Registration Dossier

Administrative data

Description of key information

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:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Does not meet important criteria of today's standard methods
Qualifier:
no guideline followed
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:
Wistar
Remarks:
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
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:
unchanged (no vehicle)
Remarks:
Test substance was administered either in diet or drinking water
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Nine months
Frequency of treatment:
Continuous in diet or drinking water (ad libitum)
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 (Table 1).
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 (Table 1).
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 cho
linesterase 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 (Table 2).
There was also significant decrease in absolute and relative heart weight in females of 0.6% (diet) and 0.07% (drinking water) dose groups (Table 2).
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):
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:
NOAEL
Effect level:
85 mg/kg bw/day (nominal)
Based on:
act. ingr.
Remarks:
Drinking water
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 lactat e 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
Dose descriptor:
LOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
act. ingr.
Remarks:
Dietary 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
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

Table 1: Body weight gain, Food, water and sample consumption of Rats on administration of LAS for 9 months

 Dose group  No. of Rats Initial BW (g)  Final BW (g)  BW gain (%)  Food (g/rat/day)  Water (g/rat/day)  Sample (g/kg bw/day) 
 0 8M  113.1±1.156   421.6±8.542   372.6±5.889  15  23  -
 0.6  8M   110.6±0.925   413.5±7.356   373.8±6.380  16  23 0.234
 1.8  8M   109.2±2.218   341.1±8.008   312.5±6.518**  14  33 0.747
 0.07  8M   110.6±1.572   411.0±5.255   371.9±6.908  17  29 0.051
 0.2  8M   108.3±1.900   385.1±5.453   356.1±6.346**  15  33  0.148
               
 0  8F   92.3±1.592   212.6±4.508   230.6±5.420  10  18  -
 0.6  8F   92.1±1.663   216.1±7.705    234.3±5.753  10  17  0.287
 1.8  8F   90.6±1.463   184.8±4.278    204.3±5.791**  9  18  0.969
 0.07  8F   92.7±1.770   206.0±3.555    222.4±4.478  11  20  0.082
 0.2  8F   91.6±1.893   209.3±5.383    228.4±3.857  12  18  0.173

*p<0.05 **p<0.01

Table 2: Organ weight of male and female rats on administration of LAS for 9 months

 Dose group  Brain (g) / (g/100g)  Heart (g) / (g/100g)   Lung (g) / (g/100g)   Liver (g) / (g/100g)   Spleen (g) / (g/100g)   Kidner (R) (g) / (g/100g)   Kidney (L) (g) / (g/100g) Adrenal (R) (mg) / (mg/100g)   Adrenal (L) (mg) / (mg/100g) Testis/Ovary (R) (g) / (g/100g)    Testis/Ovary (L) (g) / (g/100g)    Uterus (g) / (g/100g)  
 0 M  1.987±0.011 /  0.463±0.008   1.026±0.018 /  0.239±0.005    1.263±0.033 /  0.294±0.008  12.7±0.341 /  2.9±0.039  0.698±0.014 /  0.162±0.003    1.162±0.040 /  0.270±0.008   1.184±0.041 /  0.275±0.007  18.3±1.117 /  4.2±0.217   18.1±0.934 /  4.2±0.225   1.591±0.023 /  0.370±0.006   1.643±0.027 /  0.382±0.005  
 0.6 M   1.982±0.011 /  0.473±0.007   0.971±0.022* /  0.231±0.004    1.269±0.042 /  0.302±0.005    12.9±0.310 /  3.0±0.049  0.682±0.019 /  0.162±0.002     1.210±0.026 /  0.290±0.006   1.214±0.032 /  0.289±0.007   19.6±1.900 /  4.7±0.435  17.6±1.602 /  4.2±0.416     1.563±0.019 /  0.373±0.004   1.585±0.027 /  0.378±0.007   -  
 1.8 M   1.827±0.131 /  0.521±0.037   0.825±0.026* /  0.235±0.003    1.040±0.025* /  0.295±0.002    11.5±0.352* /  3.2±0.043*   0.501±0.163** /  0.143±0.003**  0.977±0.022** /  0.279±0.007   0.982±0.017** /  0.281±0.007    17.5±1.370 /  5.0±0.481  17.0±0.654 /  4.8±0.146    1.455±0.027** /  0.415±0.004**    1.491±0.033** /  0.425±0.004**  -  
 0.07 M   1.995±0.016 /  0.471±0.006   0.981±0.031 /  0.232±0.008    1.287±0.021 /  0.304±0.007    13.2±0.258 /  3.0±0.052   0.682±0.009 /  0.161±0.002    1.221±0.018 /  0.288±0.005   1.254±0.012 /  0.296±0.005*   18.6±0.680 /  4.4±0.156   19.2±1.024 /  4.5±0.262   1.606±0.022 /  0.379±0.006    1.566±0.056 /  0.370±0.015  -  
 0.2 M   1.881±0.108 /  0.478±0.028   0.975±0.183 /  0.247±0.003    1.154±0.037* /  0.293±0.007    11.6±0.184 /  2.9±0.042   0.595±0.013** /  0.150±0.002   1.124±0.025 /  0.286±0.007   1.154±0.031 /  0.293±0.008   18.4±0.914 /  4.6±0.232   17.5±1.309 /  4.4±0.354   1.483±0.059 /  0.377±0.016     1.589±0.013 /  0.404±0.005  -  
                           
