg/day were considered to be related to the test item.

HAEMATOLOGY
A number of test item-related differences were noted in the hematology parameters of the rats treated with 1000 mg/kg/day. These changes were manifested by reduced mean corpuscular hemoglobin concentration values, elevated mean absolute and relative reticulocyte counts, and a ‘left-shift’ in the reticulocyte maturity indices indicative of increased reticulocyte turnover. Females treated with 1000 mg/kg/day also had reduced hemoglobin distribution width. All remained within the upper limits of the historical control data. Both sexes showed slightly elevated methemoglobin. In the absence of differences which exceeded the historical control values and/or Heinz body formation, these were considered to be of no toxicological relevance The remaining changes noted in animals at 1000 mg/kg/day (elevated mean absolute lymphocytes and monocytes in females) did not exceed the ranges of the historical control values or were not accompanied by concomitant changes in related parameters and were therefore considered to be incidental. All changes noted at 200 mg/kg/day or at 50 mg/kg/day were considered to be incidental. No test item-related findings remained nor were late effects in the animals previously treated with 1000 mg/kg/day noted after 4 weeks of recovery.

CLINICAL CHEMISTRY
Test item-related changes in the parameters of the clinical biochemistry were noted, and included reduced glucose levels in males and females at 1000 mg/kg/day. Although some outlying values were found, the overall mean lactate dehydrogenase activity was generally higher in males and females at 1000 mg/kg/day. The mean total bilirubin level was elevated in males and females at 1000 mg/kg/day when compared with the respective contr ls, possibly indicating some degree of cell friability. Elevated mean cholesterol levels and phospholipid levels were noted in males, whereas these
parameters were only marginally elevated in females at this dose level. In rats treated previously with 1000 mg/kg/day, the mean cholesterol level remained elevated after the recovery period in males when compared with the controls. Aspartate aminotransferase activity was elevated in females treated with 1000 mg/kg/day, whereas alanine aminotransferase activity was elevated in males of this dose level when compared with their respective controls. Differences in electrolytes included elevated sodium levels in males at 200 and 1000 mg/kg/day and in females at 50 mg/kg/day and 1000 mg/kg/day, reduced potassium levels in males at 1000 mg/kg/day and females at 200 mg/kg/day and 50 mg/kg/day, increased calcium levels at 1000 mg/kg/day, increased phosphorus in females at 1000 mg/kg/day, and increased chloride levels in males at 200 mg/kg/day were noted. The mean total protein levels were elevated in males and females; both values exceeded the upper limit of the historical control values.

URINALYSIS
Changes in the urine parameters of males treated with 1000 mg/kg/day included elevated mean urine volume and reduced mean relative density. Despite two marked outliers, the differences noted in both parameters of the remaining males at 1000 mg/kg/day also diverged from the values recorded in the control males and were considered to be test item related. The mean urinary pH values of the males treated with 1000 mg/kg/day and 200 mg/kg/day were lower than the control males and this was also considered to be a test item-related change. The protein level and ketones were reduced in males and females treated with 1000 mg/kg/day when compared with the controls. These changes were not considered to be associated with any toxicological relevance. The mean relative density and the mean protein level were also significantly lower in females at 200 mg/kg/day (p<0.05), but considered to be toxicologically irrelevant. All other parameters showed either minor differences which were unrelated to dose or were unaffected. No test item-related findings remained nor were late effects in the animals previously treated with 1000 mg/kg/day noted after 4 weeks of recovery.


ORGAN WEIGHTS
Reduced thymus weights were noted in test item treated males at all dose levels. A similar but less marked trend for lower thymus weights were noted in the test item-treated females. The mean spleen-to-body weight ratio of the females treated with 1000 mg/kg/day was elevated when compared with controls. The mean absolute spleen weight and the mean spleen-to-brain weight ratio were slightly elevated. The changes in spleen weights reflected the microscopical changes (increased hemopoiesis) seen in this organ.

GROSS PATHOLOGY
Macroscopically, males and females treated with 1000 mg/kg/day showed elevated incidence of liver foci were noted when compared with the respective controls. This finding was considered to be test item related. This finding was also noted in one female at 200 mg/kg/day after 13 weeks of treatment, but was not seen in any males at this dose level. It was not evident in either sex at 50 mg/kg/day.

