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Administrative data

Description of key information

In the key repeated dose oral toxicity study (Yoneyama et al. 1976), male and female rats were exposed to LAS in drinking water daily for 9 months. Test doses were 85, 145 and 430 mg/kg bw/d plus the control. Eight to nine animals of each sex were exposed per group. Body weight was suppressed in the highest dose group only. Significant decreases in transaminase activity and renal Na,K-ATPase were seen in the 145 mg/kg bw/d group. No significant haematological or organ weight changes were noted. Based on enzyme activity, the resultant LOAEL and NOAEL values were 145 and 85 mg/kg bw/day, respectively.

In the key repeated dose dermal toxicity study (Ito et al. 1978), male and female rats were transdermally exposed to C10-13 magnesium linear alkylbenzene sulphonate (LAS-Mg, read across) in 3% polyethylene glycol (PEG, MW: 200) for 26 weeks. Test doses were 0 (water), 3% PEG, 0.5, 1.0 and 5.0% of test substance dissolved in 3% PEG. No toxicologically relevant changes were observed at any dose level. The no observed adverse effect level (NOAEL) is 5.0%, the highest dose tested.

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:
experimental study
Adequacy of study:
key study
Study period:
1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable study, followed scientific principles/standards, pre-dates GLP
Remarks:
Published studies
Reason / purpose:
reference to same study
Principles of method if other than guideline:
The purpose of this study is to determine the sub chronic toxicity of LAS in Wistar JCL rats, focusing on the liver and kidneys. Male and female rats were maintained on either test diets (0, 0.6 and 1.8%) or drinking water (0, 0.07 and 0.2%) for 9 months. 0.6 and 1.8% rats in drinking water study exhibited severe weight loss so LAS administration was stopped after 2 weeks. Mortality, clinical observations and body weights were recorded during the study. All the surviving animals were humanely euthanized at end of 9 months and gross necropsy, hematological, serum biochemical tests, enzyme tests on the liver and kidneys were performed and organs weights were measured. No histopathology was performed.
GLP compliance:
no
Remarks:
(pre-dates GLP)
Limit test:
no
Species:
rat
Strain:
other: Wistar JCL
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Male and female rats were obtained from Shizuoka Agricultural Cooperative Association for
Laboratory Animals
- Age at study initiation: 4-weeks old
- Weight at study initiation: 100 - 124 g (male rats), 82 - 100 g (female rats)
- Fasting period before study: No
- Housing: 5 animals were housed per cage.
- Diet: CE-2 food (from CLEA Japan); ad libitum
- Water: ad libitum
- Acclimation period: 1 week before the start of treatment

ENVIRONMENTAL CONDITIONS
- Temperature: 25 ± 1°C
- Humidity: 50 - 60%
- Air changes: Not reported
- Photoperiod: 12 hours dark /12 hours light

IN-LIFE DATES: Not reported
Route of administration:
other: oral: drinking water and feed
Details on route of administration:
LAS was administered to animals by mixing 0.6 and 1.8% in CE-2 food (CLEA Japan) and dissolving to 0.07 and 0.2% in drinking water.
Vehicle:
other: Test substance was administered either in diet or drinking water
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
9 months
Frequency of treatment:
Continuous in diet or drinking water (ad libitum)
Dose / conc.:
0.6 other: %
Remarks:
in diet
Dose / conc.:
1.8 other: %
Remarks:
in diet
Dose / conc.:
300 mg/kg bw/day (nominal)
Remarks:
in diet (corresponding to 0.6% dose level)
Dose / conc.:
900 mg/kg bw/day (nominal)
Remarks:
in diet (corresponding to 1.8% dose level)
Dose / conc.:
0.07 other: %
Remarks:
in drinking water
Dose / conc.:
0.2 other: %
Remarks:
in drinking water; 0.6 and 1.8% dose group (equivalent to 857.14 and 2571.43 mg/kg bw/day) were also included, however due to severe weight loss so LAS administration was stopped after 2 weeks.
No. of animals per sex per dose:
Feeding study (mixed in diet): 8 animals/sex/dose
Drinking water study: 9 animals/sex/dose
Control animals:
yes, concurrent vehicle
yes, plain diet
Positive control:
No
Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption: Yes
- Compound intake: Yes
- Time schedule for examinations: Weekly

FOOD EFFICIENCY: No

WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: Weekly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: After 9 months, blood was collected from each animal after euthanizing.
- Anesthetic used for blood collection: No
- Animals fasted: Not specified
- How many animals: Not specified
- Parameters: White blood cells (WBC), red blood cells (RBC), Hemoglobin (Hgb), Hematocrit (Hct), mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After 9 months, blood was collected from each animal after euthanizing.
- Animals fasted: Not specified
- How many animals: Not specified
- Parameters: Glutamate oxaloacetate transaminase (GOT), glutamate pyruvic transaminase (GPT), glucose content, urea nitrogen, total cholesterol, albumin, alkaline phosphatase (ALP) and cholinesterase

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

OTHER:
- Liver enzyme tests: Glucose 6-phosphatase (G6Pase), lactase dehydrogenase (LDH) and G6P-DH activity
- Kidney enzyme tests: G6Pase, LDH, GPT, GOT, ALP, acid phosphatase (ACP), Na, K-ATPase, and malate dehydrogenase (MDH)
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (However, no details in study report in mentioned)
Gross findings were obtained after euthanizing animals and organs were removed for organ weight measurements.

