Registration Dossier

Administrative data

Description of key information

No data are available for the target substance Sulfuric acids, C9-11-iso-C10 rich, alkyl esters, sodium salt. Therefore, read-across from structural analogue source substance has been applied and a NOAEL of 488 mg/kg bw/day was established for all alkyl sulfates (AS) read-across source substances.

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:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Limited details on test animals and environmental conditions. Not all haematological examinations were performed. Neurobehavioural and ophthalmoscopic examinations are missing due to the year when the study was conducted.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
limited details on test animals and environmental conditions; not all haematological examinations were performed; neurobehavioural and ophthalmoscopic examinations are missing due to the year when the study was conducted.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: Colworth Wistar-derived
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 43-87 g (males), 51-79 g (females)
- Housing: animals were housed in individual cages.
- Diet: semi-synthetic purified diet, ad libitum
- Water: ad libitum
Route of administration:
oral: feed
Vehicle:
other: semi-synthetic purified diet
Details on oral exposure:
DIET PREPARATION
- Mixing appropriate amounts with (Type of food): semi-synthetic purified diet
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily, 7 days/week
Dose / conc.:
0.07 other: % nominal in diet
Dose / conc.:
0.14 other: % nominal in diet
Dose / conc.:
0.28 other: % nominal in diet
Dose / conc.:
0.56 other: % nominal in diet
Dose / conc.:
1.13 other: % nominal in diet
Dose / conc.:
2.25 other: % nominal in diet
Dose / conc.:
58 mg/kg bw/day (actual dose received)
Remarks:
Male animals, reported daily intake of the test substance based on mean body weight and food consumption over the entire 13-week treatment period
Dose / conc.:
113 mg/kg bw/day (actual dose received)
Remarks:
Male animals, reported daily intake of the test substance based on mean body weight and food consumption over the entire 13-week treatment period
Dose / conc.:
228 mg/kg bw/day (actual dose received)
Remarks:
Male animals, reported daily intake of the test substance based on mean body weight and food consumption over the entire 13-week treatment period
Dose / conc.:
470 mg/kg bw/day (actual dose received)
Remarks:
Male animals, reported daily intake of the test substance based on mean body weight and food consumption over the entire 13-week treatment period
Dose / conc.:
961 mg/kg bw/day (actual dose received)
Remarks:
Male animals, reported daily intake of the test substance based on mean body weight and food consumption over the entire 13-week treatment period
Dose / conc.:
1 944 mg/kg bw/day (actual dose received)
Remarks:
Male animals, reported daily intake of the test substance based on mean body weight and food consumption over the entire 13-week treatment period
Dose / conc.:
66 mg/kg bw/day (actual dose received)
Remarks:
Female animals, reported daily intake of the test substance based on mean body weight and food consumption over the entire 13-week treatment period
Dose / conc.:
131 mg/kg bw/day (actual dose received)
Remarks:
Female animals, reported daily intake of the test substance based on mean body weight and food consumption over the entire 13-week treatment period
Dose / conc.:
261 mg/kg bw/day (actual dose received)
Remarks:
Female animals, reported daily intake of the test substance based on mean body weight and food consumption over the entire 13-week treatment period
Dose / conc.:
506 mg/kg bw/day (actual dose received)
Remarks:
Female animals, reported daily intake of the test substance based on mean body weight and food consumption over the entire 13-week treatment period
Dose / conc.:
1 070 mg/kg bw/day (actual dose received)
Remarks:
Female animals, reported daily intake of the test substance based on mean body weight and food consumption over the entire 13-week treatment period
Dose / conc.:
2 218 mg/kg bw/day (actual dose received)
Remarks:
Female animals, 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 group
20 control group
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: animals were observed daily for mortality and general health conditions.

BODY WEIGHT: Yes
- Time schedule for examinations: body weights of all animals were determined once per week.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): twice weekly
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in g/food consumption in g calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION: Yes
- Time schedule for examinations: twice weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the experimental period (13 weeks)
- Anaesthetic used for blood collection: Yes (halothane)
- How many animals: all
- Parameters checked: packed cell volume, haemoglobin level, mean corpuscular haemoglobin concentration and white cell count