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopically, the livers of animals treated with 1000 mg/kg/day showed degeneration, necrosis (focal or of single hepatocytes), bile duct hyperplasia, focal hepatocytic hyperplasia (very likely regenerative), peribiliary fibrosis and an increased incidence and severity of mixed inflammatory cells infiltration in the parenchyma. Increased hemopoiesis was seen in the spleen of animals at 1000 mg/kg/day. After 28 days of recovery, there was the total reversibility of the findings: the livers and spleens of animals treated previously with 1000 mg/kg/day reverted to normal.


HISTORICAL CONTROL DATA (if applicable)
Used


OTHER FINDINGS:
Functional Observational Battery: No clinical signs were evident at any dose level during the functional observational battery performed at week 13 of treatment.

Grip Strength: At 1000 mg/kg/day, the mean hindlimb grip strength value of males was lower that that of the control males and considered to be related to the slight difference in mean body weight. The mean forelimb grip strength of these males compared favorably with those of the control males.
All other animals were unaffected.

Locomotor Activity: There were no test item-related effects on the mean locomotor activity of either gender.
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: overall effects clinical signs; mortality; body weight; food consumption; ophthalmoscopic examination; haematology; clinical chemistry; urinalysis; gross pathology; organ weights; histopathology
Dose descriptor:
NOAEL
Effect level:
426 mg/kg bw/day (actual dose received)
Based on:
other: Calculated as equimolar amount Coco Isethionate
Sex:
male/female
Basis for effect level:
other: Recalculated as the equimolar amount of Coco Isethionate. Molweight sodium isethionate = 148 g/mol. Molweight Coco Isethionate = 315 g/mol. NOAEL = (200 mg/kg bw/day) *(315 g/mol)/ (148 g/mol) = 426 mg/kg bw/day
Critical effects observed:
not specified

Tabelle 5: Mean severity of Findings

Males

Females

Group

1

2

3

4

1

2

3

4

Dose (mg/g/day)

0

50

200

1000

0

50

200

1000

Number of animals examined

12

12

12

12

12

12

12

12

Liver

Mixed Cell Infiltration

7/1.0

8/1.0

9/1.0

11/1.8

5/1.2

5/1.0

7/1.0

12/1.5

Degeneration

-

-

-

3/1.3

-

-

-

4/2.0

Focal Necrosis

-

-

-

6/1.3

-

-

-

3/1.3

Single Cell Necrosis

-

-

-

7/1.1

-

-

-

4/1.5

Focal Hepatic Hyperplasia

-

-

-

3/1.7

-

-

-

3/1.7

Bile Duct Hyperplasia

-

-

-

½.0

-

-

-

6/1.5

Peribiliary fibrosis

-

-

-

½.0

-

-

-

5/1.4

Spleen

Incr. Hemopoiesis

-

-

½.0

4/1.8

2/2.0

-

-

8/2.3

Conclusions:
Based on the results of this study, the no-observed-adverse-effect-level (NOAEL) for the test item, Sodium 2-hydroxyethanesulphonate, was considered to be 200 mg/kg body weight/day.
Executive summary:

Oral administration of Sodium 2-hydroxyethanesulphonate to Wistar rats at doses of 50, 200 and 1000 mg/kg/day for 91/92 days resulted in no deaths, no clinical signs during daily or weekly observations, no clinical signs during the functional observational battery, no test item-related differences in the mean fore-or hindlimb grip strength or mean locomotor activity, no toxicologically relevant ophthalmoscopic changes, no differences in the mean food consumption, no changes in hematology parameters at 200 mg/kg/day or at 50 mg/kg/day, and no changes in urinalysis parameters at 50 mg/kg/day.

Although statistically significant differences were noted in the mean hindlimb grip strength values of males treated with 1000 mg/kg/day, these were considered to be secondary effects to the lower body weights.

