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Description of key information

No data on repeated dose toxicity are available for the target substance sulfuric acid, mono-C12-14 (even numbered)-alkyl esters, ammonium salts (CAS 90583-11-2). Therefore, read-across from structural analogue substances has been applied.

Oral and dermal repeated dose toxicity: NOAEL = 488 mg/kg bw/day

Read-across of key information from source substance sulfuric acid, mono-C12-15-alkyl esters, sodium salts (CAS 68890-70-0), supported by additional studies performed with various structural analogue substances.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available data used for the endpoint assessment of the target substance.
Adequacy of study:
key study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Key result
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'
Remarks on result:
other: Source, key, 68890-70-0, 1976a
Critical effects observed:
not specified
Conclusions:
Since the liver showed only adaptive responses, the NOAEL for male and female animals was set at 488 mg/kg bw/day (corresponding to 0.56% in diet). 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 indicate a physiological adaptation resulting from changes in hepatic metabolism required for the breakdown and detoxification of the test material. Since AP is mainly localised in the hepatic parenchyma, enlargement of the hepatic parenchymal cells accompanied by an increased organ weight are an obvious consequence.
Executive summary:

The oral repeated dose toxicity of the target substance is estimated based on an adequate and reliable subchronic oral toxicity study of a structural analogue source substance. Oral exposure for 13 weeks with the test substance resulted only in an adaptive response of the liver as the main target organ. The adaptive changes included elevated relative liver weights, hepatic periportal hypertrophy as well as increased serum alkaline phosphatase (AP) activity. The NOAEL for male and female rats was established at 488 mg/kg bw/day. As explained in the category justification, the differences in molecular structure between the target and the source substances are unlikely to lead to differences in oral repeated dose toxicity.

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 available information comprises adequate and reliable (Klimisch score 1 and 2) studies from various source substances with similar structures and intrinsic properties. Read-across is justified based on common physico-chemical, ecotoxicological and toxicological properties. The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
10 other: %
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Corresponding to 400 mg/kg bw.
Remarks on result:
other: Source, key, 68890-70-0, 1977c
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
12.5 other: %
System:
integumentary
Organ:
skin
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Conclusions:
Subchronic exposure to the test substance resulted in extensive necrosis and ulceration of the skin, changes in haematology and organ weights. The NOAEL was established at 400 mg/kg bw/day.
Executive summary:

The dermal repeated dose toxicity of the target substance is estimated based on an adequate and reliable subchronic dermal toxicity study of a structural analogue source substance. Dermal exposure for 13 weeks with the test substance resulted in extensive necrosis and ulceration of the skin, changes in haematology and organ weights. The NOAEL was established at 400 mg/kg bw/day. As explained in the category justification, the differences in molecular structure between the target and the source substances are unlikely to lead to differences in dermal repeated dose toxicity.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
400 mg/kg bw/day
Study duration:
subchronic
Species:
mouse
Quality of whole database:
The available information comprises an adequate and reliable (Klimisch score 1) study from a source substances with similar structure and intrinsic properties. Read-across is justified based on common physico-chemical, ecotoxicological and toxicological properties. The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Refer to the Category Approach Justification document provided in IUCLID6 Section 13
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
10 other: %
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Corresponding to 400 mg/kg bw.
Remarks on result:
other: Source, key, 68890-70-0, 1977c
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
12.5 other: %
System:
integumentary
Organ:
skin
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Conclusions:
Subchronic exposure to the test substance resulted in extensive necrosis and ulceration of the skin, changes in haematology and organ weights. The NOAEL was established at 400 mg/kg bw/day.
Executive summary:

The dermal repeated dose toxicity of the target substance is estimated based on an adequate and reliable subchronic dermal toxicity study of a structural analogue source substance. Dermal exposure for 13 weeks with the test substance resulted in extensive necrosis and ulceration of the skin, changes in haematology and organ weights. The NOAEL was established at 400 mg/kg bw/day. As explained in the category justification, the differences in molecular structure between the target and the source substances are unlikely to lead to differences in dermal repeated dose toxicity.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Study duration:
subchronic
Species:
mouse
Quality of whole database:
The available information comprises an adequate and reliable (Klimisch score 1) study from a source substances with similar structure and intrinsic properties. Read-across is justified based on common physico-chemical, ecotoxicological and toxicological properties. The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No. 1907/2006.

Additional information

There are no data on repeated oral and dermal toxicity available for the target substance sulfuric acid, mono-C12-14 (even numbered)-alkyl esters, ammonium salts (CAS 90583-11-2). Therefore, these endpoints are covered by read-across from structurally related alkyl sulfates (AS). The possibility of a read-across from 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 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 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, neutralised 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 represents the predominant attribute in mediating effects on mammalian health. Therefore, the members of the AS category have similar physico-chemical, environmental and toxicological properties, validating the read-across approach within the category. The approach of grouping different AS for the evaluation of their effects on human health and the environment was also made by the OECD in the SIDS initial assessment profile [1] and by a voluntary industry programme carrying out Human and Environmental Risk Assessments (HERA [2]), further supporting the read-across approach between structurally related AS.