CLINICAL CHEMISTRY:
- Time schedule for collection of blood: at the end of the experimental period (13 weeks)
- How many animals: all
- Parameters checked: serum levels of sodium, potassium, calcium, magnesium, urea, creatinine, total protein, cholesterol, triglyceride, glutamic oxaloacetic transaminase, glutamic-pyruvic transaminase, lactate dehydrogenase, hydroxybutyrate dehydrogenase, cholinesterase, alkaline phosphatase and creatinine phosphokinase
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, in all animals; absolute and relative organ weights of heart, liver, spleen, kidneys, brain, adrenals, pituitary and testes were determined.
HISTOPATHOLOGY: Yes, in all animals of the control group and the two high dose groups (1.13 and 2.25% in the diet); histopathological examination was performed in heart, liver, spleen, kidneys, brain, adrenals, pituitary, testes, lung, stomach, jejunum, ileum, caecum, colon, thyroid, pancreas, urinary bladder, seminal vesicles, ovaries, uterus, skeletal muscle, thymus, salivary glands, skin, aorta, eye, mesenteric lymph node, tongue and sternum. Since liver changes were determined in the two high dose groups, histopathological examination of all other dose groups was performed.
Statistics:
All relevant parameters, except those for pathology, were statistically examined by analysis of variance for significant effects between treatment groups and controls. Statistical significance between treatment groups and controls was indicated at p < 0.05.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
0.14 and 1.13% in the diet: each one male animal died (not treatment-related)
Mortality:
mortality observed, treatment-related
Description (incidence):
0.14 and 1.13% in the diet: each one male animal died (not treatment-related)
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
2.25% in the diet: significantly lower body weight gain in males (-20%) and females (-16%) compared to controls; 1.13% in the diet: significantly lower body weight gain in males (-10%) compared to controls
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
2.25% in the diet: significantly lower food consumption in males (-9%) and females (-6%) compared to controls (non-adverse)
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
2.25% in the diet: significantly poorer food utilisation in males (-13%) and females (-10%) compared to controls; 1.13% in the diet: significantly poorer food utilisation in males (-5%) compared to controls
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
2.25% in the diet: significantly lower water consumption in females (-15%) compared to controls
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
2.25% in the diet: signif. decreased magnesium, protein and cholesterin values (m); signif. increased GOP (m), GPT (m)and AP (m/f); 1.13% in the diet: signif. incraesed AP (m) and GPT (f); 0.28 and 0.56% in the diet: signif. increased AP (m)
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
2.25%: increased in liver (m/f), brain (m/f), testes (m); decreased in spleen (m/f), kidney (m/f) and heart (m/f); 1.13%: increased in liver (m/f), brain (m), testes (m); decreased in spleen (m), kidney (f), heart (m); 0.56%: increased in liver (m/f)
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
2.25% in the diet: no abdominal fat (m) and changes in colour and consistency of intestinal contents (m/f); 1.13% in the diet: changes in colour and consistency of intestinal contents (m)
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
2.25% in the diet: liver (m/f), kidney (f), alimentary tract (m/f), connective tissue (m/f); 0.56-1.13% in the diet: liver (m/f); 0.28% in the diet: liver (f)
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
Two male rats were killed due to ill health during this study. One of these animals, which was fed 0.14% of the test substance in the diet, was killed during Week 3 of the study due to a deformity of the posterior thorax, which is a lesion occasionally observed in Colworth Wistar rats and considered to represent injuries incurrent at birth or in the early post-partum period. The second animal, which was fed with dietary levels of 1.13%, was sacrificed during Week 6 due to rapid loss of weight and respiratory distress, which was associated with severe pulmonary oedema and emphysema and a major congenital cardiac defect, viz. patent interventricular foramen. Lesions of this type are also occasionally observed in young Colworth Wistar. Therefore, none of these lesions was considered to be related to treatment with the test substance in both animals.
No other animal died during the study period and the appearance of all 158 survivors was indicative of good health.

BODY WEIGHT AND WEIGHT GAIN (see Table 1 under “Any other information on results incl. tables”)
Males and females fed 2.25% of the test substance in diet showed significantly lower body weights and body weight gain compared to controls. This effect was also observed in males treated at dietary levels of 1.13%.

FOOD CONSUMPTION (see Table 2 under “Any other information on results incl. tables”)
The food intakes of males and females fed at a dietary dose level of 2.25% were significantly lower compared to controls, which corresponded to the decrease in body weights in both genders at this dose level.

FOOD EFFICIENCY (see Table 3 under “Any other information on results incl. tables”)
Food utilisation by male and female rats fed dietary levels of 2.25% was significantly poorer than by the control animals. This effect was also observed in males treated at dietary levels of 1.13%. The observations of poorer food utilisation corresponded well to the reported lower body weight gains in animals at dietary dose levels of 2.25 and 1.13%.

WATER CONSUMPTION
Significantly lower water consumption compared to controls was observed in females at dietary dose levels of 2.25%.

HAEMATOLOGY
No changes in haematological parameters were observed between animals of all treatment groups and controls.

CLINICAL CHEMISTRY (see Tables 4 and 5 under “Any other information on results incl. tables”)
Serum values of magnesium, total protein and cholesterol were decreased at the highest dose (2.25% in the diet) in males. In males of the same dose group, serum GOT, GPT and AP were elevated. Serum GPT was also increased in males and females receiving the second highest dose group (1.13% in the diet). Serum AP was also elevated in males receiving, 1.13, 0.56 and 0.28% of the test substance in the diet and in females receiving 1.13% and 2.25% of the test substance in the diet.

ORGAN WEIGHTS (see Tables 6 and 7 under “Any other information on results incl. tables”)
Relative liver weights (both sexes) significantly increased in the three highest dose groups (0.56%-2.25%). At the highest dietary level of feeding, the increase in relative liver weight in males and females was 19% and 42%, respectively. Furthermore, absolute weights of the liver were significantly increased in females of the two highest dose groups (1.13 and 2.25%) but not in males.
Absolute spleen weights significantly decreased in males at the two highest dose levels (1.13 and 2.25%) and in females at the highest dose. No changes in relative spleen weights were observed in any of the treated animals compared to controls.
Absolute kidney weights significantly decreased in high dose males, but relative kidney weights were normal compared to controls. Relative kidney weights significantly increased in females at the two highest dose levels (1.13 and 2.25%) while absolute kidney weights were not affected.
Relative brain weights were significantly increased in males fed the two highest dose levels (1.13 and 2.25%) and in females receiving the highest dose.
Relative weights of the testes increased at the two highest dose levels (1.13 and 2.25%).
Absolute heart weights significantly decreased in males fed the two highest dose levels (1.13 and 2.25%) and in females fed the highest dose. Relative heart weights were increased in males at the highest dose level.

