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EC number: 293-917-2
CAS number: 91648-55-4
No data are available for the target substance Sulfuric acid,
mono-C16-20 (even numbered)-alkyl esters, sodium salts (CAS 91648-55-4).
Therefore, read-across from structural analogue source substance has
been applied and a NOAEL of 488 mg/kg bw/day for oral and dermal
exposure was established for all alkyl sulfates (AS) read-across source
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).
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.
Dawley (Charles River CD) rats of 3-4 wk age, weighing 102-154 g (males)
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.
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.
were observed daily for physical appearance, signs of local or systemic
toxicity, pharmacologic effects and mortality.
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.
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.
mortality was observed during study period. No pharmacological or
toxicological signs were observed throughout the study.
treatment related effects were observed in feed efficiency and body
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.
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).
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 (%)
Table 2. Mean absolute and relative organ weights of male rats after the
2-year treatment period
Final body weight (g)
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
0.015% in the diet
0.15% in the diet
1.55% in the diet
Liver: diffuse enlargement
Liver: zonal, diffuse parenchymal hypertrophy
pigmented lipid granulomata
focal coagulative/haemorrhagic necrosis
stem cell hyperplasia
↑ 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.
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.
Table 1. Average body weight gain of rats over the 13-week treatment
Average body weight gain (g)
* 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
Mean total amount of food consumed (g)
Table 3. Mean body weight gain (g)/mean total food consumed (g) by rats
over the 13-week treatment period
Table 4. Serum analysis – Changes in biochemical parameters in male rats
over the 13-week treatment period (mean values)
Creatinine (mg/100 mL)
Total protein (g/100 mL)
Cholesterol (mg/100 mL)
Table 5. Serum analysis – Changes in biochemical parameters in female
rats over the 13-week treatment period (mean values)
Table 6. Mean absolute and relative organ weights of male rats after the
13-week treatment period
Table 7. Mean absolute and relative organ weights of female rats after
the 13-week treatment period
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.
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.
There is no study regarding sensitisation available for C16-20 AS Na
(CAS 91648-55-4). Therefore, this endpoint is covered by read-across to
structurally related alkyl sulfates (AS). 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  and by
a voluntary industry program carrying out Human and Environmental Risk
Assessments (HERA ), further supporting the read across approach
between structurally related AS. A detailed justification for grouping
of alkyl sulfates into a category is provided separately. Please refer
for more details on the read-across also to the document “AS Category
Approach Justification” attached in section 13 of IUCLID.
Reliable repeated dose toxicity studies have been conducted with C12 AS
Na (CAS 151-21-3), C10-16 AS Na (68585-47-7), C12-15 AS Na (CAS
68890-70-0), C16-18 AS Na (CAS 68955-20-4) and C13-15 AS Na (CAS
86014-79-1). Hence, alkyl sulfates with chain lengths between C10 and
C18 have been tested.
Oral feeding RDT
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 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 (LOAELs = 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 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).
C12 AS Na (CAS 151-21-3) was also tested in a 13 week feeding study on
rats (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
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).
Oral gavage RDT
In a 90 day gavage study, C16-18 AS 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.i./kg bw/day (BASF, 1987d). 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.
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% C12-15 AS 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 (Unilever, 1977c). 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 treated 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 following discussion.
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
C12 AS Na
C10-16 AS Na
C12-15 AS Na
C13-15 AS Na
C16-18 AS Na
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.
 SIDS initial assessment profile, (2007);
 (HERA Draft report, 2002);
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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