ORGAN WEIGHTS: Brain, heart, lungs, liver, spleen, kidneys, adrenal gland, testes, ovary, uterus, and appendix
HISTOPATHOLOGY: No
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Both female and male rats (drinking water study) exhibited a slight redness at the tips of their facial fur, and coarse fur all over their bodies.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was significant decrease in body weight gain in males and females of 1.8% dose group fed with diet and in males of 0.2% dose group consuming LAS contained water.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Increased water consumption was observed in males of 1.8% dose group fed with diet and 0.2% dose group consuming LAS contained water.
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
A significant reduction in WBC was observed in 0.6% (diet) male rats and in MCV and MCH was observed in 1.8% (diet) female rats compared to controls.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
There were significant alteration in cholesterol [decrease; all doses, except female rats of 0.07% dose group (drinking water)], GPT [0.6% dose group (diet) females)], GOT [1.8% dose group (diet) males], albumin [1.8% (diet) males] , ALP levels [male and female rats fed with 1.8% LAS-diet] and cholinesterase levels [in male rats fed with 1.8% LAS-diet].
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In males of 1.8% (diet), the absolute liver and testes weight was significantly decreased and the relative testes and liver weight was significantly increased and both absolute and relative spleen weight were also significantly reduced.
In females of 1.8% (diet), absolute and relative liver and caecum weight was significantly increased.
There was also significant decrease in absolute and relative heart weight in females of 0.6% (diet) and 0.07% (drinking water) dose groups.
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Liver enzyme tests:
Dietary study: G6Pase activity was reduced in 1.8% dose group males and females, G6P-DH activity was reduced in 0.6 and 1.8% dose group males and females, LDH activity was reduced in 0.6, 1.8% dose group. GOT and GPT activities were clearly reduced in males, while in females GPT activity was reduced only in 1.8% dose group and GOT activity was reduced in 1.8% dose group animals.
Drinking water study: LDH activity was reduced in 0.2% dose group males. GOT and GPT activities were clearly reduced in males and GOT activity was increased in 0.07 and 0.2% dose group animals.

Renal enzyme tests:
Dietary study: A significant difference was also observed in G6Pase activity. In females, G6Pase, Na, K-ATPase, and LDH activity were significantly reduced in 1.8% dose group (diet) animals
Drinking water study: In males, Na, K-ATPase activity was significantly reduced in 0.2% dose group. A significant difference was also observed in G6Pase activity.
Details on results:
CLINICAL SIGNS: Both female and male rats consuming LAS-containing water exhibited a slight redness at the tips of their facial fur, and coarse fur all over their bodies.

BODY WEIGHT AND WEIGHT CHANGES: There was significant decrease in body weight gain in male and females of 1.8% dose group fed with diet and in males of 0.2% dose group consuming LAS contained water.

WATER CONSUMPTION AND COMPOUND INTAKE: Increased water consumption was observed in males of 1.8% dose group fed with diet and 0.2% dose group consuming LAS contained water.

HAEMATOLOGICAL FINDINGS: A significant reduction in WBC was observed in 0.6% (diet) male rats compared to controls, and a significant reduction in MCV and MCH was observed in 1.8% (diet) female rats compared to controls.

CLINICAL BIOCHEMISTRY: Except female rats of 0.07% dose group (drinking water), a significant reduction or a reduction in cholesterol was observed in male and female rats of all dose groups compared to controls. GPT was significantly reduced in 0.6% dose group (diet) females, and reduced in females of other treatment groups. GOT was significantly reduced in 1.8% dose group (diet) males, and reduced in both females and males of other treatment groups. Albumin was significantly reduced in 1.8% (diet) males and reduced in males of 0.2% dose group (drinking water) and females of 1.8% dose group (diet). There was significant increase in ALP levels in male and female rats fed with 1.8% LAS-diet and cholinesterase levels in male rats fed with 1.8% LAS-diet.

ORGAN WEIGHT: In males of 1.8% (diet), the absolute liver and testes weight was significantly decreased and the relative testes and liver weight was significantly increased and both absolute and relative spleen weight were also significantly reduced. In females of 1.8% (diet), absolute and relative liver and caecum weight was significantly increased. There was also significant decrease in absolute and relative heart weight in females of 0.6% (diet) and 0.07% (drinking water) dose groups.

LIVER ENZYME TESTS: G6Pase activity was reduced in 1.8% dose group (diet) males and females, G6P-DH activity was reduced in 0.6 and 1.8% dose group (diet) males and females, where the percentage reduction was greater in 1.8% dose group (diet) animals. LDH activity was clearly reduced in 0.6, 1.8% dose group (diet), and 0.2% dose group (drinking water) males, but reduced in only 1.8% dose group (diet) females. GOT and GPT activities were clearly reduced in males, while in females GPT activity was reduced only in 1.8% dose group (diet) animals, and GOT activity was increased in 0.07 and 0.2% dose group (drinking water) animals but reduced in 1.8% dose group (diet) animals.

RENAL ENZYME TESTS: In males, Na, K-ATPase activity was significantly reduced in 0.2% dose group (drinking water) animals, and also reduced in other male treatment groups. A significant difference was also observed in G6Pase activity, where the reduction observed was associated with an increase in amount consumed. In females, G6Pase, Na, K-ATPase, and LDH activity were significantly reduced in 1.8% dose group (diet) animals, and G6Pase and LDH activity were also reduced in other treatment groups.
Key result
Dose descriptor:
LOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
act. ingr.
Remarks:
(dietery study)
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
water consumption and compound intake
haematology
clinical biochemistry
organ weights and organ / body weight ratios
other: Liver and kidney enzyme levels
Remarks on result:
other: Adverse effects were observed at all dose levels
Key result
Dose descriptor:
NOAEL
Effect level:
85 mg/kg bw/day (nominal)
Based on:
act. ingr.
Remarks:
(drinking water study)
Sex:
male/female
Basis for effect level:
clinical biochemistry
other: Liver and kidney enzyme levels
Remarks on result:
other: Based on significant decreases in the activities of glutamate-oxalate transaminase and lactate dehydrogenase in males and significant decrease in renal Na,K-ATPase in males and females at 145 mg/kg bw/day (0.2% drinking water).
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
145 mg/kg bw/day (nominal)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
145 mg/kg bw/day (nominal)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Conclusions:
Administration of LAS to Wistar JCL rats by test diets at dose levels of 0, 0.6 and 1.8% for 9 months (focusing on the liver and kidneys) revealed an LOAEL of 0.6% (300 mg/kg bw/day in diet), based on adverse effects at all dose levels.
Administration of LAS to Wistar JCL rats in drinking water at dose levels of 0, 0.07 and 0.2% for 9 months (focusing on the liver and kidneys) revealed an NOAEL of 0.07% (85 mg/kg bw/day in drinking water), based on significant decreases in the activities of glutamate-oxalate transaminase and lactate dehydrogenase in males and significant decrease in renal Na,K-ATPase in males and females at 145 mg/kg bw/day (0.2% drinking water).
Executive summary:

The 9 months sub-chronic oral toxicity study of LAS was performed in Wistar JCL rats, focusing on the liver and kidneys.

 

4 weeks old male and femaleWistar JCL rats(obtained from Shizuoka Agricultural Cooperative Association for Laboratory Animals) with body weight range100 - 124 g (males), 82 - 100 g (females)were used in the study. 5 animals were housed in each cage and maintained under controlled environmental conditions (temperature: Average of25 ± 1°C, humidity:50 - 60%, and 12 hours light /12 hours dark).CE-2diet (from CLEA Japan) and water were providedad libitum.

 

The animals were administered daily with the LAS at following dose levels for 9 months:

 

Mixed in diet: 0, 0.6 and 1.8% (equivalent to 0, 300 and 900 mg/kg bw/day); 8 animals/sex/dose

 

Dissolved in drinking water: 0, 0.07 and 0.2 % (equivalent to 0,85 and 145mg/kg bw/day); 9 animals/sex/dose

 

Rats in 0.6 and 1.8% dose group of drinking water study exhibited severe weight loss so LAS administration was stopped after 2 weeks

 

Clinical observations, water consumption, food consumption and body weights were recorded weekly. At the end of study, blood was collected for estimation of haematological and clinical chemistry parameters.Gross findings were observed after euthanizing animals and organs were removed for organ weight measurements. Organ weights for brain, heart, lungs, liver, spleen, kidneys, adrenal gland, testes, uterus, and appendixwere recorded. Liver and kidney enzymes were also analysed. No histopathology was performed.

 

No mortality was observed throughout the study. Both female and male rats consuming LAS-containing water exhibited a slight redness at the tips of their facial fur, and coarse fur over their bodies. There was significant decrease in body weight gain in male and females of 1.8% dose group fed with diet and in males of 0.2% dose group consuming LAS contained water.Increased water consumption was observed in males of 1.8% dose group fed with diet and 0.2% dose group consuming LAS contained water.

 

A significant reduction in WBC was observed in 0.6% (diet) male rats compared to controls, and a significant reduction in MCV and MCH was observed in 1.8% (diet) female rats compared to controls. A marked reduction in cholesterol was observed in male and female rats of all dose groups [except female rats of 0.07% dose group (drinking water)] compared to controls. This indicate hepatocyte damage. GPT was significantly reduced in 0.6% dose group (diet) females, and reduced in females of other treatment groups. GOT was significantly reduced in 1.8% dose group (diet) males, and reduced in both females and males of other treatment groups. Albumin was significantly reduced in 1.8% (diet) males and reduced in males of 0.2% dose group (drinking water) and females of 1.8% dose group (diet). There was significant increase in ALP levels in male and female rats fed with 1.8% LAS-diet and cholinesterase levels in male rats fed with 1.8% LAS-diet.

 

In males of 1.8% (diet), the absolute liver and testes weight was significantly decreased and the relative testes and liver weight was significantly increased and both absolute and relative spleen weight were also significantly reduced. In females of 1.8% (diet), absolute and relative liver and caecum weight was significantly increased. There was also significant decrease in absolute and relative heart weight in females of 0.6% (diet) and 0.07% (drinking water) dose groups.

 

Liver enzymes were markedly reduced in 1.8% fed rats, due to impaired liver function, indicates reduced enzyme synthesis and direct enzyme inhibition by LAS or its metabolites. Renal G6Pase and Na, K-ATPase activity decreased, indicating kidney impairment.

 

Administration of LAS to Wistar JCL rats bytest diets at dose levels of 0, 0.6 and 1.8% for 9 months (focusing on the liver and kidneys) revealed an LOAEL of 0.6% (300 mg/kg bw/day in diet), based on adverse effects at all dose levels.

Administration of LAS to Wistar JCL rats in drinking water at dose levels of 0, 0.07 and 0.2% for 9 months (focusing on the liver and kidneys) revealed an NOAEL of 0.07% (85 mg/kg bw/day in drinking water), based onsignificant decreases in the activities of glutamate-oxalate transaminase and lactate dehydrogenase in males and significant decrease in renal Na,K-ATPase in males and females at 145 mg/kg bw/day (0.2% drinking water).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
85 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Key oral study, experimental results are reliable with restrictions.