GROSS PATHOLOGY
High dose males had virtually no abdominal fat and changes in colour and consistency of intestinal contents. Changes in colour and consistency of intestinal contents were also observed in one male of the 1.13% dose group. Depletion of body fat and changes in intestinal contents were less frequently noted in high dose females. All other lesions noted were not considered to be related to treatment as they were identified to represent normal background pathology in rats of this age and strain.

HISTOPATHOLOGY: NON-NEOPLASTIC
Liver:
Histological changes attributable to treatment with the test substance were found in liver, kidney, alimentary tract and connective tissue. The major histopathological findings were noted in liver.
At the highest dietary level (2.25%), diffuse (6/10 females, 3/10 males) and periportal (4/10 females, 7/10 males) hypertrophy, reduced cytoplasmic (glycogenic) vacuolation (10/10 females, 9/10 males) as well as reduced cytoplasmic neutral fat and hemosiderin content were prominent in the hepatic parenchyma of rats. In addition, the hemosiderin content of Kupffer cell was greatly depleted.
Diffuse hypertrophy was also identified in 5/10 females fed 1.13% of the test substance in the diet. Furthermore, periportal hypertrophy was observed in rats (5/10 females, 8/9 males) at this dose level and the next lower dose level of 0.56% (10/10 females, 5/10 males). In addition, this lesion was also observed in females (4/10 animals), but not in males, at the 0.28% dose level.
Reduced cytoplasmic (glycogenic) vacuolation, reduced cytoplasmic neutral fat, hemosiderin content and depletion of Kupffer cell hemosiderin were observed in males and/or females receiving dietary dose levels of 0.56%-2.25%.
No treatment-related histopathological changes were observed in the livers of rats (both genders) treated with dietary dose levels of 0.07 and 0.14%

Kidney:
The incidence and severity of nephrocalcinosis were significantly reduced in females (7/10 animals) treated with 2.5% in the diet. Normally, nephrocalcinosis is frequently well defined in untreated female rats of this strain and age. Further untreated animals of this age and strain also show small foci of cortical tubular athrophy, cortical interstitial fibrosis and focal lymphocytic infiltration, which are sequelae to mineral deposition in and occlusion of renal tubules. However, in females of the high those groups this three lesions were also reduced.
No changes attributable to treatment were observed in the kidney of male and female rats fed with the second highest dose level of the substance in the diet (1.13%).

Gastro intestinal tract:
Lymphatic dilation of the small intestine was more prominent at the high dose (2.5% in the diet) compared to the controls and the 1.13% dose level. The prominence was attributable to increase in the extent of dilation of individual vessels and to an increase in the number of visible lymphatic channels.At the high dose, a higher protozoan parasite colonisation in the animals compared to controls and the 1.13% dose group was observed within the mucus covering the mucosa. However, these parasites did not colonize the mucus and thus did not result in mucosal and submucosal lesions.

Connective tissue:
At the highest dose level, a reduced quantity of stromal lipid, particularly in pancreas and parotid salivary glands, was observed compared to controls and the 1.13% dietary dose group.

Other organs:
No further treatment-related histopathological changes between treated and control animals were observed in any other organ. Incidence and intensity of histopathological changes occurring in other organs were shown to be normal background pathology observed in rats of this strain and age.
Dose descriptor:
LOAEL
Effect level:
1.13 other: % in the diet
Based on:
act. ingr.
Remarks:
corresponding to 1016 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: systemic effects that could not be regarded solely as adaptive processes, i.e. increased testes weight in males
Dose descriptor:
NOAEL
Effect level:
0.56 other: % in the diet
Based on:
act. ingr.
Remarks:
corresponding to 488 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
no

Table 1. Average body weight gain of rats over the 13-week treatment period

Dietary level of the test substance (%)

Average body weight gain (g)

Male rats

Female rats

2.25

213*

117*

1.13

242*

135

0.56

270

131

0.28

263

133

0.14

271

140

0.07

264

141

0.0 (control)

268

140

* Statistically significant (p < 0.05) compared to controls

 

Table 2. Mean total amounts of food consumed by the rats over the 13-week treatment period

Dietary level of the test substance (%)

Mean total amount of food consumed (g)

Male rats

Female rats

2.25

1502*

1192*

1.13

1581

1250

0.56

1636

1212

0.28

1614

1220

0.14

1609

1272

0.07

1573

1270

0.0 (control)

1643

1269

* Statistically significant (p < 0.05) compared to controls

 

Table 3. Mean body weight gain (g)/mean total food consumed (g) by rats over the 13-week treatment period

Dietary level of the test substance (%)

Mean total amount of food consumed (g)

Male rats

Female rats

2.25

0.141*

0.099*

1.13

0.154*

0.108

0.56

0.165

0.108

0.28

0.163

0.109

0.14

0.169

0.110

0.07

0.168

0.111

0.0 (control)

0.163

0.111

* Statistically significant (p < 0.05) compared to controls

Table 4. Serum analysis – Changes in biochemical parameters in male rats over the 13-week treatment period (mean values)

Dietary level of the test substance (%)

Magnesium (meq/L)

Creatinine (mg/100 mL)

Total protein (g/100 mL)

Cholesterol (mg/100 mL)

GOT

(mU/mL)

GPT

(mU/mL)

