Toxicological properties and risk assessment of the anionic surfactants category: Alkyl sulfates, primary alkane sulfonates, and α-olefin sulfonates

Ecotoxicology and Environmental Safety 74 (2011) 1089–1106

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Ecotoxicology and Environmental Safety journal homepage: www.elsevier.com/locate/ecoenv

Review

Toxicological properties and risk assessment of the anionic surfactants category: Alkyl sulfates, primary alkane sulfonates, and a-olefin sulfonates Axel Wibbertmann a,n, Inge Mangelsdorf a, Konrad Gamon b, Richard Sedlak c a

Fraunhofer Institute for Toxicology and Experimental Medicine, Nikolai-Fuchs-Str. 1, D-30625 Hannover, Germany Cognis GmbH, Henkelstrasse 67, D-40551, Duesseldorf, Germany c American Cleaning Institute, Washington, DC 20005, USA b

a r t i c l e i n f o

abstract

Article history: Received 10 December 2010 Received in revised form 12 February 2011 Accepted 15 February 2011 Available online 3 April 2011

The category of the anionic surfactants (ANS) consisting of 46 alkyl sulfates, 6 primary alkane sulfonates, and 9 a-olefin sulfonates has been assessed under the high production volume (HPV) chemicals program of the Organisation for Economic Cooperation and Development (OECD) in 2007. In this review the toxicological properties of these chemicals are summarized. The chemicals of this category are used predominantly in detergents, household cleaning products, and cosmetics. These chemicals show low acute and repeat dose toxicity. There was no evidence of genetic or reproductive toxicity, or carcinogenicity. There also was no indication for sensitizing properties. Skin and eye irritating effects in consumers are not to be expected. For consumers, the calculated body burden is about 10,000 times lower than the lowest NOAEL value in experimental animals, so that adverse effects caused by substances of the ANS category can be excluded. & 2011 Elsevier Inc. All rights reserved.

Keywords: Toxicology Anionic surfactants Alkyl sulfates Primary alkane sulfonates a-Olefin sulfonates

Contents 1. 2.

3.

4.

n

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090 General information on exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090 2.1. Occupational exposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090 2.2. Consumer exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090 3.1. Toxicokinetics, metabolism, and distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1091 3.2. Acute toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1091 3.2.1. Oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1091 3.2.2. Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1091 3.3. Skin irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1091 3.3.1. Influence of the counter ion for the alkyl sulfates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093 3.4. Eye irritation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093 3.5. Sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093 3.6. Repeated dose toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094 3.6.1. Oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094 3.6.2. Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1095 3.7. Mutagenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1096 3.8. Carcinogenity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1096 3.8.1. Oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1096 3.8.2. Dermal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097 3.9. Reproductive toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099 3.9.1. Fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099 3.9.2. Developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099 Exposure assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1100

Corresponding author. Fax: + 49 511 5350 335. E-mail address: [email protected] (A. Wibbertmann).

0147-6513/$ - see front matter & 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ecoenv.2011.02.007

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A. Wibbertmann et al. / Ecotoxicology and Environmental Safety 74 (2011) 1089–1106

Results and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1100 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103

1. Introduction

2. General information on exposure

The anionic surfactants (ANS) in this category include three structurally related classes of substances:

2.1. Occupational exposure

Alkyl sulfates:

Primary alkane sulfonates:

a-Olefin sulfonates:

Sulfate salts consisting of a predominantly linear alkyl chain, bearing a terminal, sulfate ester anion, neutralized with a base; single chain length or a defined chain length distribution The salt of a linear saturated alkyl chain, bearing a terminal sulfonate anion, neutralized with sodium hydroxide A mixture of sodium alkene sulfonate and hydroxyl alkane sulfonate salts, with the sulfonate group in the terminal position and the double bond, or hydroxyl group, located at various positions along a linear aliphatic chain in the vicinity of the sulfonate group

The most important common structural feature of the category members is the presence of a predominantly linear aliphatic hydrocarbon chain with a polar sulfate or sulfonate group, neutralized with a counter ion (i.e. Na + , K + , NH4+ , or an alkanolamine cation; see Fig. 1). The hydrophobic hydrocarbon chain (with a length between C8 and C18) and the polar sulfate or sulfonate groups confer surfactant properties and enable the commercial use of these substances as anionic surfactants. Common physical and/or biological pathways result in structurally similar breakdown products and are, together with the surfactant properties, responsible for the essentially identical hazard profiles with regard to human health, as will be shown in this paper. The toxicological properties of the ANS category were assessed under the high production volume (HPV) chemicals program of the Organisation for Economic Cooperation and Development (OECD). The data presented here were reviewed in 2007 at the OECD SIDS Initial Assessment Meeting (SIAM) 25 using a category approach (a grouped approach, in which data for individual members are presented and discussed together as part of a category, rather than substance-by-substance). In total, 61 anionic surfactants were assessed: 46 alkyl sulfates, 6 primary alkane sulfonates, and 9 a-olefin sulfonates (see Table 1). For the ANS category members, a comprehensive data set was collected from many sources, which is fully described in the peer-reviewed SIDS1 documentation and discussed in the SIAR2 (OECD, 2007). For those members of the category where reliable data were not available for all obligatory endpoints required according to the Manual for Investigation of HPV Chemicals,3 read across of toxicological data from closely related chemicals of the category was applied to address their properties. The project was sponsored and conducted by the Alkyl Sulfates Consortium, represented by the Soap and Detergent Association (SDA) of the U.S., in the framework of the Global ICCA (International Council of Chemical Associations) Initiative. 1

Screening Information Data Set. SIDS Initial Assessment Report. 3 http://www.oecd.org/document/7/0,2340,en_2649_34379_1947463_1_1_1_ 1,00.html. 2