Ammonium sulfate is used to produce AS NH4 within the current AS category. There is a substantial data base on ammonium sulfate online available. Ammonium sulfate is not listed in Annex VI of Regulation (EC) No. 1272/2008 (CLP). In addition, the effects of ammonium sulfate on human health were assessed by the OECD in the SIDS initial assessment report [3]. Ammonium sulfate gives no rise to concern of adverse effects on human health. Therefore, a contribution of ammonium sulfate to the effects on human health is considered to be negligible when assessing human health effects of the target substance sulfuric acid, mono-C12-14 (even numbered)-alkyl esters, ammonium salts (CAS 90583-11-2).

Reliable repeated dose toxicity studies have been conducted with the structural analogue substances sulfuric acid, mono-C12-15-alkyl esters, sodium salts (CAS 68890-70-0), sodium dodecyl sulfate (CAS 151-21-3), sulfuric acid, mono-C10-16-alkyl esters, sodium salts (CAS 68585-47-7), sulfuric acid, mono-C13-15-alkyl esters, sodium salts (CAS 86014-79-1), and sulfuric acid, mono-C16-18 (even-numbered)-alkyl esters, sodium salts (CAS 68955-20-4), and sulfuric acid, mono-C12-14-alkyl esters, compds. with triethanolamine (CAS 90583-18-9). Hence, alkyl sulfates with chain lengths between C10 and C18 have been tested.

Oral feeding repeated dose toxicity

Sulfuric acid, mono-C12-15-alkyl esters, sodium salts (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 sulfuric acid, mono-C12-15-alkyl esters, sodium salts (CAS 68890-70-0) which support the findings of the key study, 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.

Sodium dodecyl sulfate (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).

Sodium dodecyl sulfate (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 conducted with sulfuric acid, mono-C10-16-alkyl esters, sodium salts (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 sulfuric acid, mono-C13-15-alkyl esters, sodium salts (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.

Sulfuric acid, mono-C16-18 (even-numbered)-alkyl esters, sodium salts (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 repeated dose toxicity

In a 90 day gavage study, sulfuric acid, mono-C16-18 (even-numbered)-alkyl esters, sodium salts (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, 1987b). The NOEL was established at 55 mg a.i./kg bw/day. At the next higher dose level (NOAEL, 165 mg a.i./kg bw/day) food consumption and body weight gain were reduced, and relative liver weight was increased. Other changes were non-specific and probably due to the irritant effect of the test substance to the stomach mucosa. At 495 mg/kg bw/day, there were clear signs of gastritis; absolute and relative liver weights were increased. No signs of toxicity were found in the kidney.

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

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

Dermal repeated dose toxicity

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% sulfuric acid, mono-C12-15-alkyl esters, sodium salts (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 receiving 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.

 

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 alkyl sulfates (AS) used as structural analogues 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 summary 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

Sodium dodecyl sulfate (CAS 151-21-3)

13

430

> 430

Walker(1967)

Sodium dodecyl sulfate (CAS 151-21-3)

13

460

920

Unilever(1976b)

Sulfuric acid, mono-C10-16-alkyl esters, sodium salts (CAS 68585-47-7)

13

201/254

> 201/>254

P&G (1976)

Sulfuric acid, mono-C12-15-alkyl esters, sodium salts (CAS 68890-70-0)

13

488

1016

Unilever (1976a)

Sulfuric acid, mono-C13-15-alkyl esters, sodium salts (CAS 86014-79-1)

13

512

1007

Unilever (1977a)

Sulfuric acid, mono-C16-18 (even-numbered)-alkyl esters, sodium salts (CAS 68955-20-4)

13

482

970

Unilever (1977b)

Sulfuric acid, mono-C12-15-alkyl esters, sodium salts (CAS 68890-70-0)

104

113

1125

Unilever (1995a,b)

The NOAELs and LOAELs established in the different studies draw a coherent picture. The NOAEL of the chronic toxicity study (113 mg/kg bw/day) as well as the NOAEL of 254 mg/kg bw/day in the study with sulfuric acid, mono-C10-16-alkyl esters, sodium salts (CAS 68585-47-7; 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 effects and argumentations discussed above, the dietary NOAEL of 488 mg/kg bw/day for sulfuric acid, mono-C12-15-alkyl esters, sodium salts (CAS 68890-70-0; Unilever, 1976a) representing an average of all NOAEL was chosen for the risk assessment of oral and dermal exposure for the target substance sulfuric acid, mono-C12-14 (even numbered)-alkyl esters, ammonium salts (CAS 90583-11-2).

[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

[3] http://webnet.oecd.org/HPV/UI/SIDS_Details.aspx?Key=2c80d506-86bf-4719-be9b-d922022506ec&idx=0

Justification for classification or non-classification

The available data on repeated dose toxicity following oral and dermal exposure obtainded with structurally analogue substances do not meet the criteria for classification according to the CLP Regulation (EC) No. 1272/2008 and are, therefore, conclusive but not sufficient for classification. Based on read-across the target substance sulfuric acid, mono-C12-14 (even numbered)-alkyl esters, ammonium salts (CAS 90583-11-2) is also not classified for oral and dermal repeated dose toxicity. No data regarding repeated dose toxicity after inhalation are available.