AP

(mU/mL)

2.25

1.3*

0.80

6.1*

77*

73*

41*

1289*

1.13

1.4

0.80

6.4

97

60

29*

1356*

0.56

1.5

0.81

6.2

92

57

26*

1135*

0.28

1.4

0.80

6.5

113

58

20

1048*

0.14

1.5

0.76

6.4

101

63

20

838

0.07

1.7

0.78

6.6

97

63

23

941

0.0 (control)

1.6

0.80

6.5

113

61

20

868

* Statistically significant (p < 0.05) compared to controls

 

Table 5. Serum analysis – Changes in biochemical parameters in female rats over the 13-week treatment period (mean values)

Dietary level of the test substance (%)

Magnesium (meq/L)

Creatinine (mg/100 mL)

Total protein (g/100 mL)

Cholesterol (mg/100 mL)

GOT

(mU/mL)

GPT

(mU/mL)

AP

(mU/mL)

2.25

1.4

0.82

6.2

76

72

24

1350*

1.13

1.4

0.74

6.4

89

73

25*

1169*

0.56

1.4

0.82

6.3

85

61

21

957

0.28

1.5

0.82

6.4

93

72

21

1059

0.14

1.4

0.77

6.2

85

74

24

858

0.07

1.5

0.77

6.2

92

70

20

841

0.0 (control)

1.5

0.79

6.3

88

68

20

859

* Statistically significant (p < 0.05) compared to controls

Table 6. Mean absolute and relative organ weights of male rats after the 13-week treatment period

Dietary level of the test substance (%)

Final body weight (g)

Heart (g)

Liver (g)

Spleen (g)

Kidneys (g)

Brain (g)

Testes (g)

Abs.

Rel.

Abs.

Rel.

Abs.

Rel.

Abs.

Rel.

Abs.

Rel.

Abs.

Rel.

2.25

285*

0.92*

0.32*

12.5

4.4*

0.45*

0.16

2.26*

0.79

1.92

0.68*

3.10

1.10*

1.13

317*

0.95*

0.30

13.2

4.1*

0.49*

0.16

2.58

0.81

1.93

0.61*

3.21

1.02*

0.56

344

1.05

0.31

13.4

3.9*

0.55

0.16

2.69

0.79

1.95

0.57

3.20

0.93

0.28

339

1.06

0.31

12.7

3.8

0.56

0.17

2.69

0.81

1.90

0.57

3.19

0.95

0.14

348

1.05

0.30

12.9

3.7

0.57

0.16

2.71

0.79

1.98

0.57

3.19

0.92

0.07

338

1.04

0.31

12.4

3.7

0.55

0.16

2.62

0.81

1.95

0.58

3.16

0.94

0.0 (control)

342

1.03

0.30

12.6

3.7

0.55

0.16

2.72

0.79

1.92

0.56

3.19

0.94

* Statistically significant (p < 0.05) compared to controls

 

Table 7. Mean absolute and relative organ weights of female rats after the 13-week treatment period

Dietary level of the test substance (%)

Final body weight (g)

Heart (g)

Liver (g)

Spleen (g)

Kidneys (g)

Brain (g)

Abs.

Rel.

Abs.

Rel.

Abs.

Rel.

Abs.

Rel.

Abs.

Rel.

2.25

179*

0.63*

0.35

8.4*

4.7*

0.34*

0.19

1.57

0.88*

1.78

1.00*

1.13

199

0.69

0.34

8.4*

4.2*

0.38

0.19

1.66

0.84*

1.80

0.90

0.56

196

0.70

0.35

7.2

3.7*

0.40

0.20

1.57

0.80

1.79

0.91

0.28

197

0.68

0.34

6.7

3.4

0.37

0.19

1.54

0.78

1.77

0.91

0.14

204

0.70

0.35

6.9

3.4

0.39

0.19

1.62

0.80

1.78

0.88

0.07

204

0.70

0.35

6.9

3.4

0.40

0.20

1.66

0.82

1.79

0.88

0.0 (control)

204

0.71

0.35

6.7

3.3

0.40

0.20

1.60

0.79

1.80

0.89

* Statistically significant (p < 0.05) compared to controls

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.
Executive summary:

C12 -15AS Na (CAS 68890 -70 -0) was tested in a 13 week feeding study on rats. Ten rats/sex/dose in the test groups and 20 rats/sex in the control group were administered dietary levels of 0.07, 0.14, 0.28, 0.56, 1.13 and 2.25% (corresponding to 58, 113, 228, 470, 961 and 1944 mg/kg bw/day in males and 66, 131, 261, 506, 1070 and 2218 mg/kg bw/day in females). The control group received the diet alone. The NOAEL was set at 488 mg/kg bw/day for males and females since only adaptive changes in liver were observed at this dose level.

