Registration Dossier

Administrative data

Description of key information

For the whole category of alkyl sulfates (AS) a NOAEL of 488 mg/kg bw/day for oral and dermal exposure was established.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Reason / purpose:
read-across source
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
no data
Route of administration:
oral: feed
Vehicle:
other: plain diet
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:0.07, 0.14, 0.28, 0.56, 1.13, 2.25%Basis:nominal in diet
Remarks:
Doses / Concentrations:58, 113, 228, 470, 961 and 1944 mg/kg bw/day (males)Basis:other: reported daily intake of the test substance based on mean body weight and food consumption over the entire 13-week treatment period
No. of animals per sex per dose:
10 test group20 control group
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
BODY WEIGHT: - Time schedule for examinations: WeeklyFOOD AND WATER CONSUMPTION:- Time schedule for examinations: Twice weeklyHAEMATOLOGY: - Time schedule for collection of blood: At the end of the experimental period (13 weeks)- Anaesthetic used for blood collection: Yes (halothane)CLINICAL CHEMISTRY: - Time schedule for collection of blood: At the end of the experimental period (13 weeks)
Sacrifice and pathology:
GROSS PATHOLOGY: YesHISTOPATHOLOGY: Yes
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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):
effects observed, treatment-related
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
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITYTwo male rats were killed due to ill health during this study.BODY WEIGHT AND WEIGHT GAINThe two highest dose groups gained less weight.FOOD AND WATER CONSUMPTION The high dose groups ate less. High dose females drank less water.HAEMATOLOGYSerum protein decreased at the highest dose (males). CLINICAL CHEMISTRYSerum Mg, protein, cholesterol, decreased at the highest dose (males). Serum GOT was elevated in high dose males. Serum GPT, was elevated in males of the two highest dose groups (1.13% and 2.25%) and females of the second highest dose group (1.13%). Serum AP was increased in the 1.13% and 2.25% dose groups (females) and 1.13% group (males).ORGAN WEIGHTSRelative liver weights (both sexes) increased in the three highest dose groups (0.56%-2.25%). Absolute spleen weights increased in males at the two highest doses and females at the highest dose. Absolute kidney weights decreased in high dose males. Relative kidney weights increased in females at the two highest doses. Relative weights of the testes increased at the two highest doses.GROSS PATHOLOGYHigh dose males had virtually no abdominal fat and changes in color and consistency of intestinal contents. These findings were less frequently noted in high dose females.HISTOPATHOLOGY: NON-NEOPLASTICDiffuse (6 females, 3 males) and periportal (11/20) hypertrophy, reduced cytoplasmic (glycogenic) vacuolation, reduced cytoplasmic neutral fat and hemodiderin content prominent at high dose. Periportal hypertrophy also observed at nest two highest doses (1.13% and 0.56%). Periportal parenchymal hypertrophy was observed in 4 females at the 0.28% level. reduced cytoplasmic (glycogenic) vacuolation, reduced cytoplasmic neutral fat and hemodiderin conten were observed at the 0.56%-2.25% dose levels.Nephrocalcinosis is freqently observed in untreated females of the Wistar strain: the incidence and severity was reduced in the highest dose group.Lymphatic dilation of the small intestine was more prominent at the high dose.
Dose descriptor:
NOAEL
Effect level:
488 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No toxic effects.
Dose descriptor:
LOAEL
Effect level:
1 016 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Systemic effects that could not be regarded solely as adaptive processess, e.g. increased testes weight.
Critical effects observed:
not specified
Conclusions:
Since the liver as the target organ showed only adaptive responses, the NOAEL was set at 0.56% (488 mg/kg bw/day). The adaptive changes included elevated relative liver weight due to a lower body weight and reduced food consumption, hepatic periportal hypertrophy as well as increased serum alkaline phosphatase (AP) activity. An increased serum AP activity is considered to represent a physiological adaptation resulting from changes in hepatic metabolism required for the breakdown and detoxification of the test material. Since AP is mainly localized in the hepatic parenchyma, enlargement of the hepatic parenchymal cells accompanied by an increased organ weight are an obvious consequence.
Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Reason / purpose:
read-across source
Species:
rat
Strain:
other: Sprague-Dawley (Charles River CD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Charles River Laboratories, Wilmington, Massachusetts- Age at study initiation: 3-4 wks - Weight at study initiation: The mean body weight (range) for males and female rat was133 g (102-154 g) and 119 g (92-135 g), respectively.- Housing: Animals were housed individually in elevated stainless steel wire mesh cages.- Diet: Standard laboratory diet (Purina), ad libitum. Fresh food presented weekly. - Water: Ad libitum- Acclimation period: At least 12-13 d prior to treatment.ENVIRONMENTAL CONDITIONS- Temperature: 72-78°F- Relative Humidity: 45-55%- Air changes: Not reported - Photoperiod: 12 h light, 12 h darkIN-LIFE DATES: From Aug. 4, 1975 to Nov. 06, 1975
Route of administration:
oral: feed
Details on oral exposure:
DIET PREPARATION- Rate of preparation of diet: Weekly- Mixing procedure: Test substance was mixed with Purina laboratory diet.- Storage temperature of food: Not reported
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:0, 0.25, 0.5 and 1% Basis:nominal in diet
Remarks:
Doses / Concentrations:0, 55.5, 112.48 and 201.28 mg/kg bw/dBasis:other: actual ingested, males
Remarks:
Doses / Concentrations:0, 59.94, 122.84 and 254.56 mg/kg bw/dBasis:other: actual ingested, females
No. of animals per sex per dose:
20
Control animals:
yes, plain diet
Details on study design:
- Rationale for animal assignment: Rats were initially assigned to groups randomly. Those of questionable health or with outlying body weights were replaced in an attempt to balance the range and distribution of body weight values. Groups were assigned to treatment randomly. - Treatment of Groups: The test substance treatment to different dose groups is as follows: Control group (Group I): Diet, ad libitum Low dose Group (Group II): 0.25% of test substance in diet, ad libitum (equivalent to 55.5 and 59.94 mg/kg bw/d for male and female rats, respectively) Mid dose Group (Group III): 50 g/kg of test substance in diet, ad libitum (equivalent to 112.48 and 122.84 mg/kg bw/d for male and female rats, respectively) High dose Group (Group IV): 100 g/kg of test substance in diet, ad libitum (equivalent to 201.28 and 254.56 mg/kg bw/d for male and female rats, respectively)
Observations and examinations performed and frequency:
MORTALITY- Time schedule: DailyCAGE SIDE OBSERVATIONS: Yes - Time schedule: Daily- Cage side observations checked: Physical appearance, signs of local or systemic toxicity, pharmacologic effects. DETAILED CLINICAL OBSERVATIONS: Not reported BODY WEIGHT: Yes - Time schedule for examinations: At pre-test, weekly during treatment, and terminally (after fasting).FOOD CONSUMPTION : Yes- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/week: YesFOOD EFFICIENCY: Yes (weekly, beginning one week prior to treatment).- Efficiency of food utilization: Body weight gain (gm) + food consumption (gm) x 100. WATER CONSUMPTION AND COMPOUND INTAKE: NoOPHTHALMOSCOPIC EXAMINATION: Yes- Time schedule for examinations: Pretest and at study termination (wk 13)- Dose groups that were examined: All animalsHAEMATOLOGY: Yes - Time schedule for collection of blood: At 28 d and 13 wks- Anaesthetic used for blood collection: No data- Animals fasted: Yes- How many animals: 5/sex/group- Parameters checked: Hemoglobin, hematocrit, erythrocytes, total and differential leukocytes, erythrocyte morphology, mean corpuscular volume, mean corpuscular hemoglobin concentration, and mean corpuscular hemoglobin.CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: 28 d and 13 wks- Animals fasted: Yes- How many animals: 5/sex/group- Parameters checked: Serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase, blood urea nitrogen, fasting glucose, total protein, albumin, globulin, and A/G ratio.URINALYSIS: Yes - Time schedule for collection of urine: At 28 d and 13 wk time points- Metabolism cages used for collection of urine: No data - Animals fasted: Yes - Parameters checked: Gross appearance, protein, glucose, pH, specific gravity, ketones, bilirubin, and occult blood.NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes - Time schedule for necropsy: Animals were sacrificed at 28 d and at termination (90 d) of the study. 5 male and 5 female rats from each group were sacrificed at 28 d of the study. All surviving rats were sacrificed and necropsy was performed at the termination of the study.- Sacrifice Method: Animals were sacrificed by exsanguination under ether anesthesia.HISTOPATHOLOGY: Yes- How many animals: 5 male and 5 female rats at 28 d time interval and 10 male and 10 female rats at study termination from Group I and IV.- Tissues collected for histology: Adrenal (2), bone, bone marrow (sternal), brain (2 sections; with meninges), esophagus, eye (with optic nerve), gonad (testis, epididymis, ovary, oviduct), heart (with coronary vessels), intestine (small and large), kidney (2), liver (2), lung, lymph node (mesenteric and pulmonary), mammary gland (inguinal), pancreas, pituitary, prostate (ventral), salivary gland, seminal vesicle, skin, spleen, stomach, thyroid, tongue, trachea, urethra, ureters, urinary bladder, uterus (cervix and vagina), gross lesions (including a section of normal-appearing portion of same tissue), tissue masses). - Preservative used: Bouin's solution for eyes and testes and 10% neutral buffered formalin for all other tissues. - Stain used: Hematoxylin and eosin.
Other examinations:
- Organs Weight and Organ/Body Weight Ratios: The organ weight and organ/body weight ratio was determined for liver, kidney, adrenal, gonads and pituitary of animals sacrificed at 28 d and sacrificed at study termination. The details on number of animals from each group taken for calculation are provided in study report.
Statistics:
Body weight, food consumption, hematology, clinical chemistry parameters, organ weights, and organ/body weight ratios were analyzed statistically. All test substance treated groups were compared with control treatment at each time interval.
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:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
MORTALITY: No mortality was observed during study period.CLINICAL SIGNS: There were no physical observations noted which were considered related to test substance administration.BODY WEIGHT AND WEIGHT GAIN: Mean body weight values of the test substance treated groups were generally comparable to the control group throughout the treatment period. The details on individual body weight are provided in study report.FOOD CONSUMPTION: Food consumption values of the test substance treated groups were generally comparable to the controls throughout the treatment period. The details on food consumption are provided in study report.FOOD EFFICIENCY: Feed efficiency values of the test substance treated groups were generally comparable to the controls throughout the treatment period. The details on food efficiency are provided in study report.OPHTHALMOSCOPIC EXAMINATION: No treatment related visible abnormalities were observed in any of test substance treated groups. HAEMATOLOGY: Hematology values of all test substance treated groups were considered comparable to control or within normal limits. The details on individual results of hematology are provided in study report.CLINICAL CHEMISTRY: Sporadic differences from control, some of which were statistically significant, were noted in some parameters. However, these did not occur in a dose related pattern of test substance. The details on results of clinical chemistry are provided in study report.URINALYSIS: Urinalysis values of all test substance treated groups were considered comparable to controls. The details on results of urinalysis are provided in study report.ORGAN WEIGHTS: The absolute liver weights of the compound-treated groups of males were slightly higher than control at one and three months; however, no statistically significant differences were noted and no dose-dependent pattern was evident. In addition, histopathology evaluations failed to reveal any differences from control considered to be related to test substance treatment. Other scattered differences from controls were observed, however they did not occur in a pattern indicative of a test substance treatment related. The details on individual body weights are provided in study report.GROSS PATHOLOGY: No test substance treatment related alterations were observed. However, occasional tissue alternations were observed at one and three months but all occurred with approx. equal severity and distribution in the control and test substance treated animals. The details on results of gross pathology are provided in study report.HISTOPATHOLOGY: NON-NEOPLASTIC: No test substance treatment related effects were observed in high dose group. Tissues from the test substance treated animals were comparable to those of the controls. Varying degrees of chronic lung inflammation was noted in both the control and high dose rats. The changes were comparable with those observed in early chronic murine pneumonia. These lesions along with other occasional sporadic tissue changes occurred with approx. equal severity and distribution in the control rats as in the test substance treated animals and were judged to be unrelated to compound administration. The details on results of histopathology are provided in study report.
Dose descriptor:
NOAEL
Effect level:
201.28 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
other: Overall effects
Dose descriptor:
NOAEL
Effect level:
254.56 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
other: Overall effects
Dose descriptor:
NOAEL
Effect level:
1 other: % in the diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Overall effects
Critical effects observed:
not specified
Conclusions:
Administration of CNAE12S/AS to Sprague Dawley rats (male and female) at dose levels of 0, 0.25, 0.50 and 1% in diet for 90 days resulted in a NOAEL value of 1% in diet (equivalent to 201.28 and 254.56 mg/kg bw/d for male and female rats, respectively).
Executive summary:

The subchronic oral toxicity of CNAE12S/AS was determined by following the method similar to the OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents).

The study was designed to determine the toxicity of CNAE12S/AS when administered at dose levels of 0, 0.25, 0.50 and 1 % in diet for 90 d.

Sprague Dawley (Charles River CD) rats of 3-4 wk age, weighing 102-154 g (males) and 92-135 g (females)) (source: Charles River) were housed individually in elevated stainless steel wire mesh cages. Animals were maintained under standard laboratory conditions (temperature: 72-78°F, humidity: 45-55%; 12 h light/12 h dark cycle per day). The animals were acclimated for 12-13 d prior to study initiation and had free access to food and water throughout the treatment period.

Animals were randomly distributed into four groups of 20 animals/sex/dose group. The control group (Group I) received plain diet (Standard laboratory diet (Purina)). Treatment groups, Group II, III and IV, were fed on plain diet containing test substance at concentrations of 0.25, 0.5 and 1% of diet, respectively (equivalent to 55.5, 112.48 and 201.28 mg/kg bw/d for males and 59.94, 122.84 and 254.56 mg/kg bw/d for female rats, respectively). The diet was prepared weekly.

Animals were observed daily for physical appearance, signs of local or systemic toxicity, pharmacologic effects and mortality.

Food consumption, feed efficiency and body weight were observed during the study period. The organ weight and organ/body weight ratio were determined for liver, kidney, adrenal, gonads and pituitary of animals sacrificed at 28 d (interim) and after 90 d (terminal). Ophthalmoscopic examination of all animals was performed at study initiation and study termination. Clinical examinations (hematology and clinical chemistry) and urinalysis were performed on animals prior to sacrifice. Complete gross postmortem examination was performed on all animals. Complete histopathological evaluation of different tissues samples was performed for high dose and control group animals, collected after treatment of 28 and 90 d.

Animals were sacrificed at 28 d and at termination (90 d) of study. 5 male and 5 female rats from each group were sacrificed at 28 d during study. At the termination of the study, all surviving rats were sacrificed.

No mortality was observed during study period. No pharmacological or toxicological signs were observed throughout the study.

No treatment related effects were observed in feed efficiency and body weight parameters.

No treatment related effects were observed in food consumption, food efficiency, ophthalmoscopic examination, urinalysis, hematology, clinical chemistry, organ weights, gross pathology and histopathology parameters at any dose level compared to control animals.

Based on above, administration of CNAE12S/AS to Sprague Dawley rats (male and female) at dose levels of 0, 0.25, 0.50 and 1 % in diet for 90 d resulted in a NOAEL value of 1% in diet (equivalent to 201.28 and 254.56 mg/kg bw/d for male and female rats, respectively). 