Chemicals of this category are manufactured for use in consumer and commercial/institutional product formulation and are not used as intermediates/derivatives for further chemical manufacturing processes. Potential occupational exposures include the manufacturing and/or professional use of alkyl sulfate containing products, such as detergents, personal care products, paints, emulsifiers, wetting agents in the food and feed industries, adhesives, cellophane, paper and paperboard, coatings, closures, rubber articles and textiles. The alkane sulfonates are used in surfactant mixtures for shampoos and in liquid dishwashing detergents, often in conjunction with alkyl ether sulfates (AES) and in concentrated shampoos, in textile and leather auxiliaries (mercerizing), preparations for cleaning metal, steam jets and pickling baths. In the USA, almost all a-olefin sulfonate was used in personal care products and industrial applications, while in Western Europe the major use was in industrial and institutional cleaners with some small quantities used in light-duty liquids and personal care products. In Japan, the major use was in household detergents, and small volumes are currently used in personal care products, primarily shampoos. During manufacturing and formulating, workers may potentially be exposed by the dermal and respiratory routes (OECD, 2007). 2.2. Consumer exposure Chemicals in this category are used in consumer cleaning and personal care products, which may be used as sold, or diluted prior to or during use. The main potential exposure includes dermal contact as well as eye contact during handling and use. The alkyl sulfates are mainly used in household cleaning products, in personal care products, and in additives for plastics and paints. Typically, alkyl sulfates are applied in consumer products at concentrations ranging from 3% to 5%. Maximum concentrations up to 20% in consumer household cleaning products and up to 14% in personal care products have been reported. Usually, alkyl sulfates are used in conjunction with other surfactants that attenuate the irritant properties sufficiently to avoid consumer problems, i.e. the mixed surfactant systems form micelles that typically lead to a reduction in irritation potential of the mixture, compared to the irritation potential of the individual ingredients (Dillarstone and Paye, 1993; Effendy and Maibach, 2006; Paye et al., 2006). Furthermore, where skin contact occurs, application conditions like use in rinse-off products only, high dilution during application, short contact time, use in solid form or tablets sealed by individual package ensure that the inherent irritation potential of alkyl sulfates is sufficiently controlled. This is demonstrated by the long history of safe use (more than 5 decades) of alkyl sulfates in household cleaners and personal care products (OECD, 2007).

3. Results Experimental details of the studies discussed below and the composition of test materials are described more fully in OECD (2007). Most of these studies were carried out to OECD guidelines or under similar protocols.

A. Wibbertmann et al. / Ecotoxicology and Environmental Safety 74 (2011) 1089–1106

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O

O-Na+

S

Dodecyl Sulfate, Sodium Salt

O O O S

Dodecyl Sulfonate, Sodium Salt

O-Na+

O O O-Na+

S Dodecyl Alpha Olefin Sulfonate, Sodium Salt

O O S OH

O-Na+

O

Fig. 1. Structure of category chemicals using the example of the C12 chain length representatives.

3.1. Toxicokinetics, metabolism, and distribution For the category, there are several studies available on individual components of the different mixtures of the ANS category, i.e., different chain lengths and counter ions (see Tables 2 and 3). The data for experimental animals as well as studies with human volunteers demonstrate that the alkyl sulfates, alkane sulfonates and a-olefin sulfonates are well absorbed after oral uptake, as up to 98% of the applied doses were excreted rapidly via urine (Denner et al., 1969; Burke et al., 1975, 1976; Merits, 1975; Taylor et al., 1978; Black and Howes, 1980; Inoue et al., 1982). In contrast, the penetration through intact skin with o1% of the applied doses is poor (Howes, 1975; Prottey and Ferguson, 1975; Minegishi et al., 1977; Black and Howes, 1980). After absorption, these chemicals are distributed mainly to the liver (Denner et al., 1969; Burke et al., 1975, 1976; Merits, 1975; Taylor et al., 1978; Inoue et al., 1982) and the alkyl sulfates, alkane sulfonates and most probably also a-olefin sulfonates are metabolized by cytochrome P450-dependent o-oxidation and subsequent ß-oxidation of the aliphatic fatty acids. End products of the oxidation are a C4 sulfate or sulfonate (even numbered chain lengths) and a C3 or C5 sulfate or sulfonate (odd numbered chain lengths). For the alkyl sulfates, sulfate is also formed as a metabolite (Denner et al., 1969; Ottery et al., 1970; Burke et al., 1975, 1976; Merits, 1975; Taylor et al., 1978; Greb and Wingen, 1980; Black and Howes, 1980; Inoue et al., 1982). Several reasons for a lack of concern regarding bioaccumulation exist including rapid excretion of metabolites via urine, limited dermal exposure (main route of consumer exposure) and the low concentration of substances in consumer products. 3.2. Acute toxicity 3.2.1. Oral The acute oral toxicity of alkyl sulfates, in general, is moderate to low (see Table 4). The LD50 values are in the range of 290– 580 mg/kg bw for C10, 1000–2000 mg/kg bw for C10–16, greater than 2000 mg/kg bw for C12–14, C12–15, C12–16, C12–18 and C18, and greater than 5000 mg/kg bw for C16–18. For the alkane sulfonates C8 and C15–18 (both sodium salts), LD50 values of 45000 and 1440 mg/ kg bw were obtained. For the C14–18-a-olefin sulfonates (sodium salts), the LD50 values were in a range of 578–2200 mg/kg bw.