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:
comparable to guideline study with acceptable restrictions
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
Dose / conc.:
0.07 other: % nominal in diet
Dose / conc.:
0.14 other: % nominal in diet
Dose / conc.:
0.28 other: % nominal in diet
Dose / conc.:
0.56 other: % nominal in diet
Dose / conc.:
1.13 other: % nominal in diet
Dose / conc.:
2.25 other: % nominal in diet
Dose / conc.:
58 mg/kg bw/day (actual dose received)
Dose / conc.:
116 mg/kg bw/day (actual dose received)
Dose / conc.:
230 mg/kg bw/day (actual dose received)
Dose / conc.:
460 mg/kg bw/day (actual dose received)
Dose / conc.:
920 mg/kg bw/day (actual dose received)
Dose / conc.:
1 840 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10 test group
20 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:
comparable to guideline study with acceptable restrictions
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
GLP compliance:
no
Species:
rat
Sex:
male/female
Route of administration:
oral: feed
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Dose / conc.:
40 other: ppm nominal in diet
Dose / conc.:
200 other: ppm nominal in diet
Dose / conc.:
1 000 other: ppm nominal in diet
Dose / conc.:
5 000 other: ppm nominal in diet
Dose / conc.:
3 mg/kg bw/day (actual dose received)
Dose / conc.:
17 mg/kg bw/day (actual dose received)
Dose / conc.:
86 mg/kg bw/day (actual dose received)
Dose / conc.:
430 mg/kg bw/day (actual dose received)
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 hematocrit and hemoglobin 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:
comparable to guideline study with acceptable restrictions
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: 22 - 25°F
- Relative Humidity: 45-55%
- Air changes: Not reported
- Photoperiod: 12 h light, 12 h dark

IN-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
Dose / conc.:
0.25 other: % nominal in diet
Dose / conc.:
0.5 other: % nominal in diet
Dose / conc.:
1 other: % nominal in diet
Dose / conc.:
55.5 mg/kg bw/day (actual dose received)
Remarks:
males
Dose / conc.:
112.5 mg/kg bw/day (actual dose received)
Remarks:
males
Dose / conc.:
201.3 mg/kg bw/day (actual dose received)
Remarks:
males
Dose / conc.:
60 mg/kg bw/day (actual dose received)
Remarks:
females
Dose / conc.:
122.8 mg/kg bw/day (actual dose received)
Remarks:
females
Dose / conc.:
254.6 mg/kg bw/day (actual dose received)
Remarks:
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: Daily

CAGE 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: Yes

FOOD 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: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Pretest and at study termination (wk 13)
- Dose groups that were examined: All animals

HAEMATOLOGY: 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: 22 - 25°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:
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
Remarks:
Limited details on test animals and environmental conditions. Not all haematological examinations and no urinalysis were performed. Neurobehavioural and ophthalmoscopic examinations are missing due to the year when the study was conducted.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
limited details on test animals and environmental conditions; not all haematological examinations and no urinalysis were performed; neurobehavioural and ophthalmoscopic examinations are missing due to the year when the study was conducted
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: Colworth Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: males: 81.73 g (control group), 82.49 (0.015% dose group), 81.98 g (0.15% dose group), 81.16 g (1.5% dose group); females: 69.36 g (control group), 69.58 (0.015% dose group), 69.40 g (0.15% dose group), 68.80 g (1.5% dose group)
- Housing: rats were individually housed.
- Diet: ad libitum
- Water: ad libitum

IN-LIFE DATES: From: 09 Feb 1976 To: 24 Feb 1978
(The studies were finalised in 1978. Data of both studies were compiled in 1995.)
Route of administration:
oral: feed
Vehicle:
other: plain diet
Details on oral exposure:
DIET PREPARATION
- Mixing appropriate amounts with a purified diet
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily, 7 days/week
Dose / conc.:
0.015 other: % nominal in diet
Dose / conc.:
0.15 other: % nominal in diet
Dose / conc.:
1.5 other: % nominal in diet
Dose / conc.:
11 mg/kg bw/day (actual dose received)
Dose / conc.:
113 mg/kg bw/day (actual dose received)
Dose / conc.:
1 125 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
45
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: animals were inspected daily for signs of ill-health.

BODY WEIGHT: Yes
- Time schedule for examinations: body weights were determined weekly for the first 13 weeks, again at Week 16, and thereafter at intervals of 4 weeks until the end of the study.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: food consumption was determined weekly for the first 13 weeks, again at Week 16, and thereafter at intervals of 4 weeks until the end of the study.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No, only mean values for each group per week reported

WATER CONSUMPTION: Yes
- Time schedule for examinations: water consumption was determined weekly for the first 13 weeks, again at Week 16, and thereafter at intervals of 4 weeks until the end of the study.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at study termination and after overnight starvation
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes, overnight
- How many animals: all surviving animals (244/360 animals)
- Parameters checked: packed cell volume (PCV), haemoglobin, mean cell haemoglobin concentration (MCHC), total leukocytes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at study termination and after overnight starvation
- Animals fasted: Yes
- How many animals: all surviving animals (244/360 animals)
- Parameters checked: sodium, potassium, chloride, calcium, magnesium, urea, glucose, total cholesterol, triglycerides, creatinine, aspartate transaminase (ASAT), alanine transaminase (ALAT), lactate dehydrogenase, hydroxybutyrate dehydrogenase, alkaline phosphatase, pseudo cholinesterase
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, a full post-mortem examination was performed in all animals (survivors and decedents), including physical examination of the external body surface, all orifices, cranial cavity, meningeal surface of the brain, the neck, the thoracic, abdominal and pelvic cavities with their associated organs and tissues and the carcass; organ weights of heart, liver, spleen kidneys, testes, adrenals and brain were determined in all surviving animals.
HISTOPATHOLOGY: Yes, in all animals; histopathological examination was performed in heart, liver, spleen kidneys, testes, adrenals, brain, aorta, eyes, intestine, kidneys, lacrimal glands, liver, lungs, lymph nodes, mammary gland, muscle, ovaries, pancreas, pituitary, prostate, salivary gland, seminal vesicles, spleen, stomach, testes, thyroids, thymus, tongue, urinary bladder and uterus
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.
Statistics:
For all relevant parameters, except those for pathology, mean values were calculated.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: reduced weight gain in rats (particularly males) compared to controls (non-adverse)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: reduced food consumption in rats (particularly males) compared to controls (non-adverse)
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: reduced water consumption in males and females compared to controls (non-adverse)
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: reduced total white cell count in females (non-adverse)
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: increased activity of ALAT, AP and urea in males (non-adverse); decreased activities of lactate dehydrogenase and hydroxybutyrate dehydrogenase in females (non-adverse)
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: reduction in the relative organ weights of spleen, heart, kidneys and adrenals in males; increased testes weights in males; increased liver weights in male and female (non-adverse)
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: hepatic enlargement in males and females
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: major changes in liver and spleen; minor changes in kidney, heart
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No adverse effects on survival were observed after treatment with the test substance. Of the 360 rats involved, 244 (67.8%) survived to the termination of the study. Survival was highest in rats receiving the highest dose level of 1.5% (78.9%) and lowest in those fed 0.15% of the test substance in the diet (60%). Neoplasia was the most common cause of death in animals which died during the study, but death from this cause was or from any other illness was not enhance by feeding with the test substance.