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Reason / purpose:
read-across source
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: feed
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:0, 0.07, 0.14, 0.28, 0.56, 1.13, 2.25%Basis:nominal in diet
Remarks:
Doses / Concentrations:0, 58, 116, 230, 460, 920, 1840 mg/kg bw/dayBasis:actual ingested
No. of animals per sex per dose:
10 test group20 control group
Dose descriptor:
NOAEL
Effect level:
460 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Only adaptive changes (elevated liver weights and hypertrophy of the liver) were observed.
Dose descriptor:
LOAEL
Effect level:
920 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Significant decreased body weight and diffuse hepatocytic hypertrophy.
Critical effects observed:
not specified
Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Reason / purpose:
read-across source
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: feed
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:0, 0.07, 0.14, 0.28, 0.56, 1.13, 2.25%Basis:nominal in diet
Remarks:
Doses / Concentrations:0, 64, 134, 253, 512, 1007, 2096 mg/kg bw/dayBasis:actual ingested
No. of animals per sex per dose:
10 test group20 control group
Dose descriptor:
NOAEL
Effect level:
512 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Only adaptive changes (elevated liver weights and hypertrophy of the liver) were observed.
Dose descriptor:
LOAEL
Effect level:
1 007 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified
Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Reason / purpose:
read-across source
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: feed
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:0, 0.07, 0.14, 0.28, 0.56, 1.13, 2.25%Basis:nominal in diet
Remarks:
Doses / Concentrations:0, 61, 123, 230, 482, 970, 2067 mg/kg bw/dayBasis:actual ingested
No. of animals per sex per dose:
10 test group20 control group
Dose descriptor:
NOAEL
Effect level:
482 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Only adaptive changes (elevated liver weights and hypertrophy of the liver) were observed.
Dose descriptor:
LOAEL
Effect level:
970 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified
Endpoint:
chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Reason / purpose:
read-across source
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Diets were prepared by thoroughly mixing the appropriate quantity of Dobanol-25-sulphate HCB with a purified diet to provide feed containing the required amount of active ingredient, ie. the surfactant was not added to the diet as a part replacement for any ingredient, but was added “on top of the diet”. Rats were individually housed and provided with diet and water ad libitum. The animals were inspected daily for signs of ill-health while body weights, and food and water intakes, were measured weekly for the first 13 weeks, again at week 16, and thereafter at intervals of 4 weeks until the end of the study.
Route of administration:
oral: feed
Vehicle:
other: plain diet
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 years
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:0, 0.015, 0.15, 1.5% Basis:nominal in diet
Remarks:
Doses / Concentrations:0, 11, 113, 1125 mg/kg bw/dayBasis:actual ingested
No. of animals per sex per dose:
45
Control animals:
yes, plain diet
Other examinations:
Animals dying or killed during the test received a full post-mortem examination at which tissues were taken for histological examination. Animals surviving to the end of the test were starved overnight and blood was taken under anaesthesia for haematology and biochemical measurements after which the animals were killed and a number of organs (heart, liver, spleen kidneys, testes, adrenals and brain) were removed and weighed. These organs and a range of other tissues from each rat were preserved for histological examination. Histological examination was undertaken on stained tissue sections from all animals fed the control diet and each dietary level of the test substances.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
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
Histopathological findings: neoplastic:
no effects observed
Details on results:
The test materials used in the individual studies were prepared by two different production methods (high conversion bleached or HCB; and low conversion, unbleached or LCU). They differed slightly in chain length distribution, the latter having a slightly higher proportion of the C15AS. In both studies, the test material was dosed at 0, 0.015, 0.15 and 1.5% in the diet. There was no increase in tumor incidence, nor any impact on tumor type in either study. For both studies, approximately 70% of animals survived to study termination. Mortality was similar across dosage groups and controls.Animals in the 1.5% dose groups in both studies exhibited reduced food and water consumption, and slower growth rates. Within these high dose groups, there was a decreased number of total tumors and tumor-bearing animals. Elevated serum GPT, LDH and AP were observed in high dose males.Increased absolute liver weights and liver to body weight ratios, hypertrophy of the hepatic parenchyma, increased relative testicular weights, reduced incidence and severity of chronic nephropathy and nephrocalcinosis, and reduced arterial medial hypertrophy were among the findings at the higher dose levels.
Dose descriptor:
NOEL
Effect level:
113 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: no effects observed
Dose descriptor:
LOEL
Effect level:
1 125 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Liver weights and liver enzymes increased as well as histopathological changes.
Critical effects observed:
not specified
Executive summary:

In two comprehensive 2-year studies with groups of 45 animals/sex/group, a similar NOEL of 113 mg/kg bw/day was found. The LOELs were in both studies at 1125 mg/kg bw/day with a clear indication of the liver as target organ (liver weights and liver enzymes increased, histopathological changes in the liver). There was no indication of another target organ in these very comprehensive studies. No adverse effects were found with regard to the kidneys (reduced incidence of nephrocalcinosis, reduced incidence of chronic nephropathy).

Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Reason / purpose:
read-across source
Species:
rat
Sex:
male/female
Route of administration:
oral: feed
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:0, 40, 200, 1000, 5000 ppmBasis:nominal in diet
Remarks:
Doses / Concentrations:0, 3, 17, 86, 430 mg/kg bw/dayBasis:actual ingested
Dose descriptor:
NOAEL
Effect level:
>= 430 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Only adaptive increases in liver weights in female animals.
Critical effects observed:
not specified
Executive summary:

C12ASO4Na was tested in a 90-day feeding study on rats. 12 male and 12 female rats/group were fed dietary levels of 40, 200, 1000 or 5000 ppm (corresponding to 3, 17, 86 or 430 mg/kg bw/day). The control group (18 males, 18 females) received the diet alone. Daily observations were made on health. Body weight and food intake were recorded weekly. Urine samples were obtained from the 5000 ppm and control groups during Week 12. The urine was examined for color, pH, protein, reducing substances, bile salts and microscopic constituents. Terminal blood samples were taken by cardiac puncture and erythrocyte and leucocyte counts and determinations of haematocrit and haemoglobin were made. Total plasma protein and urea were determined. Gross pathological and histological examination of a wide range of organs were made.The only effects observed occurred at 5000 ppm and comprised increases in liver weights in female animals.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
From July 22, 1975 to Nov. 06, 1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study well documented, followed method comparable to guideline. According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
no
Remarks:
Pre-GLP
Limit test:
no
Species:
rat
Strain:
other: Sprague-Dawley (Charles River CD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Charles River Laboratories, Wilmington, Massachusetts- Age at study initiation: 3-4 wks - Weight at study initiation: The mean body weight (range) for males and female rat was133 g (102-154 g) and 119 g (92-135 g), respectively.- Housing: Animals were housed individually in elevated stainless steel wire mesh cages.- Diet: Standard laboratory diet (Purina), ad libitum. Fresh food presented weekly. - Water: Ad libitum- Acclimation period: At least 12-13 d prior to treatment.ENVIRONMENTAL CONDITIONS- Temperature: 72-78°F- Relative Humidity: 45-55%- Air changes: Not reported - Photoperiod: 12 h light, 12 h darkIN-LIFE DATES: From Aug. 4, 1975 to Nov. 06, 1975
Route of administration:
oral: feed
Details on oral exposure:
DIET PREPARATION- Rate of preparation of diet: Weekly- Mixing procedure: Test substance was mixed with Purina laboratory diet.- Storage temperature of food: Not reported
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:0, 0.25, 0.5 and 1% Basis:nominal in diet
Remarks:
Doses / Concentrations:0, 55.5, 112.48 and 201.28 mg/kg bw/dBasis:other: actual ingested, males
Remarks:
Doses / Concentrations:0, 59.94, 122.84 and 254.56 mg/kg bw/dBasis:other: actual ingested, females
No. of animals per sex per dose:
20
Control animals:
yes, plain diet
Details on study design:
- Rationale for animal assignment: Rats were initially assigned to groups randomly. Those of questionable health or with outlying body weights were replaced in an attempt to balance the range and distribution of body weight values. Groups were assigned to treatment randomly. - Treatment of Groups: The test substance treatment to different dose groups is as follows: Control group (Group I): Diet, ad libitum Low dose Group (Group II): 0.25% of test substance in diet, ad libitum (equivalent to 55.5 and 59.94 mg/kg bw/d for male and female rats, respectively) Mid dose Group (Group III): 50 g/kg of test substance in diet, ad libitum (equivalent to 112.48 and 122.84 mg/kg bw/d for male and female rats, respectively) High dose Group (Group IV): 100 g/kg of test substance in diet, ad libitum (equivalent to 201.28 and 254.56 mg/kg bw/d for male and female rats, respectively)
Observations and examinations performed and frequency:
MORTALITY- Time schedule: DailyCAGE SIDE OBSERVATIONS: Yes - Time schedule: Daily- Cage side observations checked: Physical appearance, signs of local or systemic toxicity, pharmacologic effects. DETAILED CLINICAL OBSERVATIONS: Not reported BODY WEIGHT: Yes - Time schedule for examinations: At pre-test, weekly during treatment, and terminally (after fasting).FOOD CONSUMPTION : Yes- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/week: YesFOOD EFFICIENCY: Yes (weekly, beginning one week prior to treatment).- Efficiency of food utilization: Body weight gain (gm) + food consumption (gm) x 100. WATER CONSUMPTION AND COMPOUND INTAKE: NoOPHTHALMOSCOPIC EXAMINATION: Yes- Time schedule for examinations: Pretest and at study termination (wk 13)- Dose groups that were examined: All animalsHAEMATOLOGY: Yes - Time schedule for collection of blood: At 28 d and 13 wks- Anaesthetic used for blood collection: No data- Animals fasted: Yes- How many animals: 5/sex/group- Parameters checked: Hemoglobin, hematocrit, erythrocytes, total and differential leukocytes, erythrocyte morphology, mean corpuscular volume, mean corpuscular hemoglobin concentration, and mean corpuscular hemoglobin.CLINICAL CHEMISTRY: Yes- Time schedule for collection of blood: 28 d and 13 wks- Animals fasted: Yes- How many animals: 5/sex/group- Parameters checked: Serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase, blood urea nitrogen, fasting glucose, total protein, albumin, globulin, and A/G ratio.URINALYSIS: Yes - Time schedule for collection of urine: At 28 d and 13 wk time points- Metabolism cages used for collection of urine: No data - Animals fasted: Yes - Parameters checked: Gross appearance, protein, glucose, pH, specific gravity, ketones, bilirubin, and occult blood.NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes - Time schedule for necropsy: Animals were sacrificed at 28 d and at termination (90 d) of the study. 5 male and 5 female rats from each group were sacrificed at 28 d of the study. All surviving rats were sacrificed and necropsy was performed at the termination of the study.- Sacrifice Method: Animals were sacrificed by exsanguination under ether anesthesia.HISTOPATHOLOGY: Yes- How many animals: 5 male and 5 female rats at 28 d time interval and 10 male and 10 female rats at study termination from Group I and IV.- Tissues collected for histology: Adrenal (2), bone, bone marrow (sternal), brain (2 sections; with meninges), esophagus, eye (with optic nerve), gonad (testis, epididymis, ovary, oviduct), heart (with coronary vessels), intestine (small and large), kidney (2), liver (2), lung, lymph node (mesenteric and pulmonary), mammary gland (inguinal), pancreas, pituitary, prostate (ventral), salivary gland, seminal vesicle, skin, spleen, stomach, thyroid, tongue, trachea, urethra, ureters, urinary bladder, uterus (cervix and vagina), gross lesions (including a section of normal-appearing portion of same tissue), tissue masses). - Preservative used: Bouin's solution for eyes and testes and 10% neutral buffered formalin for all other tissues. - Stain used: Hematoxylin and eosin.
Other examinations:
- Organs Weight and Organ/Body Weight Ratios: The organ weight and organ/body weight ratio was determined for liver, kidney, adrenal, gonads and pituitary of animals sacrificed at 28 d and sacrificed at study termination. The details on number of animals from each group taken for calculation are provided in study report.
Statistics:
Body weight, food consumption, hematology, clinical chemistry parameters, organ weights, and organ/body weight ratios were analyzed statistically. All test substance treated groups were compared with control treatment at each time interval.
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:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
MORTALITY: No mortality was observed during study period.CLINICAL SIGNS: There were no physical observations noted which were considered related to test substance administration.BODY WEIGHT AND WEIGHT GAIN: Mean body weight values of the test substance treated groups were generally comparable to the control group throughout the treatment period. The details on individual body weight are provided in study report.FOOD CONSUMPTION: Food consumption values of the test substance treated groups were generally comparable to the controls throughout the treatment period. The details on food consumption are provided in study report.FOOD EFFICIENCY: Feed efficiency values of the test substance treated groups were generally comparable to the controls throughout the treatment period. The details on food efficiency are provided in study report.OPHTHALMOSCOPIC EXAMINATION: No treatment related visible abnormalities were observed in any of test substance treated groups. HAEMATOLOGY: Hematology values of all test substance treated groups were considered comparable to control or within normal limits. The details on individual results of hematology are provided in study report.CLINICAL CHEMISTRY: Sporadic differences from control, some of which were statistically significant, were noted in some parameters. However, these did not occur in a dose related pattern of test substance. The details on results of clinical chemistry are provided in study report.URINALYSIS: Urinalysis values of all test substance treated groups were considered comparable to controls. The details on results of urinalysis are provided in study report.ORGAN WEIGHTS: The absolute liver weights of the compound-treated groups of males were slightly higher than control at one and three months; however, no statistically significant differences were noted and no dose-dependent pattern was evident. In addition, histopathology evaluations failed to reveal any differences from control considered to be related to test substance treatment. Other scattered differences from controls were observed, however they did not occur in a pattern indicative of a test substance treatment related. The details on individual body weights are provided in study report.GROSS PATHOLOGY: No test substance treatment related alterations were observed. However, occasional tissue alternations were observed at one and three months but all occurred with approx. equal severity and distribution in the control and test substance treated animals. The details on results of gross pathology are provided in study report.HISTOPATHOLOGY: NON-NEOPLASTIC: No test substance treatment related effects were observed in high dose group. Tissues from the test substance treated animals were comparable to those of the controls. Varying degrees of chronic lung inflammation was noted in both the control and high dose rats. The changes were comparable with those observed in early chronic murine pneumonia. These lesions along with other occasional sporadic tissue changes occurred with approx. equal severity and distribution in the control rats as in the test substance treated animals and were judged to be unrelated to compound administration. The details on results of histopathology are provided in study report.
Dose descriptor:
NOAEL
Effect level:
201.28 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
other: Overall effects
Dose descriptor:
NOAEL
Effect level:
254.56 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
female
Basis for effect level:
other: Overall effects
Dose descriptor:
NOAEL
Effect level:
1 other: % in the diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Overall effects
Critical effects observed:
not specified
Conclusions:
Administration of CNAE12S/AS to Sprague Dawley rats (male and female) at dose levels of 0, 0.25, 0.50 and 1% in diet for 90 days resulted in a NOAEL value of 1% in diet (equivalent to 201.28 and 254.56 mg/kg bw/d for male and female rats, respectively).
Executive summary:

The subchronic oral toxicity of CNAE12S/AS was determined by following the method similar to the OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents).

The study was designed to determine the toxicity of CNAE12S/AS when administered at dose levels of 0, 0.25, 0.50 and 1 % in diet for 90 d.

Sprague Dawley (Charles River CD) rats of 3-4 wk age, weighing 102-154 g (males) and 92-135 g (females)) (source: Charles River) were housed individually in elevated stainless steel wire mesh cages. Animals were maintained under standard laboratory conditions (temperature: 72-78°F, humidity: 45-55%; 12 h light/12 h dark cycle per day). The animals were acclimated for 12-13 d prior to study initiation and had free access to food and water throughout the treatment period.

Animals were randomly distributed into four groups of 20 animals/sex/dose group. The control group (Group I) received plain diet (Standard laboratory diet (Purina)). Treatment groups, Group II, III and IV, were fed on plain diet containing test substance at concentrations of 0.25, 0.5 and 1% of diet, respectively (equivalent to 55.5, 112.48 and 201.28 mg/kg bw/d for males and 59.94, 122.84 and 254.56 mg/kg bw/d for female rats, respectively). The diet was prepared weekly.

Animals were observed daily for physical appearance, signs of local or systemic toxicity, pharmacologic effects and mortality.

Food consumption, feed efficiency and body weight were observed during the study period. The organ weight and organ/body weight ratio were determined for liver, kidney, adrenal, gonads and pituitary of animals sacrificed at 28 d (interim) and after 90 d (terminal). Ophthalmoscopic examination of all animals was performed at study initiation and study termination. Clinical examinations (hematology and clinical chemistry) and urinalysis were performed on animals prior to sacrifice. Complete gross postmortem examination was performed on all animals. Complete histopathological evaluation of different tissues samples was performed for high dose and control group animals, collected after treatment of 28 and 90 d.

Animals were sacrificed at 28 d and at termination (90 d) of study. 5 male and 5 female rats from each group were sacrificed at 28 d during study. At the termination of the study, all surviving rats were sacrificed.

No mortality was observed during study period. No pharmacological or toxicological signs were observed throughout the study.

No treatment related effects were observed in feed efficiency and body weight parameters.

No treatment related effects were observed in food consumption, food efficiency, ophthalmoscopic examination, urinalysis, hematology, clinical chemistry, organ weights, gross pathology and histopathology parameters at any dose level compared to control animals.

Based on above, administration of CNAE12S/AS to Sprague Dawley rats (male and female) at dose levels of 0, 0.25, 0.50 and 1 % in diet for 90 d resulted in a NOAEL value of 1% in diet (equivalent to 201.28 and 254.56 mg/kg bw/d for male and female rats, respectively). 