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
Endpoint:
chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable study, followed scientific principles/standards, pre-dates-GLP.
Reason / purpose:
reference to same study
Principles of method if other than guideline:
The purpose of this study is to determine the chronic toxicity (transdermal) of C10 - C13 linear alkylbenzene sulfonic acid magnesium salt (LAS-Mg) in CRJ-SD rats. Male and female rats were transdermally administered with 0 (water), 3% PEG, 0.5, 1.0 and 5.0% of test substance dissolved in 3% polyethyleneglycol (PEG, MW: 200) for 26 weeks. General symptoms and body weight of animals were recorded on a daily-basis and food intake were recorded weekly. Urinalysis and hematological examinations were performed in week 5 and 13 of the study. At the end of study, urinalysis, haematological and serum biochemistry were also done. All the surviving animals were humanely euthanized after 26 weeks and organs (liver, kidneys, spleen, adrenal glands, lungs, heart, thymus, reproductive organ, pituitary, brain and thyroid) were collected for recording absolute and relative organ weights. All the collected organs were examined under the microscope for histopthalogical changes.
GLP compliance:
no
Remarks:
(pre-dates GLP)
Limit test:
no
Species:
rat
Strain:
other: CRJ-SD
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Male and female rats were obtained from Charles River Laboratories Japan, Inc.
- Age at study initiation: Approximately 4 weeks
- Weight at study initiation: Not reported
- Fasting period before study: Not reported
- Housing: Animals were housed in cages with 2 animals/cage.
- Diet: Solid feed (CE-2, CLEA Japan, Inc.); ad libitum
- Water: Tap water; ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 1°C
- Humidity: 55 ± 5%
- Air changes: Not reported
- Photoperiod: Not reported

IN LIFE DATES: Not reported
Type of coverage:
not specified
Vehicle:
other: 3% polyethyleneglycol (PEG, MW: 200)
Details on exposure:
TEST SITE
- Area of exposure: Shaved backs of animals
- % coverage: 3 x 3 cm2 area in the middle of the backside
- Type of wrap if used: Not reported
- Time intervals for shavings or clippings: Weekly

REMOVAL OF TEST SUBSTANCE
- Washing: Not reported
- Time after start of exposure: Not reported

TEST MATERIAL
- Amount(s) applied: 0.1 mL
- Concentration: 0.5, 1.0 and 5.0% of C10-C13 LAS-Mg in 3% polyethyleneglycol

VEHICLE
- 3% polyethyleneglycol (PEG, MW: 200)

USE OF RESTRAINERS FOR PREVENTING INGESTION: No
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
26 weeks
Frequency of treatment:
Once daily for 26 weeks (excluding Sundays)
Dose / conc.:
0.5 other: %
Dose / conc.:
1 other: %
Dose / conc.:
5 other: %
No. of animals per sex per dose:
20 animals/sex/dose group
Control animals:
other: 2 Control animals groups were applied with either PEG or distilled water.
Details on study design:
- Dose selection rationale: Not reported
- Rationale for animal assignment: Not reported
- Rationale for selecting satellite groups: No satellite groups were used in the study
Positive control:
Not included
Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes
- Time schedule: All animals were observed daily for general symptoms.

DERMAL IRRITAION: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed daily.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule: Amount of food intake was measured once per week.

FOOD EFFICIENCY: Yes

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: During weeks 5, 11 and 26
- Anaesthetic used for blood collection: Yes. The animals were anesthetized with sodium pentobarbital
- Animals fasted: Not reported
- How many animals: During weeks 5 and 11, blood was collected from 10 animals/sex from PEG group, control group and 5.0% group and in week 26, blood was collected from all animals.
- Parameters checked: Red blood cell count, white blood cell count, hemoglobin level and hematocrit level were measured, and white blood cell fractions were calculated by Giemsa-staining the blood smear samples.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At end of study i.e. 26 weeks
- Animals fasted: Not reported
- How many animals: All animals
- Parameters checked: s-GOT, s-GPT, alkaline phosphatase, total protein, albumin, glucose, cholesterol, bilirubin, creatinine, urea nitrogen, inorganic phosphates and Cl-, Na+, K+, Ca2+ and Mg2+

URINALYSIS: Yes
- Time schedule for collection of urine: During weeks 5, 11 and 26
- Metabolism cages used for collection of urine: No
- Animals fasted: Not reported
- How many animals: During weeks 5 and 11, urine was collected from 10 animals/sex from PEG group, control group and 5.0% group and in week 26, urine was collected from all animals.
- Method: Lab sticks, Urobilistix and iktstix method (Semi-quantitative investigation)
- Parameters: pH, protein, glucose, ketone bodies, occult blood, urobilinogen and bilirubin

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
All animals were euthanized after blood sampling and organs were immediately collected.

TISSUE COLLECTED FOR ORGAN WEIGHTS AND HISTOPATHOLOGY: Liver, kidneys, spleen, adrenal glands, lungs, heart, thymus, reproductive organ, pituitary, brain and thyroid