In all tests, clinical signs of intoxication were non-specific (e.g. lethargy, decreased motor activity and respiratory rate, diarrhea) and, at necropsy, major findings were irritation of the gastrointestinal tract and anemia of inner organs. The counter ion did not show any significant influence on toxicity. 3.2.2. Dermal In rabbits, dermal LD50 values were 200 mg/kg bw for the C12 and 4500 mg/kg bw for the C12–13 and C10–16 alkyl sulfates. The treatment caused moderate to severe skin irritation and clinical signs reported included tremor, tonic–clonic convulsions, respiratory failure, body weight loss (C12 alkyl sulfate) and decreased body weights (C10–16 alkyl sulfates). For the a-olefin sulfonate C14–16 ¼/OHASO3 Na, there were no specific signs of intoxication in rats at the highest tested dose level of 740 mg/kg bw (see Table 5). 3.3. Skin irritation When tested in rabbits according to OECD TG 404, aqueous solutions of about 30% C8–14 and C8–16, 90% solution of C12–14, and 60% solution of C14–18/18 ¼alkyl sulfates were all corrosive. C12 and C12–14 at a concentration of 25% under occlusive conditions, and C12, C12–15, C13–15 and C15–16 alkyl sulfates at Z5–7% were moderate to strong irritants. C16–18 ASO4Na showed only slight irritation up to concentrations of 31.5%. The a-olefin sulfonate C14–16 ¼/OHASO3Na was irritating when tested at a concentration of 40% according to OECD TG 404. a-olefin sulfonate (C14–18 ¼/OHASO3Na) at 5% was only very slightly irritating. As the results were obtained by testing mixtures rather than discrete chain lengths and at such high concentrations resulting in severe irritating and/or corrosive effects, no clear conclusion concerning correlation between chain length and irritancy potential can be drawn. However, in comparative studies investigating skin effects such as transepidermal water loss (Wilhelm et al., 1993), epidermal electrical conductance (Dugard and Scheuplein, 1973), skin swelling (Choman, 1961; Schulz and Rose, 1957), extraction of amino acids and proteins (Prottey and Ferguson, 1975) and development of erythema in human volunteers (Kligman and Wooding, 1967; Wilhelm et al., 1993), a maximum of effects was consistently seen with C12 ASO4Na. A 20% concentration of C12 ASO4Na is routinely used as a positive internal control giving borderline irritant reactions in skin irritation studies performed on human volunteers. As C12 ASO4Na is assumed to be the most irritating alkyl

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Table 1 Members of the ANS category. CAS no.

Chemical name (Synonym)

Chemical shorthand

Molecular formula

Alkyl sulfates 139-96-8 142-31-4 142-87-0 151-21-3 1072-15-7 1120-01-0 1120-04-3 1191-50-0 2235-54-3 3026-63-9 4706-78-9 7065-13-6 7739-63-1 13393-71-0 39943-70-9 68081-96-9 68081-97-0 68081-98-1 68585-47-7 68611-55-2 68890-70-0 68955-19-1 68955-20-4 73296-89-6 85586-07-8 85665-45-8 85681-68-1 86014-79-1 90583-10-1 90583-12-3 90583-13-4 90583-16-7 90583-18-9 90583-19-0 90583-23-6 90583-24-7 90583-27-0 90583-31-6 91648-54-3 91783-22-1 91783-23-2 96690-75-4 117875-77-1 Not available Not available Not available

Sulfuric acid, mono-dodecyl ester, compd. with triethanolamine (1:1) Sulfuric acid, mono-octyl ester, sodium salt Sulfuric acid, monodecyl ester, sodium salt Sulfuric acid, mono-dodecyl ester, sodium salt n-Nonylsulfate, sodium salt Sulfuric acid, mono-hexadecyl ester, sodium salt Sulfuric acid, mono-octadecyl ester, sodium salt Sulfuric acid, mono-tetradecyl ester, sodium salt Sulfuric acid, mono-dodecyl ester, ammonium salt 1-Tridecanol, hydrogen sulfate, sodium salt Potassium dodecyl sulfate Potassium hexadecyl sulfate Potassium decyl sulfate Sulfuric acid, mono-pentadecyl ester, sodium salt Sulfuric acid, monodecyl ester, compd. with 2,2’,2’’-nitrilotris[ethanol] (1:1) Sulfuric acid, mono-C10–16-alkyl esters, ammonium salts Sulfuric acid, mono-C10–16-alkyl esters, magnesium salts Sulfuric acid, mono-C14–18-alkyl esters, sodium salts Sulfuric acid, mono-C10–16-alkyl esters, sodium salts Sulfuric acid, mono-C10–16-alkyl esters Sulfuric acid, mono-C12–15-alkyl esters, sodium salts Sulfuric acid, mono-C12–18-alkyl esters, sodium salts Sulfuric acid, mono-C16–18-alkyl esters, sodium salts Sulfuric acid, mono-C12–16-alkyl esters, sodium salts Sulfuric acid, mono-C12–14-alkyl esters, sodium salts Sulfuric acid, mono-C8–14-alkyl esters, compounds with triethanolamine Sulfuric acid, mono-(C14–18 and C16–18 –unsatd.alkyl) esters, sodium salts Sulfuric acid, mono-C13–15-alkyl esters, sodium salts Sulfuric acid, mono-C8–14-alkyl esters, ammonium salts Sulfuric acid, mono-C12–16-alkyl esters, ammonium salts Sulfuric acid, mono-C12–18-alkyl esters, ammonium salts Sulfuric acid, mono-C12–14-alkyl esters, compounds with ethanolamine Sulfuric acid, mono-C12–14-alkyl esters, compounds with triethanolamine Sulfuric acid, mono-C8–14-alkyl esters, lithium salts Sulfuric acid, mono-C12–14-alkyl esters, magnesium salts Sulfuric acid, mono-C12–18-alkyl esters, potassium salts Sulfuric acid, mono-C8–16-alkyl esters, sodium salts Sulfuric acid, mono-(C14–18 and C18–unsaturated)-alkyl esters, sodium salts Sulfuric acid, mono-C14–15-alkyl esters, sodium salts Sulfuric acid, mono-C12–13-alkyl esters, potassium salts Sulfuric acid, mono-C12–13-alkyl esters, sodium salts Sulfuric acid, mono-C12–14-alkyl esters, ammonium salts, compds. with triethanolamine Sulfuric acid, mono-C10–16-alkyl esters, compounds with triethanolamine Sulfuric acid, mono-C15–16-alkyl esters Sulfuric acid, mono-C12–18-alkyl esters, magnesium salts Potassium undecyl sulfate