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
Some examinations like neurobehaviour are missing due to the year when the study was conducted.
GLP compliance:
no
Remarks:
pre-GLP
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
no data
Route of administration:
oral: feed
Vehicle:
other: plain diet
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:0.07, 0.14, 0.28, 0.56, 1.13, 2.25%Basis:nominal in diet
Remarks:
Doses / Concentrations:58, 113, 228, 470, 961 and 1944 mg/kg bw/day (males)Basis:other: reported daily intake of the test substance based on mean body weight and food consumption over the entire 13-week treatment period
No. of animals per sex per dose:
10 test group20 control group
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
BODY WEIGHT: - Time schedule for examinations: WeeklyFOOD AND WATER CONSUMPTION:- Time schedule for examinations: Twice weeklyHAEMATOLOGY: - Time schedule for collection of blood: At the end of the experimental period (13 weeks)- Anaesthetic used for blood collection: Yes (halothane)CLINICAL CHEMISTRY: - Time schedule for collection of blood: At the end of the experimental period (13 weeks)
Sacrifice and pathology:
GROSS PATHOLOGY: YesHISTOPATHOLOGY: Yes
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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):
effects observed, treatment-related
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
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITYTwo male rats were killed due to ill health during this study.BODY WEIGHT AND WEIGHT GAINThe two highest dose groups gained less weight.FOOD AND WATER CONSUMPTION The high dose groups ate less. High dose females drank less water.HAEMATOLOGYSerum protein decreased at the highest dose (males). CLINICAL CHEMISTRYSerum Mg, protein, cholesterol, decreased at the highest dose (males). Serum GOT was elevated in high dose males. Serum GPT, was elevated in males of the two highest dose groups (1.13% and 2.25%) and females of the second highest dose group (1.13%). Serum AP was increased in the 1.13% and 2.25% dose groups (females) and 1.13% group (males).ORGAN WEIGHTSRelative liver weights (both sexes) increased in the three highest dose groups (0.56%-2.25%). Absolute spleen weights increased in males at the two highest doses and females at the highest dose. Absolute kidney weights decreased in high dose males. Relative kidney weights increased in females at the two highest doses. Relative weights of the testes increased at the two highest doses.GROSS PATHOLOGYHigh dose males had virtually no abdominal fat and changes in color and consistency of intestinal contents. These findings were less frequently noted in high dose females.HISTOPATHOLOGY: NON-NEOPLASTICDiffuse (6 females, 3 males) and periportal (11/20) hypertrophy, reduced cytoplasmic (glycogenic) vacuolation, reduced cytoplasmic neutral fat and hemodiderin content prominent at high dose. Periportal hypertrophy also observed at nest two highest doses (1.13% and 0.56%). Periportal parenchymal hypertrophy was observed in 4 females at the 0.28% level. reduced cytoplasmic (glycogenic) vacuolation, reduced cytoplasmic neutral fat and hemodiderin conten were observed at the 0.56%-2.25% dose levels.Nephrocalcinosis is freqently observed in untreated females of the Wistar strain: the incidence and severity was reduced in the highest dose group.Lymphatic dilation of the small intestine was more prominent at the high dose.
Dose descriptor:
NOAEL
Effect level:
488 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: No toxic effects.
Dose descriptor:
LOAEL
Effect level:
1 016 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Systemic effects that could not be regarded solely as adaptive processess, e.g. increased testes weight.
Critical effects observed:
not specified
Conclusions:
Since the liver as the target organ showed only adaptive responses, the NOAEL was set at 0.56% (488 mg/kg bw/day). The adaptive changes included elevated relative liver weight due to a lower body weight and reduced food consumption, hepatic periportal hypertrophy as well as increased serum alkaline phosphatase (AP) activity. An increased serum AP activity is considered to represent a physiological adaptation resulting from changes in hepatic metabolism required for the breakdown and detoxification of the test material. Since AP is mainly localized in the hepatic parenchyma, enlargement of the hepatic parenchymal cells accompanied by an increased organ weight are an obvious consequence.
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
no
Remarks:
Not mandatory at that time.
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: feed
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:0, 0.07, 0.14, 0.28, 0.56, 1.13, 2.25%Basis:nominal in diet
Remarks:
Doses / Concentrations:0, 58, 116, 230, 460, 920, 1840 mg/kg bw/dayBasis:actual ingested
No. of animals per sex per dose:
10 test group20 control group
Dose descriptor:
NOAEL
Effect level:
460 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Only adaptive changes (elevated liver weights and hypertrophy of the liver) were observed.
Dose descriptor:
LOAEL
Effect level:
920 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Significant decreased body weight and diffuse hepatocytic hypertrophy.
Critical effects observed:
not specified
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
no data on immunology and neuronal endpoints
GLP compliance:
no
Remarks:
Not mandatory at that time.
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: feed
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:0, 0.07, 0.14, 0.28, 0.56, 1.13, 2.25%Basis:nominal in diet
Remarks:
Doses / Concentrations:0, 64, 134, 253, 512, 1007, 2096 mg/kg bw/dayBasis:actual ingested
No. of animals per sex per dose:
10 test group20 control group
Dose descriptor:
NOAEL
Effect level:
512 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Only adaptive changes (elevated liver weights and hypertrophy of the liver) were observed.
Dose descriptor:
LOAEL
Effect level:
1 007 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
no
Remarks:
Not mandatory at that time.
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: feed
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:0, 0.07, 0.14, 0.28, 0.56, 1.13, 2.25%Basis:nominal in diet
Remarks:
Doses / Concentrations:0, 61, 123, 230, 482, 970, 2067 mg/kg bw/dayBasis:actual ingested
No. of animals per sex per dose:
10 test group20 control group
Dose descriptor:
NOAEL
Effect level:
482 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Only adaptive changes (elevated liver weights and hypertrophy of the liver) were observed.
Dose descriptor:
LOAEL
Effect level:
970 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
Some examinations like urinalysis are missing.
GLP compliance:
no
Remarks:
Tests were conducted prior to the implementation of GLP (1976-1978).
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Diets were prepared by thoroughly mixing the appropriate quantity of Dobanol-25-sulphate HCB with a purified diet to provide feed containing the required amount of active ingredient, ie. the surfactant was not added to the diet as a part replacement for any ingredient, but was added “on top of the diet”. Rats were individually housed and provided with diet and water ad libitum. The animals were inspected daily for signs of ill-health while body weights, and food and water intakes, were measured weekly for the first 13 weeks, again at week 16, and thereafter at intervals of 4 weeks until the end of the study.
Route of administration:
oral: feed
Vehicle:
other: plain diet
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 years
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:0, 0.015, 0.15, 1.5% Basis:nominal in diet
Remarks:
Doses / Concentrations:0, 11, 113, 1125 mg/kg bw/dayBasis:actual ingested
No. of animals per sex per dose:
45
Control animals:
yes, plain diet
Other examinations:
Animals dying or killed during the test received a full post-mortem examination at which tissues were taken for histological examination. Animals surviving to the end of the test were starved overnight and blood was taken under anaesthesia for haematology and biochemical measurements after which the animals were killed and a number of organs (heart, liver, spleen kidneys, testes, adrenals and brain) were removed and weighed. These organs and a range of other tissues from each rat were preserved for histological examination. Histological examination was undertaken on stained tissue sections from all animals fed the control diet and each dietary level of the test substances.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
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
Histopathological findings: neoplastic:
no effects observed
Details on results:
The test materials used in the individual studies were prepared by two different production methods (high conversion bleached or HCB; and low conversion, unbleached or LCU). They differed slightly in chain length distribution, the latter having a slightly higher proportion of the C15AS. In both studies, the test material was dosed at 0, 0.015, 0.15 and 1.5% in the diet. There was no increase in tumor incidence, nor any impact on tumor type in either study. For both studies, approximately 70% of animals survived to study termination. Mortality was similar across dosage groups and controls.Animals in the 1.5% dose groups in both studies exhibited reduced food and water consumption, and slower growth rates. Within these high dose groups, there was a decreased number of total tumors and tumor-bearing animals. Elevated serum GPT, LDH and AP were observed in high dose males.Increased absolute liver weights and liver to body weight ratios, hypertrophy of the hepatic parenchyma, increased relative testicular weights, reduced incidence and severity of chronic nephropathy and nephrocalcinosis, and reduced arterial medial hypertrophy were among the findings at the higher dose levels.
Dose descriptor:
NOEL
Effect level:
113 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: no effects observed
Dose descriptor:
LOEL
Effect level:
1 125 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Liver weights and liver enzymes increased as well as histopathological changes.
Critical effects observed:
not specified
Executive summary:

In two comprehensive 2-year studies with groups of 45 animals/sex/group, a similar NOEL of 113 mg/kg bw/day was found. The LOELs were in both studies at 1125 mg/kg bw/day with a clear indication of the liver as target organ (liver weights and liver enzymes increased, histopathological changes in the liver). There was no indication of another target organ in these very comprehensive studies. No adverse effects were found with regard to the kidneys (reduced incidence of nephrocalcinosis, reduced incidence of chronic nephropathy).