BODY WEIGHT AND WEIGHT GAIN
Weight gain was poorer for the rats fed at the highest dose level (1.5%), particularly the male animals, when compared to controls.

FOOD CONSUMPTION
Reduced food consumption compared to controls was observed at the highest dose level (1.5%), especially for males, which is consistent with the observed decrease in body weight gain in these animals.

WATER CONSUMPTION
During the study, a lower water consumption compared to controls was noted in both sexes at the highest dose level (1.5%).

HAEMATOLOGY
The only effect on haematological parameters was a reduction in the total white cell count for females receiving the test substance at a dietary dose level of 1.5% (highest dose).

CLINICAL CHEMISTRY (see Tables 1 under “Any other information on results incl. tables”)
The activities of alanine aminotransferase (ALAT) and alkaline phosphatase (AP) were increased in the blood of male rats of the highest dose group (1.5%), as also was the urea level. In contrast, the activities of lactate dehydrogenase and hydroxybutyrate dehydrogenase were lower for female rats of this dose group. The increased incidence of multifocal sublobular hepatic necrosis, which is occasionally observed in the liver of aging rats, was probably responsible for the elevated activity of ALAT in males of the high dose group. The increase in AP activity at the high dose group was rather associated with the hepatic parenchymal hypertrophy resulting from the physiological adaptive response to the increased metabolic demand.

ORGAN WEIGHTS (see Tables 2 under “Any other information on results incl. tables”)
A reduction in the relative organ weights of spleen, heart, kidneys and adrenals was observed for male rats at dietary levels of 1.5%, while absolute and relative testes weights in males were increased at this dose level. Much heavier adrenal weights were found for female rats fed the same dose levels, but this was considered to be due to some experimental error. The main treatment-related effect comprised an increase in absolute and relative liver weights in both male and female rats at the highest dose level.

GROSS PATHOLOGY (see Tables 3 under “Any other information on results incl. tables”)
Liver:
Diffuse hepatic enlargement was observed in 10 rats fed 0-0.15% of the test substance in the diet. However, this macroscopic feature was identified in 12 animals of the high dose group (1.5% in the diet), thus being treatment-related. In contrast, the incidence of raised areas, nodules and masse in the groups fed 0 and 0.015% in the diet (in total: 16 and 20 animals, respectively) was greater than in the 0.15 and 1.5% test groups (in total: 12 and 11 animals, respectively).

Thymus:
Macroscopic nodules/masses were recorded in 28 rats fed 0-0.15% of the test substance in the diet. In contrast, these lesions were identified only in one animals of the high dose group (1.5% in the diet).

Pancreas:
Nodules/masses were observed in 8 rats fed 0-0.15% in the diet. Similar lesions were observed in 8 animals fed a dietary dose level of 1.5%.

Kidney:
Diffuse granularity/pitting was recorded in 74 male rats fed 0-0.15% of the test substance in the diet. In 23 of these animals, the lesions wre graded moderate or severe. In contrast, in the males of the high dose group (1.5% in the diet), only 11 cases of renal granularity/pitting were identified and in only 4 cases the lesions were rated moderate or severe.