Test item-related findings were generally restricted to slightly lower mean absolute and relative body weights in males treated with 1000 mg/kg/day, changes in the hematology parameters of the rats treated with 1000 mg/kg/day (reduced mean corpuscular hemoglobin concentration values, elevated mean absolute and relative reticulocyte counts, and a ‘left-shift’ in the reticulocyte maturity indices indicative of increased reticulocyte turnover, reduced hemoglobin distribution width in females only), the clinical biochemistry parameters at 1000 mg/kg/day (reduced glucose levels, elevated total bilirubin levels, elevated cholesterol and phospholipid levels, elevated aspartate or alanine aminotransferase activities at 1000 mg/kg/day) including electrolytes (elevated sodium levels at 50, 200 or 1000 mg/kg/day, reduced potassium levels at 50, 200 or 1000 mg/kg/day, increased calcium levels at 1000 mg/kg/day, increased phosphorus in females at 1000 mg/kg/day, increased chloride levels in males at 200 mg/kg/day), increased spleen weights in rats at 1000 mg/kg/day, macroscopical changes in the liver (a higher incidence of tan foci reported in the liver of males and females treated with 1000 mg/kg/day) after the treatment period only, microscopical changes in the liver (presence of degeneration, necrosis (focal or of single hepatocytes), bile ducts hyperplasia, focal hepatocytic hyperplasia, peribiliary fibrosis and an increased incidence and severity of mixed inflammatory cells infiltration in the parenchyma) and spleen (increased hemopoiesis) with complete post-recovery reversibility.

Based on the results of this study, the no-observed-adverse-effect-level (NOAEL) for the test item, Sodium 2-hydroxyethanesulphonate, was considered to be 200 mg/kg body weight/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
426 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Good, two studies, kliminsch score 1and 2

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Quality of whole database:
waived

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Quality of whole database:
waived

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
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
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)
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
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
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
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.
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.

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
Critical effects observed:
not specified

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).

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.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 260 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Quality of whole database:
the dermal repeated dose 28d study covers local effects

Additional information

There are two repeated dose oral studies carried out on related substances to Sodium Lauroyl Methyl Isethionate (SLMI).

In a 28d oral study in the rat (Lea, 1995), on Coco fatty acids 2-sulfoethyl ester, sodium salts (Sodium Coco Isethionate, SCI), where the highest level of 1% in the diet corresponded to approximately 1000mg/kg bw/d. The NOAEL was >1% in the diet (ca. >1000mg/kg bw/d).

A 90d oral study on rats (Klimisch 1, GLP), on sodium 2-hydroxyethanesulfonate [1562-00-1] (sodium isethionate, SI), (Braun, 2009) is available. Studies carried out on another related substance to SLMI; Fatty acids, C12-18 and C18-unsaturated, 2-sulfoethyl esters, sodium salt [85408-62-4], showed that quick hydrolyses of materials of this type is expected in the gastrointestinal tract and metabolized in the liver. This results in the fatty acid chain being removed to leave as a metabolite sodium isethionate. Therefore as the fatty acid portion of the SLMI molecule can be expected be rapidly metabolized in the body and would not be expected to exhibit any toxic effect, it can be assumed that any toxic effects seen would be due to the remaining sodium 2-hydroxyethanesulfonate (sodium isethionate). The study achieved a NOAEL of 200mg/kg bw/d, based primarily on adverse effects in the liver and on reduced bodyweights in males seen at the highest dose level of ca. 1000mg/kg bw/d compared to the ca. 1000mg/kg bw/d seen in the 28 day dietary study on SCI.

The NOAEL based on sodium isethionate was recalculated as the equimolar amount of SLMI. Molecular weight sodium isethionate = 148, g/mol. Molecular weight of SLMI = 344 g/mol. NOAEL = (200 mg/kg bw/d) *(344 g/mol)/ (148 g/mol) = 464 mg/kg bw/d

Therefore, giving a NOAEL of 426mg/kg bw/d for SLMI for repeated oral exposure

In a 28day dermal study of the read across substance Sodium Coco Isethionate on rats (Greico, 1991) there was no evidence of systemic toxicity in the treated animals up to the highest dose of 2070mg/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. When converted for the molecular weight of SLMI the NOAEL is 2260mg/kg bw/d.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Good GLP kiminsch code 1 study on read across material Sodium isethionate

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Only study available

Justification for classification or non-classification

No signs of toxicity were observed in the oral and dermal toxicity studies with SCI and SI up to the highest doses tested. Therefore SLMI has not been classified for repeated dose toxicity