HISTOPATHOLOGY: Above collected organs and stomach, duodenum, ileum, cecum, pancreas, bone marrow and skin were fixed in 10% formalin, embedded in paraffin and underwent H&E staining before being examined under the microscope
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
In half of the animals of highest tested dose, mild redness of test site was observed one week after starting to apply it, but this disappeared after one week with desquamation. This did not occur again thereafter. Among female animals, all animals in the 5.0% group and one animal from the 1.0% group developed mild redness after one month since the start of study, but these went away after one week. After two, three months, half the animals in the 5.0% group exhibited mild redness, and it was seen sporadically thereafter.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One male animal from the control group (Week 16) and one male animal from the 5.0% group (Week 23) died during the study, but the cause remains unknown after finding no abnormalities through the necropsies.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Male animals in the 0.5% group exhibited mild weight suppression from Week 11, but this had recovered by Week 16. At the end of the experiment, slight weight suppression was observed in male animals from the 0.5% group.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
5 weeks interim analysis: There were significant increase in segmented neutrophils and significant decrease in white blood cell count for male animals in PEG group and increase in hematocrit levels in male animals in 5.0% dose group
13 weeks interim analysis: level: Significant increase in red blood cells and hemoglobin levels were observed in males of 5.0% dose group and increased white blood cell count was also observed for male and female animals in the PEG and 5.0% groups. In white blood cell fractions, decrease in eosinophils was observed for female animals in the 5.0% group.
6 month analysis: Significant decrease in white blood cell count were observed for female animals in the 5.0% group, as well as for both male and female animals in the 1.0% group. Significant increase in lymphocytes for male animals in the PEG group and significant decrease in monocytes for male animals in the 5.0 and 0.5% groups were also observed.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
PEG group: Significant decrease was observed in s-GOT levels for female animals and in sodium and s-GPT levels for all animals.
5.0% dose group: There was significant reduction in glucose in females, in calcium levels in males and sodium and s-GPT in all animals. Elevated levels of A/G ratio and cholesterol were also observed in females.
1.0% dose group: There is significant decrease in glucose in females and sodium levels in all animals and increase in urea nitrogen in females of this group.
0.5% dose group: There is significant decrease in sodium levels in all animals of this group and increase in urea nitrogen in females of this group.
Urinalysis findings:
no effects observed
Description (incidence and severity):
Similar levels of all tested parameters (protein, occult blood, Urobilinogen and pH) were observed in treated animals as compare to control animals in 13 as well as 26 weeks interim analysis.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
There were decrease in actual and relative liver weights of 0.5% (low) dose group. No dose dependency was observed for this effect.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
- Liver stasis was observed for one male animal in the 1.0% group, while blood spots and fading color were observed for another male animal in the same group. Furthermore, white serpentine bulges were observed for three male animals each in the 5.0 and 0.5% groups, as well as in four male animals in 1.0% group and one male animal in the 0.5% group.
- Kidney edema was observed for one female each in the control and 0.5% groups.
- Yellow discoloration was observed in pancreas for one male animal in the control group.
- Lungs stasis was observed for one male animal in the 1.0% group.
- Heart hypertrophy was observed for one male animal in the 1.0% group.
- Blood spots in thymus were observed for two male animals each in the control, PEG and 1.0% groups, as well as in four male animals in the 5.0 and 0.5% groups.
- Testicular atrophy was observed for one male in the 1.0% group, while ovarian edema was observed for one female animal each in the control and 1.0% groups.
- Pituitary edema was observed for one male animal in the 1.0% group.
- Stomach hematoma was observed in the cardia for one male animal in the 1.0% group, while an ulcer of 1 mm in diameter was observed for another male animal in the same group. Edema was observed in the stomach for one male animal in the control group.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Control group:
- Sinusoid bleeding was observed for one male and one female animal each, while focal necrosis was observed for one female animal.
- Renal tubular hyaline casts were observed for seven male animals and one female animal, while interstitial small round cell infiltration and renal tubular epithelial cell swelling were observed for two male and one female animals
- Fibrosis of islets of Langerhans observed for one male animal
- Interstitial myocarditis was observed for one male and one female animal each.
PEG group:
- Sinusoid bleeding was observed for three male animals, focal necrosis was observed in one male animal and Kupffer cell migration was observed for one female animal
- Renal tubular hyaline casts were observed for five male animals and one female animal, while interstitial small round cell infiltration and renal tubular epithelial cell swelling were observed for one male and one female animal each
- Adrenal gland: A hemorrhagic foci was observed in the stratum corneum for one male animal.
- Fibrosis of islets of Langerhans observed for one male animal.
5.0% dose group:
- Sinusoid bleeding was observed for five male animals, while focal necrosis was observed for two male animals. Kupffer cell migration was observed for one female animal.
- Renal tubular hyaline casts were observed for three male and female animals each, while interstitial small round cell infiltration was observed for two male animals. Renal tubular calcification was observed for another male animal.
- Fibrosis of islets of Langerhans observed for one male animal.
- Interstitial myocarditis was observed for two male animals and one female animal.
1.0% dose group:
- Sinusoid bleeding was observed for five male animals, while focal necrosis was observed for another male animal.
- Renal tubular hyaline casts were observed for five male and one female animals, interstitial small round cell infiltration was observed for one male and one female animal each, and renal tubular calcification was observed for two female animals
- Fibrosis of islets of Langerhans observed for four male animals
- Interstitial myocarditis was observed for one male animal.
- Decline in sperm production was observed for one male animal.
0.5% dose group:
- Sinusoid bleeding was observed for four male animals and one female animal, while large lipid droplets were observed for one male animal. Kupffer cell migration was observed for one female animal.
- Renal tubular hyaline casts were observed for five male and two female animals, interstitial small round cell infiltration was observed for one male animal and another male animal exhibited renal tubular epithelial cell swelling. Furthermore, renal tubular calcification was observed for one female animal.
- Fibrosis of islets of Langerhans observed for three male animals.
- Interstitial myocarditis was observed for three male animals.
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
- In half of the animals of highest tested dose, mild redness of test site was observed one week after starting to apply it, but this disappeared after one week with desquamation. This did not occur again thereafter.
- Among female animals, all animals in the 5.0% group and one animal from the 1.0% group developed mild redness after one month since the start of study, but these went away after one week.
- After two, three months, half the animals in the 5.0% group exhibited mild redness, and it was seen sporadically thereafter.
- One male animal from the control group (Week 16) and one male animal from the 5.0% group (Week 23) died during the study, but the cause remains unknown after finding no abnormalities through the necropsies.

BODY WEIGHT AND WEIGHT GAIN
- Male animals in the 0.5% group exhibited mild weight suppression from Week 11, but this had recovered by Week 16.
- At the end of the experiment, slight weight suppression was observed in male animals from the 0.5% group.

FOOD CONSUMPTION AND COMPOUND INTAKE
- No significant difference was noted in males or females between the control and test substance groups.