 0 F   1.853±0.023 /  0.846±0.016   0.647±0.013 /  0.294±0.003    0.870±0.026 /  0.397±0.012    6.2±0.150 /  2.8±0.051   0.441±0.016 /  0.201±0.006    0.650±0.021 /  0.296±0.006   0.650±0.021 /  0.296±0.008   24.8±1.381 /  11.2±0.443   25.7±1.385 /  11.7±0.487   29.3±2.738 /  13.4±1.225    31.2±4.007 /  14.2±1.857    0.687±0.037 /  0.313±0.017   
 0.6 F   1.859±0.011 /  0.845±0.027   0.595±0.019* /  0.269±0.006**   0.810±0.032 /  0.367±0.015   6.6±0.355 /  2.9±0.061   0.425±0.010 /  0.193±0.009    0.648±0.023 /  0.292±0.004   0.655±0.026 /  0.296±0.008   25.8±1.563 /  11.7±0.820   24.8±1.641 /  11.3±0.863   23.3±3.504 /  10.8±1.740    32.8±3.120 /  14.9±1.380    0.660±0.033 /  0.301±0.020    
 1.8 F   1.788±0.031 /  0.954±0.015**  
 0.455±0.008 /  0.242±0.002
  0.761±0.028 /  0.405±0.009  7.1±0.195** /  3.8±0.082**    0.351±0.012** /  0.187±0.004   0.580±0.015 /  0.309±0.003   0.586±0.021* /  0.312±0.007    19.6±1.981* /  10.3±0.924  21.3±1.487* /  11.3±0.609    25.3±2.853 /  13.4±1.417     31.5±2.322 /  16.7±1.165     0.588±0.066 /  0.312±0.034   
 0.07 F   1.854±0.019 /  0.844±0.016   0.611±0.011* /  0.277±0.004**   0.801±0.027 /  0.365±0.014   6.3±0.139 /  2.8±0.063   0.424±0.007 /  0.193±0.004    0.669±0.017 /  0.304±0.006   0.677±0.010 /  0.308±0.005  22.0±1.619 /  10.0±0.720    21.0±1.763 /  9.8±0.790   30.0±1.490 /  13.6±0.740    31.7±2.300 /  12.2±1.200     0.729±0.051 /  0.331±0.022   
 0.2 F   1.691±0.112 /  0.810±0.053   0.593±0.015 /  0.287±0.004   0.817±0.040 /  0.393±0.021   6.1±0.220 /  2.9±0.071   0.428±0.014 /  0.205±0.006    0.651±0.015 /  0.312±0.006   0.670±0.020 /  0.321±0.008*   23.2±1.495 /  11.1±0.677   24.3±1.154 /  11.6±0.431   28.4±1.633 /  13.6±0.821    28.6±1.900 /  13.7±0.830    0.644±0.032 /  0.308±0.014   
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 a 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 a NOAEL of 0.07% (85 mg/kg bw/day in drinking water), based on adverse effects at all dose levels, 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.