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
Limited information concerning test conditions and/or experimental methods
Species:
rat
Sex:
male/female
Route of administration:
oral: feed
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:0, 40, 200, 1000, 5000 ppmBasis:nominal in diet
Remarks:
Doses / Concentrations:0, 3, 17, 86, 430 mg/kg bw/dayBasis:actual ingested
Dose descriptor:
NOAEL
Effect level:
>= 430 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Only adaptive increases in liver weights in female animals.
Critical effects observed:
not specified
Executive summary:

C12ASO4Na was tested in a 90-day feeding study on rats. 12 male and 12 female rats/group were fed dietary levels of 40, 200, 1000 or 5000 ppm (corresponding to 3, 17, 86 or 430 mg/kg bw/day). The control group (18 males, 18 females) received the diet alone. Daily observations were made on health. Body weight and food intake were recorded weekly. Urine samples were obtained from the 5000 ppm and control groups during Week 12. The urine was examined for color, pH, protein, reducing substances, bile salts and microscopic constituents. Terminal blood samples were taken by cardiac puncture and erythrocyte and leucocyte counts and determinations of haematocrit and haemoglobin were made. Total plasma protein and urea were determined. Gross pathological and histological examination of a wide range of organs were made.The only effects observed occurred at 5000 ppm and comprised increases in liver weights in female animals.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
488 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

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Reason / purpose:
read-across source
Species:
mouse
Strain:
C57BL
Sex:
male/female
Details on test animals and environmental conditions:
- Housing: Individual cages on sawdust- Diet: pelleted diet ad libitum- Water: ad libitum
Type of coverage:
not specified
Vehicle:
water
Details on exposure:
0.2 mL of an aqueous solution were applied twice weekly.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
No data
Frequency of treatment:
Twice weekly
Remarks:
Doses / Concentrations:0, 5, 10, 12.5, 15% a.s.Basis:other: nominal
Remarks:
Doses / Concentrations:0, 200, 400, 500 and 600 mg/kg bw/dayBasis:other: Based on an average weight of 20 g/mouse and a 5 days/week treatment.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
The mice were weighed weekly, and their water intakes determined twice weekly by subtracting the amount left from that given.
Sacrifice and pathology:
At necropsy the liver, spleen, kidneys, heart, brain and testes were removed and weighed. Blocks of these and various tissues were reserved for histological examination.
Other examinations:
After 13 weeks skin blood samples were taken by cardiac puncture. The blood samples were used for haematological estimations - packed cell volume, haemoglobin level, mean corpuscular haemoglobin concentration and white cell count.
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):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
not examined
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
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITYOne mouse treated with 12.5% died after 1 week due to dehydration and anorexia. WATER CONSUMPTIONAt 10% and above the water intake was increased.HAEMATOLOGYHaemoglobin levels reduced and wbc counts increased in high dose males.ORGAN WEIGHTSAbsolute and relative heart weights were higher in high dose females. Relative liver weights were increased in both sexes at the 15% and in females at the 12.5% concentration. Increased absolute kidney weights (males) and relative kidney weights (females) were found at the 15% dose level.GROSS PATHOLOGY & HISTOPATHOLOGYExudate adherent to skin (4/20) was observed at the 15% dose level. Loss of hair colour lateral and ventral to application site observed at all treatment levels. Extensive ulceration and necrosis of the epidermis of the decedent at the 12.5% treatment level. Dose-related ulceration of the epidermis (4/20) with inflammatory exudate (11/20) observed at 15% and 12.5% treatment levels. OTHER FINDINGSAt concentrations of 12.5 and 15%, cytotoxic effects were found in the epidermis.
Dose descriptor:
NOAEL
Effect level:
10 other: %
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Corresponding to 400 mg/kg bw.
Dose descriptor:
LOAEL
Effect level:
12.5 other: %
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Extensive necrosis and ulceration of the skin, changes in haematology and organ weights.
Critical effects observed:
not specified
Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
Deficiencies in biochemical and haematological data; Application only twice per week. (Study was conducted before the implementation of OECD 411)
GLP compliance:
no
Remarks:
GLP not mandatory at that time.
Species:
mouse
Strain:
C57BL
Sex:
male/female
Details on test animals and environmental conditions:
- Housing: Individual cages on sawdust- Diet: pelleted diet ad libitum- Water: ad libitum
Type of coverage:
not specified
Vehicle:
water
Details on exposure:
0.2 mL of an aqueous solution were applied twice weekly.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
No data
Frequency of treatment:
Twice weekly
Remarks:
Doses / Concentrations:0, 5, 10, 12.5, 15% a.s.Basis:other: nominal
Remarks:
Doses / Concentrations:0, 200, 400, 500 and 600 mg/kg bw/dayBasis:other: Based on an average weight of 20 g/mouse and a 5 days/week treatment.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
The mice were weighed weekly, and their water intakes determined twice weekly by subtracting the amount left from that given.
Sacrifice and pathology:
At necropsy the liver, spleen, kidneys, heart, brain and testes were removed and weighed. Blocks of these and various tissues were reserved for histological examination.
Other examinations:
After 13 weeks skin blood samples were taken by cardiac puncture. The blood samples were used for haematological estimations - packed cell volume, haemoglobin level, mean corpuscular haemoglobin concentration and white cell count.
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):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
not examined
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
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITYOne mouse treated with 12.5% died after 1 week due to dehydration and anorexia. WATER CONSUMPTIONAt 10% and above the water intake was increased.HAEMATOLOGYHaemoglobin levels reduced and wbc counts increased in high dose males.ORGAN WEIGHTSAbsolute and relative heart weights were higher in high dose females. Relative liver weights were increased in both sexes at the 15% and in females at the 12.5% concentration. Increased absolute kidney weights (males) and relative kidney weights (females) were found at the 15% dose level.GROSS PATHOLOGY & HISTOPATHOLOGYExudate adherent to skin (4/20) was observed at the 15% dose level. Loss of hair colour lateral and ventral to application site observed at all treatment levels. Extensive ulceration and necrosis of the epidermis of the decedent at the 12.5% treatment level. Dose-related ulceration of the epidermis (4/20) with inflammatory exudate (11/20) observed at 15% and 12.5% treatment levels. OTHER FINDINGSAt concentrations of 12.5 and 15%, cytotoxic effects were found in the epidermis.
Dose descriptor:
NOAEL
Effect level:
10 other: %
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Corresponding to 400 mg/kg bw.
Dose descriptor:
LOAEL
Effect level:
12.5 other: %
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Extensive necrosis and ulceration of the skin, changes in haematology and organ weights.
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
400 mg/kg bw/day
Study duration:
subchronic
Species:
mouse