C12 ASO4 TEA C8 ASO4 Na C10 ASO4 Na C12 ASO4 Na C9 ASO4 Na C16 ASO4 Na C18 ASO4 Na C14 ASO4 Na C12 ASO4 NH4 C13 ASO4 Na C12 ASO4 K C16 ASO4 K C10 ASO4 K C15 ASO4 Na C10 ASO4 TEA C10–16 ASO4 NH4 C10–16 ASO4 Mg C14–18 ASO4 Na C10–16 ASO4 Na C10–16 ASO4 C12–15 ASO4 Na C12–18 ASO4 Na C16–18 ASO4 Na C12–16 ASO4 Na C12–14 ASO4 Na C8–14 ASO4 TEA C14–18 and C16–18 ¼ ASO4 Na C13–15 ASO4 Na C8–14 ASO4 NH4 C12–16 ASO4 NH4 C12–18 ASO4 NH4 C12–14 ASO4 MEA C12–14 ASO4 TEA C8–14 ASO4 Li C12–14 ASO4 Mg C12–18 ASO4 K C8–16 ASO4 Na C14–18 and C18 ¼ ASO4 Na C14–15 ASO4 Na C12–13 ASO4 K C12–13 ASO4 Na C12–14 ASO4 TEA C10–16 ASO4 TEA C15–16 ASO4 C12–18 ASO4 Mg C11 ASO4 K

C18H41NO7S C8H17O4SNa C10H21O4SNa C12H25O4SNa C9H19O4SNa C16H33O4SNa C18H37O4SNa C14H29O4SNa C12H29NO4S C13H27O4SNa C12H25O3SK C16H33O4SK C10H21O4SK C15H31O4SNa C16H37NO7S Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs C11H23O4SK

C12 ASO3 Na C8 ASO3Na C10 ASO3 Na C18 ASO3 Na C14 ASO3 Na C15–18 ASO3 Na

C12H25O3SNa C8H17O3SNa C10H21O3SNa C18H37O3SNa C14H29O3SNa Mixture of homologs

C16 ¼ /OHASO3 Na C12 ¼ /OHASO3 Na C14–16 ¼/OHASO3 Na C12–14 ¼/OHASO3 Na C15–18 ¼/OHASO3 Na C16–18 ¼/OHASO3 Na C14 ¼ /OHASO3 Na C14–18 ¼/OHASO3 Na C14/16/18 ¼ /OHASO3 Na

Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs Mixture of homologs

Primary alkane 2386-53-0 5324-84-5 13419-61-9 13893-34-0 27175-91-3 68815-15-6

sulfonates (PAS) Sodium dodecane-1-sulfonate 1-Octanesulfonic acid, sodium salt Sodium decane-1-sulfonate Sodium octadecane-1-sulfonate Sodium tetradecane-1-sulfonate Sulfonic acids, C15–18-alkane, sodium salts

a-Olefin sulfonates 11067-19-9 Sodium hexadecene-1-sulfonate 30965-85-6 Dodecene-1-sulfonic acid, sodium salt 68439-57-6 Sulfonic acids, C14–16-alkane hydroxy and C14–16-alkene, sodium salts 85536-12-5 Sulfonic acids, C12–14-alkane hydroxy and C12–14-alkene, sodium salts 91082-14-3 Sulfonic acids, C15–18-alkane hydroxy and C15–18-alkene, sodium salts 91722-28-0 Sulfonic acids, C16–18-alkane hydroxy and C16–18-alkene, sodium salts 93686-14-7 Sulfonic acids, C14-alkane hydroxy and C14-alkene, sodium salts 863609-89-6 Sulfonic acids, C14–18-alkane hydroxy and C14–18-alkene, sodium salts Not available Sulfonic acids, C14/16/18-alkane hydroxy and C14/16/18-alkene, sodium salts (1:1:1) Bold: HPV chemical.

sulfate, in humans a concentration of about 20% is the threshold concentration causing irritating effects. In formulated consumer products, alkyl sulfates are usually used in conjunction with other surfactants, which results in the formation of micelles typically causing a reduction in the irritation potential of the mixture when

compared with the irritation potential of the individual ingredients. Although there are no data available for the alkane sulfonates, a possible skin irritation potential can be assumed based on the similar chemical structure for the alkyl sulfates or a-olefin sulfonates of comparable chain lengths (Table 6).

A. Wibbertmann et al. / Ecotoxicology and Environmental Safety 74 (2011) 1089–1106

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Table 2 Data availability for toxicokinetics, metabolism and distribution. Compound

Endpoints investigated

Reference

Chain length

Counter ion

Dermal absorption

Oral absorption

Distribution

Metabolism

Excretion

Alkyl sulfates C10 C11 C12 C12

K K K Na

   +

 +  

  + 

+ + + +

+ + + +

C16 C16 C18

K Na Na

  

 + +

  +

+ + +

+ + +

Alkane sulfonates Na C12

+

+

+

+

+

Prottey and Ferguson (1975); Taylor et al. (1978)

 +

 

+ 

+ 

+ 

Inoue et al. (1982) Minegishi et al. (1977)