FOOD EFFICIENCY
- No effects were observed in test substance treated animals as compare to control animals

HAEMATOLOGY
- 5 weeks interim analysis: There were significant increase in segmented neutrophils and significant decrease in white blood cell count for male animals in PEG group and increase in hematocrit levels in male animals in 5.0% dose group
- 13 weeks interim analysis: level: Significant increase in red blood cells and hemoglobin levels were observed in males of 5.0% dose group and increased white blood cell count was also observed for male and female animals in the PEG and 5.0% groups. In white blood cell fractions, decrease in eosinophils was observed for female animals in the 5.0% group.
- 6 month analysis: Significant decrease in white blood cell count were observed for female animals in the 5.0% group, as well as for both male and female animals in the 1.0% group. Significant increase in lymphocytes for male animals in the PEG group and significant decrease in monocytes for male animals in the 5.0 and 0.5% groups were also observed.

CLINICAL CHEMISTRY
- PEG group: Significant decrease was observed in s-GOT levels for female animals and in sodium and s-GPT levels for all animals.
- 5.0% dose group: There was significant reduction in glucose in females, in calcium levels in males and sodium and s-GPT in all animals. Elevated levels of A/G ratio and cholesterol were also observed in females.
- 1.0% dose group: There is significant decrease in glucose in females and sodium levels in all animals and increase in urea nitrogen in females of this group.
- 0.5% dose group: There is significant decrease in sodium levels in all animals of this group and increase in urea nitrogen in females of this group.

URINALYSIS
Similar levels of all tested parameters (protein, occult blood, Urobilinogen and pH) were observed in treated animals as compare to control animals in 13 as well as 26 weeks interim analysis.
ORGAN WEIGHTS
- There were decrease in actual and relative liver weights of 0.5% (low) dose group. No dose dependency was observed for this effect.

GROSS PATHOLOGY
- Liver stasis was observed for one male animal in the 1.0% group, while blood spots and fading color were observed for another male animal in the same group. Furthermore, white serpentine bulges were observed for three male animals each in the 5.0 and 0.5% groups, as well as in four male animals in 1.0% group and one male animal in the 0.5% group.
- Kidney edema was observed for one female each in the control and 0.5% groups.
- Yellow discoloration was observed in pancreas for one male animal in the control group.
- Lungs stasis was observed for one male animal in the 1.0% group.
- Heart hypertrophy was observed for one male animal in the 1.0% group.
- Blood spots in thymus were observed for two male animals each in the control, PEG and 1.0% groups, as well as in four male animals in the 5.0 and 0.5% groups.
- Testicular atrophy was observed for one male in the 1.0% group, while ovarian edema was observed for one female animal each in the control and 1.0% groups.
- Pituitary edema was observed for one male animal in the 1.0% group.
- Stomach hematoma was observed in the cardia for one male animal in the 1.0% group, while an ulcer of 1 mm in diameter was observed for another male animal in the same group. Edema was observed in the stomach for one male animal in the control group.

HISTOPATHOLOGY
Control group:
- Sinusoid bleeding was observed for one male and one female animal each, while focal necrosis was observed for one female animal.
- Renal tubular hyaline casts were observed for seven male animals and one female animal, while interstitial small round cell infiltration and renal tubular epithelial cell swelling were observed for two male and one female animals
- Fibrosis of islets of Langerhans observed for one male animal
- Interstitial myocarditis was observed for one male and one female animal each.
PEG group:
- Sinusoid bleeding was observed for three male animals, focal necrosis was observed in one male animal and Kupffer cell migration was observed for one female animal
- Renal tubular hyaline casts were observed for five male animals and one female animal, while interstitial small round cell infiltration and renal tubular epithelial cell swelling were observed for one male and one female animal each
- Adrenal gland: A hemorrhagic foci was observed in the stratum corneum for one male animal.
- Fibrosis of islets of Langerhans observed for one male animal.
5.0% dose group:
- Sinusoid bleeding was observed for five male animals, while focal necrosis was observed for two male animals. Kupffer cell migration was observed for one female animal.
- Renal tubular hyaline casts were observed for three male and female animals each, while interstitial small round cell infiltration was observed for two male animals. Renal tubular calcification was observed for another male animal.
- Fibrosis of islets of Langerhans observed for one male animal.
- Interstitial myocarditis was observed for two male animals and one female animal.
1.0% dose group:
- Sinusoid bleeding was observed for five male animals, while focal necrosis was observed for another male animal.
- Renal tubular hyaline casts were observed for five male and one female animals, interstitial small round cell infiltration was observed for one male and one female animal each, and renal tubular calcification was observed for two female animals
- Fibrosis of islets of Langerhans observed for four male animals
- Interstitial myocarditis was observed for one male animal.
- Decline in sperm production was observed for one male animal.
0.5% dose group:
- Sinusoid bleeding was observed for four male animals and one female animal, while large lipid droplets were observed for one male animal. Kupffer cell migration was observed for one female animal.
- Renal tubular hyaline casts were observed for five male and two female animals, interstitial small round cell infiltration was observed for one male animal and another male animal exhibited renal tubular epithelial cell swelling. Furthermore, renal tubular calcification was observed for one female animal.
- Fibrosis of islets of Langerhans observed for three male animals.
- Interstitial myocarditis was observed for three male animals.
Key result
Dose descriptor:
NOAEL
Effect level:
5 other: %
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No significant adverse effect was seen at any dose level.
Remarks on result:
other: Based on no growth, functional and morphological abnormalities, other than the localized effects at any tested dose levels.
Conclusions:
Transdermal administration of C10-13 magnesium linear alkylbenzene sulphonate (LAS-Mg; purity: 96.9%) to CRJ-SD rats at dose levels of 0 (water), 3% PEG, 0.5, 1.0 and 5.0% of test substance dissolved in 3% polyethyleneglycol (PEG, MW: 200) for 26 weeks revealed no observed adverse effect level (NOAEL) of 5.0%, based no toxicologically relevant changes at any dose level.
Executive summary:

A 26-weeks repeated dose toxicity study (transdermal) was conducted in male and female CRJ-SD rats to evaluate the chronic effects of C10-13 magnesium linear alkylbenzene sulphonate (LAS-Mg; purity: 96.9%).