Four week old male and female Wistar 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. Five animals were housed in each cage and maintained under controlled environmental conditions (temperature: Average of 25 ± 1°C, humidity: 50 - 60%, and 12 hours light /12 hours dark).CE-2 diet (from CLEA Japan) and water were provided ad 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) male 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, KATPase 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 on adverse effects at all dose levels, 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

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

Endpoint conclusion
Quality of whole database:
Information available only for TEA

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Quality of whole database:
Information available only regarding TEA

Additional information

Oral

No information is available on the repeated dose toxicity of LAS TEA. The endpoint was addressed with data from LAS Na and TEA.

TEA:

 In a 90 -day toxicity study TEA was administered to male and female rats in the feed at dose levels of 0, 250, 500, and 1000 mg/kg bw/day for 91 days. No treatment-related effects were observed in the animals.The NOAEL is 1000 mg/kg bw/day (TSCATS, 1989).

LAS Na:

Male and female rats were exposed to LAS Na (125, 250, 500 mg/kg bw/day) orally by gavage daily for 28 days. The results showed suppressed body weight gain, differences in some serum biochemical measures when compared to the controls, and decreased (spleen, heart, thymus) or increased (liver) organ weights in the animals of the highest dose level. The resultant LOAEL and NOAEL values were 250 and 125 mg/kg bw/day, respectively (Ito et al., 1978).

In a 6-month toxicity test male and female rats were exposed to LAS Na (CAS 69669-44-9) in the diet daily:40, 115, 340, 1030 mg/kg bw/day. Diarrhea, suppressed growth, increased cecal weight, and degeneration of renal tubes characterized the highest dose group. Similar but less severe signs were seen in other doses with the exception of the lowest dose of 0.07%, 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 (Yoneyama et al., 1972).

In a 9-month toxicity study male and female rats were exposed to LAS Na (CAS 69669-44-9; 85, 145, 430 mg/kg bw/day) in drinking water daily. Body weight was suppressed in the highest dose. Significant decreases in transaminase activity and renal Na,K-ATPase was seen in the second group. The resultant LOAEL and NOAEL values were 145 and 85 mg/kg bw/day, respectively (Yoneyama et al., 1976).

Dermal

TEA:

In a 90 -day dermal toxicity study, Fischer rats were treated with 0, 125, 250, 500, 1000 or 2000 mg/kg bw/day, 5 days/week. Application of 2000 mg/kg bw resulted in a significant decrease in body weight gain, and grossly visible crusts at the site of application were noted in males and females administered 1000 or 2000 mg/kg bw. NOAELs for local effects were determined to be 125 and 250 mg/kg bw/day for males and females, respectively. The NOAEL's for systemic effects were established to be 125 and 500 mg/kg bw/day for males and females, respectively, based on kidney effects (Battelle, 1987a).

In a second dermal toxicity study, this time with mice, TEA (0, 250, 500, 1000, 2000 or 4000 mg/kg bw/day) was applied daily on the skin for 90 days. The NOAEL for local effects was determined to be 250 mg/kg bw/day (acanthosis at the application site). NOAEL's for systemic effects were established to be 1000 and 250 mg/kg bw/day for males and females, respectively, based on kidney effects.

The local effects should be mainly attributed to triethanolamine (free amine) and not to the ammonium cation. Therefore, such effects are most probably not relevant for LAS TEA.

LAS Na:

No dermal repeated-dose toxicity studies are available for LAS Na.


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: cecum; urogenital: kidneys

Justification for classification or non-classification

Based on the results of the repeated dose toxicity studies, LAS TEA does not need to be classified according to (CLP) Regulation (EC) No. 1272/2008. Although adverse effects have been seen after repeated exposures of animals to LAS Na, these were seen at dose levels well above the classification criteria limit of 100 mg/kg bw (LOAEL 115 mg/kg bw).