Burke et al. (1975) Burke et al. (1976) Denner et al. (1969) Blank and Gould (1961), Howes (1975); Prottey and Ferguson (1975) Merits (1975) Merits (1975) Burke et al. (1975)

a-Olefin sulfonates C14 C14

Na Na

Table 3 Individual data availability for toxicokinetics, metabolism and distribution. Data availability (chain lengths, counter ions) and results for sub-category ASO4 Metabolism and excretion Excretion in urine Amounts excreted in urine (% of dose in 48 h) Amounts excreted in feces (% of dose in 48 h) Main metabolites

Distribution

C10, C11, C12, C16, C18 Na, K, TEA C12 (complete within 6 h) C10, 11, within 48 h) C10–18 74–98% (5 mg/kg, oral) C12: negligible C11,

18: o 10%

16, 18

(mainly

as metabolites

Even chain numbers: Butyric acid 4-sulfate odd chain number: Propionic acid-3 sulfate, pentanoic acid-5-sulfate Sulfate C10, C12, C18 K Whole body autoradiography after i.p. application Liver, kidney

3.3.1. Influence of the counter ion for the alkyl sulfates Ciuchta and Dodd (1978) compared possible skin irritating properties of the sodium, ammonium and triethanolamine salts of lauryl sulfate (C12 ASO4) in a Draize test and found only a slightly higher irritancy of the ammonium and sodium salts as compared to the triethanolamine salt (see Table 7), indicating that the nature of the counter ion does not play an important role in skin irritation of alkyl sulfates.

3.4. Eye irritation At concentrations of Z10%, C12-containing alkyl sulfates was severely irritating to the eyes of rabbits and caused irreversible corneal effects. With increasing alkyl chain length there is a decrease in the irritating potential, as shown with C16–18 ASO4Na only causing mild irritating effects at a concentration of 25%. In concentrated form, the C14–16-a-olefin sulfonates are severely irritating, but cause irreversible effects only if applied as undiluted powder. Lower concentrations ( o10%) cause mild to moderate and reversible effects (see Table 8). For the alkane sulfonates, there are no experimental data available. However, taking data from the a-olefin sulfonates taking into account, it can be assumed that these substances also will cause eye irritation.

ASO3

A¼ /OHSO3

C12, C16 Na C12, C16 (not complete within 6 h)

C14 C14 (not complete within 24 h)

C12: 87–96% (5 mg/kg oral) C16: 48–65% (5 mg/kg oral) C12:o 10% unabsorbed C16: 40% unabsorbed Even chain number: Buyric acid 4-sulfonate Odd chain number: not investigated No Sulfate C12, C16 Na Whole body autoradiography after i.p. application Liver, kidney

C14: 72% (100 mg/kg oral, 5 days) C14: 22% (mainly unabsorbed, 5 days) No data

C14 Na radioactivity in organs after oral application, gastrointestinal tract, liver, kidney

3.5. Sensitization In several valid tests performed according to OECD TG 406, alkyl sulfates and C14–18-a-olefin sulfonates caused no skin sensitizing effects in experimental animals (see Table 9). Although in two out of three LLNAs (Ikarashi et al., 1993; Basketter et al., 1994; Montelius et al., 1994) positive reactions (i.e. an increase in cell proliferation) were seen with C12 ASO4Na, these effects can be attributed to a non-antigen-specific proliferative stimulus induced by the irritating effect of the tested concentrations (4–25%) as discussed by Montelius et al. (1994). According to Basketter et al. (1994) and Basketter (2002), C12 ASO4Na causes Langerhans’ cell migration from the epidermis to draining lymph nodes with a consequent transient increase in cell proliferation. Subsequent cell typing studies have shown the lymph node cell changes to be characteristic of irritancy and not of allergy (Basketter, 2002). For the alkane sulfonates there are no reliable data available. However, taking the data from the alkyl sulfates as well as a-olefin sulfonates into account, no sensitization is expected. In humans, several Repeat Insult Patch Tests have been conducted with C8 ASO4Na (Procter and Gamble, 1993a, 1993b, 1994a, 1994b, 1994c), C16–18 ASO4Na (Procter and Gamble, 1991) and C12 ASO4NH4 (Procter and Gamble, 1996). In all of these

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Table 4 Acute oral toxicity. CAS No.

Chemical shorthand

Species

LD50 (mg/kg bw for active ingredient (a.i.))

Reference

Alkyl sulfates 85665-45-8 90583-10-1 142-87-0 68081-96-9 68585-47-7 68611-55-2 139-96-8 151-21-3 2235-54-3 91783-22-1 85586-07-8 85586-07-8 90583-18-9 90583-23-6 90583-16-7 96690-75-4 68890-70-0 68890-70-0 73296-89-6 68955-19-1 86014-79-1 68081-98-1 90583-31-6 99999-99-9a 68955-20-4 85681-68-1

C8–14 ASO4 TEA C8–14 ASO4 NH4 C10 ASO4 Na C10–16 ASO4 NH4 C10–16 ASO4 Na C10–16 ASO4 C12 ASO4 TEA C12 ASO4 Na C12 ASO4 NH4 C12–13 ASO4 K C12–14 ASO4 Na C12–14 ASO4 Na C12–14 ASO4 TEA C12–14 ASO4 Mg C12–14 ASO4 MEA C12–14 ASO4 NH4/TEA C12–15 ASO4 Na C12–15 ASO4 Na C12–16 ASO4 Na C12–18 ASO4 Na C13–15 ASO4 Na C14–18 ASO4 Na C14–18 and C18 ¼ASO4 Na C15–16 ASO4 C16–18 ASO4Na C14–18 and 16–18 ¼ASO4Na

Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat Rat Mouse Rat Rat Rat Mouse Mouse Rat Mouse Rat Mouse Rat Rat Mouse Rat Rat