Approximately 4 weeks old male and females animals were housed in cages (2 animals/cage). Solid feed (CE-2, CLEA Japan, Inc.) and tap water were provided ad libitum. The animals were maintained under standard laboratory conditions (temperature: 22 ± 1°C; relative humidity: 55 ± 5%). Prior to the treatment, animals were acclimatized under laboratory conditions for 1 week.

The test substance was administered daily at 5 dose levels of i.e. 0 (water), 3% PEG, 0.5, 1.0 and 5.0% of test substance dissolved in 3% polyethyleneglycol (PEG, MW: 200) for 26 weeks with 20 animals/sex/dose group.

General symptoms and body weight of animals were recorded on a daily-basis and food intake were recorded weekly. Urinalysis and hematological examinations were performed in week 5 and 13 of the study.  At the end of study, urinalysis, haematological, serum biochemistry were also done. All the surviving animals were humanely euthanized after 26 weeks and organs (liver, kidneys, spleen, adrenal glands, lungs, heart, thymus, reproductive organ, pituitary, brain and thyroid) were collected for recording absolute and relative organ weights.  All the collected organs (including stomach, duodenum, ileum, cecum, pancreas, bone marrow and skin) were then fixed in 10% formalin, embedded in paraffin and underwent H&E staining before being examined under the microscope.

One male animal from the control group (Week 16) and one male animal from the 5.0% group (Week 23) died during the study, but the cause remains unknown after finding no abnormalities through the necropsies. There were mild redness of test site at Week 1 (in 5.0% dose) and after one month of start of study (in the 5.0% group and one animal from the 1.0% group), but these went away after one week. There was slight weight suppression in male animals from the 0.5% group at the end of the experiment. No toxicologically significant changes were observed in food efficiency of treated animals when compared to controls.

There were no toxicologically relevant changes to the urine, hematological and serum biochemical findings.

No changes were seen in the organ weights of treated animals, and gross necropsy reveal only white serpentine bulges being seen in the livers of male animals in the control and test groups. Histopathological findings were non-specific and had no dose-dependency.

Transdermal administration of C10-13 magnesium linear alkylbenzene sulphonate (LAS-Mg; purity: 96.9%) to CRJ-SD rats at dose levels of 0 (water), 3% PEG, 0.5, 1.0 and 5.0% of test substance dissolved in 3% polyethyleneglycol (PEG, MW: 200) for 26 weeks revealed no observed adverse effect level (NOAEL) of 5.0%, based no toxicologically relevant changes at any dose level.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
Study duration:
subchronic
Species:
rat
Quality of whole database:
Supporting study, read-across, experimental results are reliable with restrictions. Highest dose tested was 5% LAS-Mg. The NOAEL per body weight cannot be calculated as body weights were not reported.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Oral Administration

Six studies are available to document the potential effects from repeated oral exposures to LAS.

In the key study (Yoneyama et al. 1976), male and female rats were exposed to LAS in drinking water daily for 9 months. Test doses were 85, 145 and 430 mg/kg bw/d plus the control. Eight to nine animals of each sex were exposed per group. Body weight was suppressed in the highest dose group only. Significant decreases in transaminase activity and renal Na,K-ATPase were seen in the 145 mg/kg bw/d group. No significant haematological or organ weight changes were noted. Based on enzyme activity, the resultant LOAEL and NOAEL values were 145 and 85 mg/kg bw/day, respectively.

In a supporting study (Yoneyama et al. 1972), male and female rats were exposed to LAS in the diet daily for 6 months. The doses were 40, 115, 340 and 1030 mg/kg bw/d plus the control group. Significant diarrhea, suppressed growth, increased cecal weight, and degeneration of renal tubes were observed in the highest dose group. Similar but less severe signs were seen in other doses with the exception of the lowest dose of 40 mg/kg bw/d, which showed no adverse effects related to exposure to LAS. The resultant LOAEL and NOAEL values were 115 and 40 mg/kg bw/day, respectively.

In another supporting study (Ito et al. 1978), male and female rats were exposed to LAS via gavage daily for 28 days at three dose levels plus the control (0, 125, 250 and 500 mg/kg bw/d). Body weight gain was suppressed, some serum biochemical measures were different from the controls, and some organ weights were either decreased (spleen, heart, thymus) or increased (liver) in either the male or female high dose groups. No mortalities or histopathological abnormalities were observed. The resultant LOAEL and NOAEL values were 250 and 125 mg/kg bw/day, respectively, based on serum-biochemical differences from the controls.

The same authors (Ito et al. 1978) also conducted a study using Mg LAS at doses of 0, 75, 150 and 300 mg/kg bw/d and following the same protocol. The resultant LOAEL and NOAEL values were 300 and 150 mg/kg bw/day, respectively, based on body weight gain, hematology, serum-biochemical and organ weight differences from the controls.