HISTOPATHOLOGY: NON-NEOPLASTIC (see Tables 3 under “Any other information on results incl. tables”)
Liver:
The most significant treatment-related changes in the liver involved the increases in the incidence and severity of parenchymal hypertrophy, focal coagulative and/or haemorrhagic necrosis and pigmented lipid granuloma.
Zonal (periportal) or diffuse parenchymal hypertrophy was observed in 21 males and 33 females fed a dietary concentration of 1.5% of the test substance (high dose group). In contrast, this feature was only observed in 3 rats fed 0.015 and 0.15% of the test substance in the diet. The hepatic parenchymal hypertrophy in animals of the high dose group correlated with the observed increase in liver weight at this dose group. However, this histopathological finding was considered to probably represent a physiological adaptive respond to increased metabolic demand after treatment with the test substance.
Sublobular foci of coagulative and/or haemorrhagic necrosis were observed in the livers of 22 rats fed dietary concentrations of 0-0.15%, whereas these lesions were recorded in 19 animals of the high dose group. Granulomata, composed of vacuolated macrophage aggregates containing fine particles of a dark pigment (pigmented lipid granuloma) were located between cords of hepatocytes and around portal tracts. These lesions were present in the livers of small numbers of females fed 0, 0.015 and 0.15% of the test substance in the diet and in one male control animals. However, in the high dose group, lesions were present in the livers of 19 rats. The focal coagulative/haemorrhagic necrosis and the lipid granuloma were considered to be lesions, which occasionally occur in the livers of ageing rats of one or both sexes. Sublobular foci of hepatic necrosis may be attributable to enteric bacterial infection while lipid granuloma may represent the aggregation, within Kupffer cells, of enzymatically digestible debris normally retained in mesenteric macrophages and macrophage syncytia.
The incidence and/or severity of a few other histopathological changes in the liver (e.g. portal bailer stasis) were altered in the high dose group, but not considered to be of biological relevance due to the fact that these lesions only occurred in one sex of the animals.
Hepatic extramedullary erythropoiesis was, however, observed less frequently in the high dose group compared to groups fed 0-0.15% of the test substance in the diet.

Spleen:
The severity of splenic extramedullary erythropoiesis was reduced in females fed the high dose (1.5% in the diet) when compared to dose fed 0-0.15% of the test substance in the diet. Likewise, in females of the high dose group, the incidence of myelopoiesis and stem cell hyperplasia was reduced. In contrast, in females of the high dose group, the severity of red pulp hemosiderin deposition was greater than in animals of the same sex fed 0-0.15% of the test substance in the diet.

Kidney:
A reduced severity and/or incidence of chronic nephropathy and pelvic nephrocalcinosis were observed among rats fed the high dose (1.5% in the diet).

Heart:
A reduced severity and/or incidence of arterial medial hypertrophy was observed among rats fed the high dose (1.5% in the diet).

HISTOPATHOLOGY: NEOPLASTIC
The total number of tumour and the number of tumour bearing rats was reduced for rats fed 1.5% of the test substance in the diet (high dose) and this was largely due to a decrease in liver and lymphoreticular tumours, while the tumour incidence in male rats of the same dose group did not differ from the incidence of control rats. The former consisted of more benign tumours and fewer malignant tumours than for controls. The total numer of pancreatic tumours was increaesd in males of the high dose group, but this was due to a slight increase in both exocrine and islet tumours; when each tumour type was considered separately, the increase in this incidence had no biological significance.
Dose descriptor:
LOEL
Effect level:
1.5 other: % in the diet
Based on:
act. ingr.
Remarks:
corresponding to 1125 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: liver weights and liver enzymes increased associated with histopathological changes in males (adaptive changes, rather than adverse effects)
Dose descriptor:
NOEL
Effect level:
0.15 other: % in the diet
Based on:
act. ingr.
Remarks:
corresponding to 113 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: overall effects
Critical effects observed:
not specified

Table 1. Serum analysis – Changes in biochemical parameters in male rats over the 2-year treatment period (mean values)

Dietary level of the test substance (%)

Urea

(mmol/L)

ALAT

(U(L)

AP

(U/L)

1.5

7.076

58.0

824.3

0.15

5.279

40.0

506.8

0.015

5.204

36.7

568.2

0.0 (control)

5.933

34.9

520.0

 

 

Table 2. Mean absolute and relative organ weights of male rats after the 2-year treatment period

Dietary level of the test substance (%)

Final body weight (g)

Heart (g)

Liver (g)

Spleen (g)

Kidneys (g)

Adrenals (g)

Testes (g)

Abs.

Rel.

Abs.

Rel.

Abs.

Rel.

Abs.

Rel.

Abs.

Rel.

Abs.

Rel.

1.5

474.6

1.322

0.280

15.579

3.290

0.865

0.183

3.711

0.787

0.04333

0.00936

3.540

0.766

0.15

473.3

1.437

0.306

13.120

2.776

0.910

0.194

3.952

0.841

0.04126

0.00882

3.168

0.672

0.015

477.6

1.412

0.296

13.760

2.896

0.898

0.188

3.962

0.834

0.03787

0.00800

3.149

0.664

0.0 (control)

471.5

1.530

0.326

13.713

2.917

1.103

0.238

4.112

0.878

0.04807

0.01024

3.204

0.683

Table 3. Pathology. Summary of biologically significant treatment-induced effects observed in rats fed 0-1.5% dietary concentrations of the test substance for up to 2 years

Findings

0.015% in the diet

0.15% in the diet

1.55% in the diet

Male

Female

Male

Female

Male

Female

Macroscopic pathology

Liver: diffuse enlargement

        raised areas/nodules/masses

-

-

-

-

-

-

-

Thymus: nodules/masses

-

-

-

-

-

Pancreas: nodules/masses

-

-

-

-

-

Kidneys: granularity/pitting

-

-

-

-

-

Histopathology

Liver: zonal, diffuse parenchymal hypertrophy

        pigmented lipid granulomata

        focal coagulative/haemorrhagic necrosis

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Spleen: erythropoiesis

           myelopoiesis

           stem cell hyperplasia

           hemosiderin deposition

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 

↑ or ↓: increase or decrease in incidence/severity of features;

-: no change in in incidence/severity

 

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. Absoulte values reported within this entry are for the high conversion bleached material.