4 3652 4 1650 Z 290 1827 1830 1780 4 2000 1200 4 135 1700 4 200 2600 4 200 2710 1686 11,200 Z 2800 3800 2600 4 2000 2900 Z 2752 4 1140 6800 4 1100 5500

Henkel and Cie GmbH (1970), Henkel KGaA (1999a) Henkel and Cie GmbH (1972b) Henkel KGaA (1985a) Procter and Gamble (1975a) Procter and Gamble (1974) Procter and Gamble (1974) Kao Co. (1995) Henkel KGaA (1983) Stepan Co. (1980) Procter and Gamble (1978b) Brown and Muir (1970) Unilever Research (1977a) Brown and Muir (1970) Procter and Gamble (1975b) Henkel and Cie GmbH (1971) Henkel and Cie GmbH (1972a) Unilever Research (1975b, 1975c, 1975d) Unilever Research (1975a) Henkel and Cie GmbH (1976) Procter and Gamble (1974); Henkel KGaA (1989a) Unilever Research (1975j) Procter and Gamble (1972) Henkel KGaA (1992b) Unilever Research (1976b) Henkel KGaA (1987g; 1995) Henkel KGaA (1982)

Alkane sulfonates 5324-84-5 68815-15-6

C8 ASO3 Na C15–18 ASO3 Na

Rat Mouse

4 5000 1440

Stepan Co. (1985) Henkel KGaA (1971)

a-Olefin sulfonates 93686-14-7 68439-57-6 91082-14-3

C14 ¼ /OHASO3 Na C14–16 ¼ /OHASO3 Na C15–18 ¼ /OHASO3 Na

Mouse Rat Mouse

2430 Z 578 1368

Lion Co. (1969) Hoechst AG (1984b); Molins-kao (1986b) Henkel KGaA (1971)

Bold¼ HPV chemical; a

Fictitious CAS No. for compounds with specific chain length but without a defined CAS-number.

Table 5 Acute dermal toxicity. CAS No.

Chemical shorthand

Species

LD50 (mg/kg bw for active ingredient (a.i.))

Reference

Alkyl sulfates 68081-96-9 68081-97-0 151-21-3 91783-22-1

C10–16 ASO4 NH4 C10–16 ASO4 Mg C12 ASO4 Na C12–13 ASO4 K

Rabbit Rabbit Rabbit Rabbit

4 500 4 500 ca. 200 4 500

Procter and Gamble (1975c) Procter and Gamble (1975d) Carson and Oser (1964) Procter and Gamble (1978a)

a-Olefin sulfonates 68439-57-6

C14–16 ¼ /OHASO3 Na

Rat

4 740

Molins-kao (1986a)

Bold¼ HPV chemical.

studies there was no indication for sensitizing effects at tested concentrations of r4%. In human volunteers the a-olefin sulfonate C14–16 ¼/OHASO3 was not sensitizing in a Draize Test performed with 8 commercial samples (8% in water). Due to considerable irritation, the final challenge was made at 4% (Ter Haar, 1983).

3.6. Repeated dose toxicity 3.6.1. Oral For the alkyl sulfates, reliable studies with oral dosing ranging from 3 to 104 weeks have been performed with C12 ASO4 Na, C12–14 ASO4 TEA, C12–15 ASO4 Na, C16–18 ASO4 Na and C13–15 ASO4 Na (see Tables 10 and 11). Typically, the liver was the only target organ for

systemic toxicity and as adverse effects on this organ increased liver weights, enlargement of liver cells, and elevated levels of liver enzymes were observed. After dosing of rats via diet over 13 weeks, the LOAEL for liver toxicity (parenchymal hypertrophy, increased relative liver weights) for C16–18 ASO4 Na was 230 mg/kg bw/day, while the lowest NOAEL derived from a 13 week gavage study with C16–18 ASO4 Na was 55 mg/kg bw/day. In most studies, a reduced body weight gain was observed, which was accompanied at higher concentrations by reduced food intake. Abdominal fat was reduced considerably at these dose levels. Gastrointestinal irritation was the primary effect after application via gavage but not after incorporation of test substances into the diet, which is consistent with the primary irritant properties of the alkyl sulfates and the bolus effect after application by gavage.

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Table 6 Results of studies on skin irritation. CAS No. Active ingredient

Chemical shorthand

Test conditions

Results

Reference

Alkyl sulfates 90583-10-1 32.9% 90583-27-0 29–31% 151-21-3 25% 151-21-3 5%

C8–14 ASO4NH4 C8–16 ASO4Na C12 ASO4Na C12 ASO4Na

Corrosive Corrosive Severely irritating (PII: 7.73) Moderately to strongly irritating

Henkel KGaA (1991g) Henkel KGaA (1991d) Henkel KGaA (1987c) Unilever Research (1982)

139-96-8 40% 139-96-8 no data 85586-07-8, 90% 90583-18-9, 25% 90583-23-6, 30.5% 68890-70-0, 5%

C12 ASO4TEA C12 ASO4TEA C12–14 ASO4Na C12–14 ASO4TEA C12–14 ASO4Mg C12–15 ASO4Na

Moderately irritating (PII: 4.92) Moderately irritating (PII: 4.67) Corrosive Severely irritating (PII: 5.8) Severely irritating (PII: 7.9) strongly to severely irritating

Procter and Gamble (1976a) Procter and Gamble (1976b) Henkel KGaA (1994) Henkel KGaA (1987c, 1999b) Henkel KGaA (1987e) Unilever Research (1982)

90583-12-3, 30% 86014-79-1, 1–30.5%

C12–16 ASO4NH4 C13–15 ASO4Na

OECD TG 404 (4h, semi-occlusive) OECD TG 404 (4h, semi-occlusive) 4 h, occlusive similar to OECD TG 404 (4 h, semi-occlusive) Open Patch test Open Patch test OECD TG 404 (4h, semi-occlusive) 4h, occlusive 4h, occlusive similar to OECD TG 404 (4 h, semi-occlusive) 4h, occlusive similar to OECD TG 404 (4 h, semi-occlusive)