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Reason / purpose:
read-across source
Species:
mouse
Strain:
C57BL
Sex:
male/female
Details on test animals and environmental conditions:
- Housing: Individual cages on sawdust- Diet: pelleted diet ad libitum- Water: ad libitum
Type of coverage:
not specified
Vehicle:
water
Details on exposure:
0.2 mL of an aqueous solution were applied twice weekly.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
No data
Frequency of treatment:
Twice weekly
Remarks:
Doses / Concentrations:0, 5, 10, 12.5, 15% a.s.Basis:other: nominal
Remarks:
Doses / Concentrations:0, 200, 400, 500 and 600 mg/kg bw/dayBasis:other: Based on an average weight of 20 g/mouse and a 5 days/week treatment.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
The mice were weighed weekly, and their water intakes determined twice weekly by subtracting the amount left from that given.
Sacrifice and pathology:
At necropsy the liver, spleen, kidneys, heart, brain and testes were removed and weighed. Blocks of these and various tissues were reserved for histological examination.
Other examinations:
After 13 weeks skin blood samples were taken by cardiac puncture. The blood samples were used for haematological estimations - packed cell volume, haemoglobin level, mean corpuscular haemoglobin concentration and white cell count.
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):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
not examined
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
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITYOne mouse treated with 12.5% died after 1 week due to dehydration and anorexia. WATER CONSUMPTIONAt 10% and above the water intake was increased.HAEMATOLOGYHaemoglobin levels reduced and wbc counts increased in high dose males.ORGAN WEIGHTSAbsolute and relative heart weights were higher in high dose females. Relative liver weights were increased in both sexes at the 15% and in females at the 12.5% concentration. Increased absolute kidney weights (males) and relative kidney weights (females) were found at the 15% dose level.GROSS PATHOLOGY & HISTOPATHOLOGYExudate adherent to skin (4/20) was observed at the 15% dose level. Loss of hair colour lateral and ventral to application site observed at all treatment levels. Extensive ulceration and necrosis of the epidermis of the decedent at the 12.5% treatment level. Dose-related ulceration of the epidermis (4/20) with inflammatory exudate (11/20) observed at 15% and 12.5% treatment levels. OTHER FINDINGSAt concentrations of 12.5 and 15%, cytotoxic effects were found in the epidermis.
Dose descriptor:
NOAEL
Effect level:
10 other: %
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Corresponding to 400 mg/kg bw.
Dose descriptor:
LOAEL
Effect level:
12.5 other: %
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Extensive necrosis and ulceration of the skin, changes in haematology and organ weights.
Critical effects observed:
not specified
Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
Deficiencies in biochemical and haematological data; Application only twice per week. (Study was conducted before the implementation of OECD 411)
GLP compliance:
no
Remarks:
GLP not mandatory at that time.
Species:
mouse
Strain:
C57BL
Sex:
male/female
Details on test animals and environmental conditions:
- Housing: Individual cages on sawdust- Diet: pelleted diet ad libitum- Water: ad libitum
Type of coverage:
not specified
Vehicle:
water
Details on exposure:
0.2 mL of an aqueous solution were applied twice weekly.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
No data
Frequency of treatment:
Twice weekly
Remarks:
Doses / Concentrations:0, 5, 10, 12.5, 15% a.s.Basis:other: nominal
Remarks:
Doses / Concentrations:0, 200, 400, 500 and 600 mg/kg bw/dayBasis:other: Based on an average weight of 20 g/mouse and a 5 days/week treatment.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
The mice were weighed weekly, and their water intakes determined twice weekly by subtracting the amount left from that given.
Sacrifice and pathology:
At necropsy the liver, spleen, kidneys, heart, brain and testes were removed and weighed. Blocks of these and various tissues were reserved for histological examination.
Other examinations:
After 13 weeks skin blood samples were taken by cardiac puncture. The blood samples were used for haematological estimations - packed cell volume, haemoglobin level, mean corpuscular haemoglobin concentration and white cell count.
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):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
not examined
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
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITYOne mouse treated with 12.5% died after 1 week due to dehydration and anorexia. WATER CONSUMPTIONAt 10% and above the water intake was increased.HAEMATOLOGYHaemoglobin levels reduced and wbc counts increased in high dose males.ORGAN WEIGHTSAbsolute and relative heart weights were higher in high dose females. Relative liver weights were increased in both sexes at the 15% and in females at the 12.5% concentration. Increased absolute kidney weights (males) and relative kidney weights (females) were found at the 15% dose level.GROSS PATHOLOGY & HISTOPATHOLOGYExudate adherent to skin (4/20) was observed at the 15% dose level. Loss of hair colour lateral and ventral to application site observed at all treatment levels. Extensive ulceration and necrosis of the epidermis of the decedent at the 12.5% treatment level. Dose-related ulceration of the epidermis (4/20) with inflammatory exudate (11/20) observed at 15% and 12.5% treatment levels. OTHER FINDINGSAt concentrations of 12.5 and 15%, cytotoxic effects were found in the epidermis.
Dose descriptor:
NOAEL
Effect level:
10 other: %
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Corresponding to 400 mg/kg bw.
Dose descriptor:
LOAEL
Effect level:
12.5 other: %
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Extensive necrosis and ulceration of the skin, changes in haematology and organ weights.
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Study duration:
subchronic
Species:
mouse

Additional information

For the whole category of alkyl sulfates (AS) a NOAEL of 488 mg/kg bw/day was established.

The possibility of a read-across to other alkyl sulfates in accordance with Regulation (EC) No 1907/2006 Annex XI 1.5. Grouping of substances and read-across approach was assessed. In Annex XI 1.5 it is given that a read-across approach is possible for substances, whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity. The AS reported within the AS category show structural similarity. The most important common structural feature of the category members is the presence of a predominantly linear aliphatic hydrocarbon chain with a polar sulfate group, neutralized with a counter ion. This structural feature confers the surfactant properties of the alkyl sulfates. The surfactant property of the members of the AS category in turn represent the predominant attribute in mediating effects on mammalian health. Therefore, the AS of the AS category have similar physico-chemical, environmental and toxicological properties, validating the read across approach within the category. The approach of grouping different AS for the evaluation of their effects on human health and the environment was also made by the OECD in the SIDS initial assessment profile [1] and by a voluntary industry programme carrying out Human and Environmental Risk Assessments (HERA [2]), further supporting the read across approach between structurally related AS.  

Therefore this endpoint is covered by read across to structurally related alkyl sulfates. Reliable repeated dose toxicity studies have been conducted with C12AS Na (CAS 151-21-3), C10-16AS Na (68585-47-7), C12-14AS TEA (CAS 90583-18-9), C12-15AS Na (CAS 68890-70-0), C16-18AS Na (CAS 68955-20-4) and C13-15AS Na (CAS 86014-79-1). Hence, alkyl sulfates with chain lengths between C10 and C18 have been tested.

Oral gavage RDT

A 90% aqueous solution of C12AS Na (CAS 151-21-3) was administered for 28 days by gavage to groups of five animals/sex/dose at dose levels of 30, 100 or 300/600 mg/kg bw/day (the dose of 300 mg/kg bw/day was changed into 600 mg/kg bw/day after 10 days of treatment). The study was performed in accordance with OECD 407 except for the functional observation battery and revealed a NOEL of 90 mg a.i./kg bw/day (Potokar et al., 1987a). At the LOAEL (270/540 mg a.i./kg bw/day), feed intake and body weight gain were reduced and water intake increased. Bleeding and ulceration of the stomach, as well as transient alterations of the tongue and myocard were found. There was an increase in leucocytes and in alanine aminotransferase (ALT) activity, as well as a decrease in haematocrit and erythrocyte volume (MCV). Relative weights of adrenals, kidneys, brain, gonads and liver were increased; the relative thymus weight was decreased.

With the same study design (which meets all requirements of the OECD 407 except for functional observation battery tests), C12-14AS TEA (CAS 90583-18-9) was administered by gavage as a ca. 40% aqueous solution at dose levels of 0, 70, 250 or 750 mg/kg bw/day (corresponding to 0, 29, 102 and 306 mg/kg bw/day active ingredient) to groups of five rats/sex/dose (Potokar et al., 1988). At 250 mg/kg bw/day (i.e. 102 mg a.i./kg bw/day), signs of local irritation were found in the forestomach (inflammation, ulceration in some animals), but no indication of a systemic toxicity. Therefore, this level is considered as the systemic NOAEL. At 750 mg/kg bw/day (i.e. 306 mg a.s./kg bw/day), the severity of gastric irritation increased, and the animals showed leucocytosis (LOAEL).

In a 90 day gavage study, C16-18AS Na (CAS 68955-20-4) was administered as 55% aqueous solution to groups of 10 rats/sex/dose at dose levels of 100, 300 and 900 mg/kg bw/day, corresponding to ca. 55, 165 and 495 mg a.s./kg bw/day (Potokar et al., 1987b). The NOEL was established at 55 mg a.i./kg bw/day. At the next higher dose level (NOAEL, 165 mg a.i./kg bw/day) food consumption and body weight gain were reduced, and relative liver weight was increased. Other changes were non-specific and probably due to the irritant effect of the test substance to the stomach mucosa. At 495 mg/kg bw/day, there were clear signs of gastritis; absolute and relative liver weights were increased. No signs of toxicity were found in the kidney.

Oral feeding RDT 

C12AS Na (CAS 151-21-3) was tested as well in a 90 day feeding study on rats (Walker et al., 1967). 12 male and 12 female rats/group were fed dietary levels of 40, 200, 1000 or 5000 ppm (corresponding to 3, 17, 86 or 430 mg/kg bw/day). The control group (18 males, 18 females) received the diet alone. Daily observations were made on health. Body weight and food intake were recorded weekly. Urine samples were obtained from the 5000 ppm and control groups during Week 12. The urine was examined for colour, pH, protein, reducing substances, bile salts and microscopic constituents. Terminal blood samples were taken by cardiac puncture and erythrocyte and leukocyte counts and determinations of haematocrit and haemoglobin were made. Total plasma protein and urea were determined. Gross pathological and histological examinations of a wide range of organs were made. The only effects observed occurred at 5000 ppm and comprised increases in liver weights in female animals. Regarding this as an adaptive effect, the NOAEL can be set at the highest dose level of 5000 ppm (430 mg/kg bw/day).

