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Description of key information

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

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
488 mg/kg bw/day

Additional information

The study investigating the dermal route, the most relevant for human exposure, 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. For this reason studies based on dietary exposure appears to be more appropriate to assess potential systemic toxicity resulting from repeated exposures to AS.

Reliable studies have been conducted with C12ASO4Na (CAS 151-21-3), C12-14ASO4TEA (CAS 90583-18-9), C12-15ASO4Na (CAS 68890-70-0) and C16-18ASO4Na (CAS 68955-20-4) and C13-15ASO4Na (CAS 86014-79-1). Hence,alkyl sulfates with chain lengths between C12and C18have been tested.

A 90 % aqueous solution of C12ASO4Na was administered for 28 days by gavage to groups of 5 animals/sex/dose at dose levels of 30, 100 or 300/600 mg/kg bw (the dose of 300 mg/kg bw was changed into 600 mg/kg bw 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.s./kg bw (Potokar et al., 1987a). At the LOAEL (270/540 mg a.s./kg bw), feed intake and body weight gain were reduced, and water intake increased. Bleeding and ulceration of the stomach, as well as transient alterations of the tongue and myocard were found. There was an increase in leucocytes and in alanine aminotransferase (ALT) activity, as well as a decrease in haematocrit and erythrocyte volume (MCV). Relative weights of adrenals, kidneys, brain, gonads and liver were increased; the relative thymus weight was decreased.

With the same study design (which meets all requirements of the OECD 407 except for functional observation battery tests), C12-14ASO4TEA was administered by gavage as a ca. 40% aqueous solution at dose levels of 0, 70, 250 or 750 mg/kg bw (corresponding to 0, 29, 102 and 306 mg a.s./kg bw) to groups of 5 rats/sex/dose (Potokar et al., 1988). At 250 mg/kg bw (i.e. 102 mg a.s./kg bw), 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 (i.e. 306 mg a.s./kg bw), the severity of gastric irritation increased, and the animals showed leucocytosis (LOAEL).

In a 90 day gavage study, C16-18ASO4Na was administered as 55% aqueous solution to groups of 10 rats/sex/dose at dose levels of 100, 300 and 900 mg/kg bw, corresponding to ca. 55, 165 and 495 mg a.s./kg bw (Potokar et al., 1987b). The NOEL was established at 55 mg a.s./kg bw. At the next higher dose level (NOAEL, 165 mg a.s./kg bw) 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, there were clear signs of gastritis; absolute and relative liver weights were increased. No signs of toxicity were found in the kidney.

 

C12ASO4Na was tested as well in a 90-day feeding study on rats (Walker et al., 1967). Twelve 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). 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. Regarding this as an adaptive effect, the NOAEL can be set at the highest dose level of 5000 ppm (430 mg/kg bw).

In another subchronic study with C16-18ASO4Na (Munday et al., 1977a), 10 animals/sex/group were fed diets containing 0, 0.07, 0.14, 0.28, 0.56, 1.13 or 2.25 % (corresponding to 0, 61, 123, 230, 482, 970, or 2067 mg/kg bw), the NOAEL was established at 482 mg/kg bw as only adaptive changes (elevated liver weights and hypertrophy of the liver) were observed. At the LOAEL (970 mg/kg bw) 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.

C13-15ASO4Na (subchronic, dietary study, Munday et al., 1977b) shows an identical profile with a similar NOAEL (512 mg/kg bw) and LOAEL(1007 mg/kg bw).

C12-15ASO4Na 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 10 rats/sex/dose in a study that meets current standards (except for neurotoxicity and immunotoxicity testing; Munday et al., 1976), the NOEL was set at 0.14% (122 mg/kg bw). Since the liver as the target organ showed only adaptive responses, theNOAELwas set at 0.56% (488 mg/kg bw). 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 repeated dose toxicity studies the NOAELs were set at 113 mg/kg bw (LOAELs = 1125 mg/kg bw; Munday et al., 1995a & b). Animals in the high dose groups in both studies exhibited reduced food and water consumption and slower growth rates. Other pathological findings were increased absolute liver weights and liver to body weight ratios, hypertrophy of the hepatic parenchyma, increased relative testicular weights, reduced incidence and severity of chronic nephropathy and nephrocalcinosis and reduced arterial medial hypertrophy.

 

In 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). Hence, the NOAEL used for the risk assessment should be based on a dietary study to avoid too conservative assumption.

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 Table1 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.

 

Table1: NOAELs and LOAELs (as a.s.) for repeated dietary dose toxicity studies of AS in rats

Substance

Duration

(weeks)

NOAEL

(mg/kg bw)

LOAEL

(mg/kg bw)

Reference

C12ASO4Na

13

430

> 430

Walker et al. (1967)

C12-15ASO4Na

13

488

1016

Munday et al. (1976)

C13-15ASO4Na

13

512

1007

Munday et al. (1977b)

C16-18ASO4Na

13

482

970

Munday et al. (1977a)

C12-15ASO4Na

104

113

1125

Munday et al. (1995a,b)

 

As the subchronic NOAELs are not conflicting with the chronic LOAEL, one of these can be chosen as basis for the risk assessment. Concentrating on the more recent NOAELs of study reports instead on literature, the medium one, e.g. 488 mg/kg bw was selected.

Based on the described effects and argumentations, the dietary NOAEL of 488 mg/kg bw (Munday et al., 1976), was chosen for the risk assessment.

Justification for classification or non-classification

Classification criteria according to 67/548/EEC and (EC)1272/2008 are not fulfilled.