The same authors (Ito et al. 1978) also conducted a 26-weeks repeated dose toxicity study (oral) using male and female CRJ-SD rats to evaluate the chronic effects of C10-13 magnesium linear alkylbenzene sulphonate (LAS-Mg; purity: 96.9%). The test substance was administered daily at 4 dose levels of i.e. 0, 75, 150 and 300 mg/kg bw/day using a metallic gastric sonde to CRJ-SD rats with 20 animals/sex/dose group. One male animal in 300 mg/kg bw/day dose group died (in week 21) from weakness due to significant weight loss involving diarrhea and loss of appetite. There were wetting in the area surrounding animals’ mouths after dosing, and a few animals had abnormal airway sounds. Soft stools were seen in animals after one month, then recovered in few days. There was slight body weight suppression in the male animals of 300 mg/kg bw/day dose group. No toxicologically significant changes were observed in food efficiency of treated animals when compared to controls. At end of dosing period, haematological findings revealed significant reduction in hematocrit levels for female animals in 300 mg/kg bw/day dose group. There was significant reduction in bilirubin, protein, albumin and calcium levels in male animals and significant reduction in s-GPT, glucose, calcium and magnesium levels in female animals of 300 mg/kg bw/day dose group. There was also significant reduction in s-GOT, s-GPT, alkaline phosphatase, protein, albumin, sodium and calcium levels in male animals and significant reduction in chloride levels in female animals of 150 mg/kg bw/day dose groups. Changes were also observed in protein levels in urine in treated male animals as compare to control groups. Necropsy revealed atrophy and bloating of the liver and spleen, respectively. Significant increased relative liver weights (males), thymus weights (males) and pituitary (males) weights were observed in 150 mg/kg bw/day dose group animals as compare to control. Reduction in relative heart weights (females), kidneys weights (males) and adrenal gland weights (females) were also observed in highest dose treated group. Significant increased relative thymus weights were observed in male animals as compare to control and decreased relative heart weights in females and relative kidneys weights in males of 150 mg/kg bw/day dose group. Significant dip in relative adrenal glands weights of females was seen in low dose group. Histopathological examinations revealed Kupffer cell migration (at 150 mg/kg bw/day dose group), focal necrosis (at 75 mg/kg bw/day dose group) and sinusoid bleeding in the liver. In the kidneys, renal tubular epithelial cell swelling, hyaline casts and interstitial small round cell infiltration were observed (at 300 mg/kg bw/day dose group). Fibrosis of islets of Langerhans (at 75 mg/kg bw/day dose group) was also observed. However, histopathological effects seen in liver and pancreas were not dose dependent. Oral administration of C10-13 magnesium linear alkylbenzene sulphonate (LAS-Mg; purity: 96.9%) to CRJ-SD rats at dose levels of 0, 75, 150 and 300 kg/kg bw/day for 26 weeks revealed no observed adverse effect level (NOAEL) of 150 mg/kg bw/day, based on weight suppression, mortality, fluctuations in hematological and serum biochemistry, altered organ weights and histopathological alterations in kidney at 300 mg/kg bw/day.

In the final study (Yoneyama et al. 1976), a 9 month sub-chronic oral toxicity study of LAS was performed in SLC-ICR mice, focusing on the liver and kidneys. 4 week old male and female SLC-ICR mice were administered LAS daily at following dose levels for 9 months: 1) Mixed in diet: 0 and 0.6% (equivalent to 0 and 780 mg/kg bw/day); 9 males in 0.6% fed group and 8 males in control group; 8 females in control as well as 0.6% fed group or 2) Dissolved in drinking water: 0, 0.07, 0.2 and 0.6 (equivalent to 0,133, 380 and 1140 mg/kg bw/day); 9 animals each in test substance treatment groups and 8 animals in control group. Mice in 1.8% dose group of both feeding and drinking water study exhibited severe weight loss so LAS administration was stopped after 2 weeks. No mortality was observed throughout the study. There was significant inhibition of weight increase in both males and females of 0.6% dose group consuming LAS water compared to controls, while there was a significant increase in body weight compared to controls in males of 0.6% dose group fed with LAS in diet and 0.07% dose group consuming LAS water. Individual daily food consumption was higher in all treatment groups compared to controls. Water consumption was reduced in males of 0.6% dose group (drinking water study) and in females of 0.6% dose group (dietary study) and 0.2% dose group (drinking water study) and increased in males of 0.6% dose group (dietary study), 0.07 and 0.2% dose groups (drinking water study) and female of 0.07% dose groups (drinking water study). In males of 0.6% dose group (dietary study) and 0.07% dose group (drinking water study), the absolute liver weight was significantly increased, in males of 0.6% dose group (dietary study), 0.2 and 0.6 dose groups (drinking water study), the relative liver weight was significantly increased, and in 0.07% (drinking water) males the relative liver weight was increased. Relative lung, heart and kidney weights were also increased in male mice consuming 0.07% LAS water. In females, the relative liver weight was significantly increased in all treatment groups. Relative spleen, heart and kidney weights were also increased in female mice consuming 0.6% LAS water. There were reductions in LDH activity in male mice of 0.6% group fed with LAS diet and GOT activity in male mice of 0.6% group consuming LAS water were significant. GOT activity in female mice of 0.2% group (drinking water study) was also significantly reduced. G6Pase was significantly reduced in males and female mice of 0.6% group consuming LAS water compared to controls, and also reduced in other treatment groups. No NOAEL can be identified for dietary study in mice, as only one dose level for LAS was fed to animals throughout the study. Administration of LAS to SLC-ICR mice by either test diets (0 and 0.6) or drinking water (0, 0.07, 0.2 and 0.6) for 9 months (focusing on the liver and kidneys) revealed an NOAEL of 0.07% (133 mg/kg bw/day in drinking water), based on observed adverse effects on organ weight and liver and kidney enzymes. Repeated administration of LAS impair renal and liver function.

   

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:  

Highest NOAEL below lowest LOAEL from three long term studies = 85 mg/kg bw

Dermal Administration

The key dermal study evaluates the potential effects from repeated exposures to LAS-Mg, the magnesium salt analogue of LAS (read across). Repeated dose oral studies demonstrate that LAS-Mg has comparable repeated dose toxicity to LAS. The study covers transdermal administration of LAS-Mg in 3% polyethylene glycol for 26 weeks. No adverse effects were observed. The resultant NOAEL value is 5% LAS-Mg.

Justification for classification or non classification:

Effects in long-term repeated dose studies conducted on LAS and lasting up to 9 months (subchronic studies) are related to enzymatic, body and organ weight reductions but not mortality.

Justification for classification or non-classification

Based on the absence of observed specific organ toxicity in three repeated dose studies (28-day, 90-day and six months duration), LAS does not demonstrate specific target organ toxicity.