C12AS Na (CAS 151-21-3) was also tested in a 13 week feeding study on rats by Munday et al. (1976b). Ten rats/sex/dose in the test groups and 20 rats/sex in the control group were administered dietary levels of 0, 0.07, 0.14, 0.28, 0.56, 1.13 and 2.25% (corresponding to 0, 58, 116, 230, 460, 920 and 1840 mg/kg bw/day). The control group received the diet alone. The NOAEL was set at 460 mg/kg bw/day since only adaptive changes were observed at this dose level.

Another subchronic feeding study was done with C10-16AS Na (CAS 68585-47-7; Killeen and Rapp, 1976). Administration of 0, 0.25, 0.5 and 1% test substance in diet (corresponding to 0, 58, 118 and 228 mg/kg bw/day for males and females based on a.i.) to 20 Sprague-Dawley rats/sex/dose revealed no treatment-related effects either in-life or at necropsy. In addition, histopathological examinations did not show any changes considered to be related to compound administration. Hence, the NOAEL calculated by the mean food consumption was set at 254 mg/kg bw/day based on a.i. for females and 201 mg/kg bw/d based on a.i. for males.

C12-15AS Na (CAS 68890-70-0) was investigated in a 13 week and in two 2 year studies with rats, all using the dietary route of exposure. When tested for 13 weeks at dietary concentrations of 0, 0, 0.07, 0.14, 0.28, 0.56, 1.13 or 2.25% in groups of ten rats/sex/dose in a study that meets current standards (except for neurotoxicity and immunotoxicity testing; Munday et al., 1976a), the NOEL was set at 0.14% (122 mg/kg bw/day). Since the liver as the target organ showed only adaptive responses, the NOAEL was set at 0.56% (488 mg/kg bw/day). The adaptive changes included elevated relative liver weight due to a lower body weight and reduced food consumption, hepatic periportal hypertrophy as well as increased serum alkaline phosphatase (AP) activity. An increased serum AP activity is considered to represent a physiological adaptation resulting from changes in hepatic metabolism required for the breakdown and detoxification of the test material. Since AP is mainly localized in the hepatic parenchyma, enlargement of the hepatic parenchymal cells accompanied by an increased organ weight are an obvious consequence.

In the chronic dietary repeated dose toxicity studies the NOELs were set at 113 mg/kg bw/day (LOAELs = 1125 mg/kg bw/day; Munday et al., 1995a,b). Animals in the high dose groups in both studies exhibited reduced food and water consumption and slower growth rates. Other pathological findings were increased absolute liver weights and liver to body weight ratios, hypertrophy of the hepatic parenchyma, increased relative testicular weights, reduced incidence and severity of chronic nephropathy and nephrocalcinosis and reduced arterial medial hypertrophy.

In another subchronic study with C13-15AS Na (CAS 86014-79-1; Munday et al., 1977a), ten animals/sex/group were fed diets containing 0, 0.07, 0.14, 0.28, 0.56, 1.13 or 2.25% (corresponding to 0, 64, 134, 253, 512, 1007, or 2096 mg/kg bw/day), the NOAEL was established at 512 mg/kg bw/day since only adaptive changes (elevated liver weights and hypertrophy of the liver) were observed. At the LOAEL (1007 mg/kg bw/day) and higher dosages effects observed included enlargement of the kidneys without histological identifiable structural change, increased patency of intestinal lymphatics, decreased serum cholesterol concentration and elevated serum activity of the enzymes cholinesterase and glutamic-oxalacetic transaminase.

C16-18AS Na (CAS 68955-20-4; subchronic, dietary study, Munday et al., 1977b) shows an identical profile with a similar NOAEL (482 mg/kg bw/day) and LOAEL (970 mg/kg bw/day).

Dermal RDT 

A repeated dose toxicity study with dermal application is also available. Dose levels employed in the 90 day study were 0, 5, 10, 12.5 and 15% C12-15AS Na (CAS 68890-70-0) corresponding to 0, 200, 400, 500 and 600 mg/kg bw/day based on an average weight of 20 g bw/mouse and a 5 days/week treatment (McCormick, 1977). Ten C57BL mice per sex and group were treated with a dose volume of 0.2 mL with the control group being sterile water. An unknown area of all animals was with the appropriate dose two times per week. All animals were observed daily for signs of general health, mortality and gross skin irritation effects. Gross signs of toxicity and body weights were recorded on a weekly basis throughout the study. Effects at the site of application were consistent with the irritant properties of the test material. Dose-related ulceration of the epidermis with inflammatory exudate was observed at the 12.5% and 15% concentrations. Dose-dependent increases in edema, vascular dilatation, epidermal acanthosis, hyperkeratosis and hypergranulosis were prominent at the 10% treatment level and above. Haemoglobin levels were reduced and white blood cell counts increased in males of the high dose group. No clinical chemistry measurements were performed. Other noteworthy systemic effects included increases in liver-to-body weight ratios in both sexes at the 15% concentration, and in females at the 12.5% concentration. Absolute kidney weights increased in males and kidney weight-to-body weight ratios increased in females at the 15% treatment level. These target organs are consistent with those observed in the oral studies. Effects at these more distant organs suggest that a higher level of percutaneous absorption of the test material may have occurred at high doses with the longer duration of exposure in this study. The systemic NOAEL was set at 400 mg/kg bw/day. However, the dietary NOAEL of 488 mg/kg bw/day will be used for risk assessment. For details refer to the folowing discussion.

Conclusion 

In summary, gastrointestinal irritation, particularly of the forestomach, was the primary effect after application via gavage but not after application via the diet. This is consistent with the primary irritant properties of the AS and the bolus effect after application by gavage. Notably, gavage studies that included recovery groups indicated that systemic effects other than forestomach irritation were fully reversible. Moreover, administration via gavage (see developmental toxicity studies as well) does not allow differentiating between systemic effects as a consequence of the local irritation or due to specific substance properties (e.g. leucocytosis). The study investigating the dermal route resulted in significant local irritation. It provided some evidence of systemic toxicity however there is insufficient information to determine if these effects represented a direct toxic effect from systemic exposure to AS or if the response was associated with the significant dermal inflammation. Thus, the NOAEL used for the risk assessment should be based on a dietary study to assess potential systemic toxicity resulting from repeated exposures to AS. After administration in the diet, the liver was the only target organ identified. Adaptive effects on this organ included an increase in liver weight, enlargement of liver cells and elevated levels of liver enzymes. Liver effects were more apparent in dietary studies, partly because these allowed administration of higher doses of the test material with less GI tract injury.

The listing of all dietary NOAELs and LOAELs in Table 1 shows that the spacing of the concentrations in the chronic toxicity studies was very high. On the other hand, the NOAELs of the subchronic studies are all in the same range and about 4.5 times higher.

  

Table 1: NOAELs and LOAELs (for a.i.) for repeated dietary dose toxicity studies of AS in rats

Substance

Duration

(weeks)

NOAEL

(mg/kg bw/day)

LOAEL

(mg/kg bw/day)

Reference

C12AS Na

13

430

> 430

Walker et al. (1967)

C12AS Na

13

460

920

Munday et al. (1976b)

C10-16AS Na

13

201/254

> 201/>254

Killeen and Rapp (1976)

C12-15AS Na

13

488

1016

Munday et al. (1976a)

C13-15AS Na

13

512

1007

Munday et al. (1977a)

C16-18AS Na

13

482

970

Munday et al. (1977b)

C12-15AS Na

104

113

1125

Munday et al. (1995a,b)

The NOAELs and LOAELs achieved within the different studies draw a coherent picture. The NOAEL of the chronic toxicity study (113 mg/kg bw/d) as well as the NOAEL of 254 mg/kg bw/d in the study of Killeen and Rapp (1976) represent unreasonably low doses for risk assessment. The relatively low values are due to the chosen dose level and the dose spacing, respectively. No effects were observed at both dose levels. Since the subchronic and chronic LOAELs are in the same range and the subchronic NOAELs do not conflict with the chronic LOAEL, one of the subchronic NOAELs can be chosen as basis for risk assessment. Based on the described effects and argumentations, the dietary NOAEL of 488 mg/kg bw/d (Munday et al., 1976a) representing an average of all NOAEL was chosen for the risk assessment of oral and dermal exposure.

References:

[1] SIDS initial assessment profile, (2007);
http://www.aciscience.org/docs/Alkyl_Sulfates_Final_SIAP.pdf

[2] (HERA Draft report, 2002);
http://www.heraproject.com/files/3-HH-04-%20HERA%20AS%20HH%20web%20wd.pdf


Justification for classification or non-classification

 The available data on repeated toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.