Henkel KGaA (1987a) Unilever Research (1983a)

90583-31-6, 57–60% 99999-99-9a, 5%

C14–18 and C18 ¼ ASO4Na C15–16 ASO4

Severely irritating (PII: 7.4) 1%: Slightly irritating; 3–5%: slightly – moderately irritating; Z 7%: strongly irritating Corrosive Moderately irritating

68955-20-4, 25% 68955-20-4, 5–31.5%

C16–18 ASO4Na C16–18 ASO4Na

Moderately irritating (PII: 2.33) 5%: Slight effects;Z 10%: slight to moderate effects

Henkel KGaA (1987c) Unilever Research (1983b)

Irritating Very slightly irritating 5%: Not irritating; 10%: very slightly irritating

Hoechst AG (1988b) Lion Co. (1978a; 1978b) Lion Co. (1989)

OECD TG 404 (4h, semi-occlusive) similar to OECD TG 404 (4 h, semi-occlusive) 4h, occlusive similar to OECD TG 404 (4 h, semi-occlusive)

Henkel KGaA (1991a) Unilever Research (1982)

a-Olefin sulfonates 68439-57-6, ca. 40% 863609-89-6, 5–15% 863609-89-6, 5–10%

C14–16 ¼/OHASO3Na C14–18 ¼/OHASO3Na C14–18 ¼/OHASO3Na

OECD TG 404 (4h, semi-occlusive) Draize test (open; guinea pigs) Draize test (open; guinea pigs)

PII: primary irritation index; Bold¼ HPV chemical; a

Fictitious CAS No for compounds with specific chain length but without a defined CAS-number.

range as for alkyl sulfates and a-olefin sulfonates and with the liver as a potential target organ.

Table 7 Counter ion effects on primary skin irritation for C12 ASO4. Concentration (a.i.%)

2 10 20

PII in rabbits (24 h occlusive patch) Counter ion Na

NH4

TEA

5–5.5 6 6

5.2 5.8 6

3.5 5 5.2

PII: primary irritation index.

The a-olefin sulfonates have been tested in a comprehensive two-year feeding study with CFY rats and oral dosing via diet with 0–5000 ppm of C14–16 ¼/OHASO3 Na (up to 259 mg/kg bw/day). Apart from decreased body weights in high-dosed animals between weeks 14 and 26, the treatment even at the highest dose caused no adverse effect on blood chemistry and urinalysis and the histopathological findings were all comparable to control values (see Table 11; Lion Co., 1975; Hunter and Benson, 1976), so that a NOAEL of 96–132 mg/kg bw/day can be derived. In another study with rats dosed via gavage with 0–500 mg/kg bw/day of C14 ¼/OHASO3 Na for 6 months, the highest dose level caused an increase in mortality, a decrease in food consumption, and changes in GOT, GPT and ALP values and adrenal weights. At 250 mg/kg bw/day there was a decrease in body weights, while no adverse effects were reported at a dose level of 100 mg/kg bw/ day (see Table 11; Kitasato University, 1968). No repeated oral dose toxicity studies with alkane sulfonates have been found. However, based on the similarity of metabolic pathways between alkane sulfonates, alkyl sulfates and a-olefin sulfonates, the repeated dose toxicity of alkane sulfonates is expected to be similar with NOAEL and LOAEL values in the same

3.6.2. Dermal Data concerning repeated dermal application for the category members are limited, i.e. there are no data available for the alkane sulfonates and a-olefin sulfonates, and with regard to the alkyl sulfates only C12–15 ASO4 Na has been tested in two studies with mice (see Table 12). However, studies performed by Prottey and Ferguson (1975) and Minegishi et al. (1977) are showing that only very small amounts will be absorbed after dermal application and these data are indicating a low dermal toxicity after repeated application (see Table 13). In the first (range finding) study groups of 3 mice per sex and dose were treated with 0.2 ml of a 0–18% aqueous solution twice weekly (corresponding to ca. 0–720 mg/kg bw/day) over 3 weeks. The highest concentration caused epidermal necrosis and ulceration of such severity, that the animals died or were sacrificed for animal welfare reasons. There were no deaths at 5–10% and the general health of these animals remained good. As there were no significant systemic effects in animals treated with a 10% solution, from this study a NOAEL of 400 mg/kg bw/day can be derived (Unilever Research, 1976c). In the corresponding 13 week study, groups of 10 mice per sex and dose were treated with 0.2 ml of a 0–15% aqueous solution twice weekly (corresponding to ca. 0–600 mg/kg bw/day). At 12.5% one animal died due to anorexia and dehydration, while the health of survivors remained good throughout the trial. Systemic effects such as changes in organ weights (liver, kidney and heart weights) were seen at Z12.5%. From this study also a NOAEL of 400 mg/kg bw/day can be derived, as there were no significant systemic effects in mice treated with a 10% solution (Unilever Research, 1977c).