Conclusions:
Since the liver as the target organ showed only adaptive responses, the LOEL was set at 1.5% (1115 mg/kg bw/day). The adaptive changes included elevated absolute and relative liver weight, hepatic periportal hypertrophy as well as increased serum alkaline phosphatase (AP).
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.
The increased incidence of multifocal sublobular hepatic necrosis, which is occasionally observed in the liver of aging rats, was probably responsible for the elevated activity of alanine aminotransferase in males of the high dose group.
Executive summary:

In the chronic dietary repeated dose toxicity studies, the NOELs were set at 113 mg/kg bw/day (LOELs = 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.

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:
comparable to guideline study with acceptable restrictions
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
Dose / conc.:
0.07 other: % nominal in diet
Dose / conc.:
0.14 other: % nominal in diet
Dose / conc.:
0.28 other: % nominal in diet
Dose / conc.:
0.56 other: % nominal in diet
Dose / conc.:
1.13 other: % nominal in diet
Dose / conc.:
2.25 other: % nominal in diet
Dose / conc.:
61 mg/kg bw/day (actual dose received)
Dose / conc.:
123 mg/kg bw/day (actual dose received)
Dose / conc.:
230 mg/kg bw/day (actual dose received)
Dose / conc.:
482 mg/kg bw/day (actual dose received)
Dose / conc.:
970 mg/kg bw/day (actual dose received)
Dose / conc.:
2 067 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10 test group
20 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:
sub-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
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
Dose / conc.:
0.07 other: % nominal in diet
Dose / conc.:
0.14 other: % nominal in diet
Dose / conc.:
0.28 other: % nominal in diet
Dose / conc.:
0.56 other: % nominal in diet
Dose / conc.:
1.13 other: % nominal in diet
Dose / conc.:
2.25 other: % nominal in diet
Dose / conc.:
64 mg/kg bw/day (actual dose received)
Dose / conc.:
134 mg/kg bw/day (actual dose received)
Dose / conc.:
253 mg/kg bw/day (actual dose received)
Dose / conc.:
512 mg/kg bw/day (actual dose received)
Dose / conc.:
1 007 mg/kg bw/day (actual dose received)
Dose / conc.:
2 096 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10 test group
20 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 conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
488 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The whole data base is conclusive and of high quality.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are no data on repeated dose toxicity available for Sulfuric acids, C9-11-iso-C10 rich, alkyl esters, sodium salt. Therefore, this endpoint is covered by read across to structurally related alkyl sulfates (AS) in accordance with Regulation (EC) No. 1907/2006 Annex XI 1.5 “Grouping of substances and read-across approach”. In Annex XI 1.5 it is given that a read-across approach is possible for substances whose physico-chemical, 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 read-across approach show structural similarity. The most important common structural feature of the source and target substances 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 source and target substances in turn represent the predominant attribute in mediating effects on mammalian health. Therefore, the AS have similar physico-chemical, environmental and toxicological properties. 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.

Regarding repeated dose toxicity one relevant key study with Sulfuric acid, mono-C12-15-alkyl esters, sodium salts (C12-15 AS Na, CAS 68890-70-0) and further supporting studies with structurally analogue read-across source substances Sulfuric acid, mono-C13-15-alkyl esters, sodium salts (C13-15 AS Na, CAS 86014-79-1), sodium dodecyl sulfate (C12 AS Na, CAS 151-21-3), Sulfuric acid, mono-C10-16-alkyl esters, sodium salts (C10-16 AS Na, CAS 68585-47-7), Sulfuric acid, mono-C12-15-alkyl esters, sodium salts (C12-15 AS Na, CAS 68890-70-0), and Sulfuric acid, mono-C16-18-alkyl esters, sodium salts (C16-18 AS Na, CAS 68955-20-4) are available. Hence, alkyl sulfates with chain lengths between C10 and C18 have been tested and are considered to derive data for the target substance Sulfuric acids, C9-11-iso-C10 rich, alkyl esters, sodium salt.

Oral feeding repeated dose toxicity 

C12-15 AS 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 the key study that meets current standards (except for neurotoxicity and immunotoxicity testing; Unilever, 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 supporting chronic dietary repeated dose toxicity studies with C12-15 AS Na (CAS 68890-70-0) the NOELs were set at 113 mg/kg bw/day (LOAEL = 1125 mg/kg bw/day; Unilever, 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.

C12 AS Na (CAS 151-21-3) was tested in a 90 day feeding study on rats (Walker, 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).

C12 AS Na (CAS 151-21-3) was also tested in a 13 week feeding study on rats by Unilever (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 C10-16 AS Na (CAS 68585-47-7; P&G, 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.

In another subchronic study with C13-15 AS Na (CAS 86014-79-1; Unilever, 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.

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

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 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

C12 AS Na

13

430

> 430

Walker (1967)

C12 AS Na

13

460

920

Unilever (1976b)

C10-16 AS Na

13

201 (m) /

254 (f)

> 201 (m) /

> 254 (f)

P&G (1976)

C12-15 AS Na

13

488

1016

Unilever (1976a)

C13-15 AS Na

13

512

1007

Unilever (1977a)

C16-18 AS Na

13

482

970

Unilever (1977b)

C12-15 AS Na

104

113

1125

Unilever (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 P&G (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 (Unilever, 1976a) representing an average of all NOAEL was chosen for the risk assessment of oral and dermal exposure.

[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) No. 1272/2008 (CLP) and are therefore conclusive but not sufficient for classification.