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A. Wibbertmann et al. / Ecotoxicology and Environmental Safety 74 (2011) 1089–1106

Table 8 Results of studies on eye irritation. CAS no. Active ingredient

Chemical shorthand

Test conditions

Results

Reference

Alkyl sulfates 90583-10-1, 0.5–20%

C8–14 ASO4NH4

Draize test

Henkel KGaA (1977b)

151-21-3, 25 2235-54-3, 2–20%

C12 ASO4Na C12 ASO4NH4

OECD TG 405 Draize test

139-96-8, 1.25–20%

C12 ASO4TEA

Draize test

139-96-8, 2–20%

C12 ASO4TEA

Draize test

85586-07-8, 5–20%

C12–14 ASO4Na

Draize test

85586-07-8, 5% 90583-16-7, 0.5–20%

C12–14 ASO4Na C12–14 ASO4MEA

Draize test Draize test

90583-23-6, 90583-18-9, 68890-70-0, 73296-89-6,

C12–14 C12–14 C12–15 C12–16

ASO4Mg ASO4TEA ASO4Na ASO4Na

OECD TG 405 OECD TG 405 Draize test Draize test

90583-12-3, 10% 90583-12-3, 30% 68955-19-1, 0.5–20%

C12–16 ASO4NH4 C12–16 ASO4NH4 C12–18 ASO4Na

OECD TG 405 OECD TG 405 Draize test

68955-19-1, 5% 90583-24-7, 5% 86014-79-1, 5% 99999-99-9a, 5% 68955-20-4, 25% 68955-20-4, 5% 68955-20-4, 5%

C12–18 C12–18 C13–15 C15–16 C16–18 C16–18 C16–18

Draize test Draize test Draize test Draize test OECD TG 405 Draize test Draize test

o5%: Not irritating Z5%: Moderately irritating Irreversible effects 2%: Not irritating 10–20%: Irritating 1.25%: Not irritating Z2.5%: Irritation especially when not rinsed (nearly reversible within 7 d) 2%: Not irritating 10–20%: Irritating Z 5%: Highly irritating (not reversible at 20%) Moderately irritating r10%: Not irritating 20%: Slightly irritating Irreversible effects Irreversible effects Moderately irritating r1%: not irritating Z5%: moderately irritating (not reversible at Z 10%) Irritating Irreversible effects r1%: Not irritating Z5%: Moderately irritating (not reversible at Z 10%) Moderately irritating Moderately irritating Moderately irritating Moderately irritating Moderately irritating Slightly to moderately irritating Moderately irritating r0.5%: Not irritating Z1%: Slightly irritating (fully reversible within 96 h) Irritating (fully reversible within 7 d) Severely irritating and irreversible effects (cornea, conjunctivae) in 2/3 animals at d 21 Severely irritating (fully reversible)

Iimori et al. (1972)

10% 25% 5% 0.5–20%

a-Olefin sulfonates 99999-99-9a, 0.01–5%

ASO4Na ASO4K ASO4Na ASO4 ASO4Na ASO4Na ASO4Na

C10,C12,C14,C16,C18 ¼ / OHASO3Na

Draize test

68439-57-6, 40% 68439-57-6, 90%

C14–16 ¼/OHASO3Na C14–16 ¼/OHASO3Na

OECD TG 405 OECD TG 405

68439-57-6, 20–40%

C14–16 ¼/OHASO3Na

Draize test

Henkel KGaA (1987i) Ciuchta and Dodd (1978) Serrano et al. (1977)

Ciuchta and Dodd (1978) Henkel KGaA (1979) Unilever Research (1976k) Henkel KGaA (1977b) Henkel KGaA (1987l) Henkel KGaA (1987i) Unilever Research (1975g) Henkel KGaA (1977b)

Henkel KGaA (1987l) Henkel KGaA (1988c) Henkel KGaA (1977b); Kaestner and Frosch (1981) Henkel KGaA (1985b, 1985c) Henkel KGaA (1985b, 1985c) Unilever Research (1975h) Unilever Research (1976k) Henkel KGaA (1987i) Unilever Research (1975i) Unilever Research (1976j)

Hoechst AG (1988c) Hoechst AG (1984a)

Ter Haar (1983)

Bold¼ HPV chemical; a

Fictitious CAS No. for compounds with specific chain length but without a defined CAS-number.

3.7. Mutagenicity

3.8. Carcinogenity

Alkyl sulfates with different chain lengths and counter ions were tested in variety of in vitro and in vivo test systems (Bacterial Reverse Mutation Test, Mammalian Cell Gene Mutation Test, Mammalian Chromosome Aberration Test, Rodent Dominant Lethal Test, Mammalian Erythrocyte Micronucleus Test, and Mammalian Bone Marrow Chromosome Aberration Test) performed according to current standards and there was no indication for a genotoxic potential (see Tables 14 and 15). Also, the results of several in vitro studies (Bacterial Reverse Mutation Test and Mammalian Chromosome Aberration Test) with the a-olefin sulfonates were negative. For the alkane sulfonates, there are no genotoxicity studies available. However, based on the overall negative results in the genotoxicity assays with alkyl sulfates and a-olefin sulfonates, the absence of structural elements indicating mutagenicity, and the overall database on different types of sulfonates which all tested negative in mutagenicity assays, alkane sulfonates are not expected to have genotoxic potential.

3.8.1. Oral Two 2-year oral feeding studies using alkyl sulfate C12–15 ASO4Na with test materials of a slightly differing chain length distribution have been performed, both using 45 Wistar rats/sex/ group dosed orally with 0–1.5% via diet (ca. 0–1125 mg a.i./ kg bw). Both studies had survival rates of about 70% and there was no indication that the substances caused an increased tumor incidence or a change in the spectrum of the spontaneous tumor types. High-dose rats showed a decrease in food and water intake and decreased growth rates and in these groups the total number of tumors and total number of rats with tumors was decreased, which was attributed due to a decreased caloric intake. In addition, in these rats increased absolute and relative liver weights, hypertrophy of the hepatic parenchyma, and a decrease in the incidence and severity of chronic nephropathy and nephrocalcinosis were noted (Unilever Research, 1995a, 1995b).

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Table 9 Results of studies on skin sensitization. CAS no.

Chemical shorthand

Species

Protocol

Results

Reference

Alkyl sulfates 142-31-4

C8 ASO4Na

Mouse

LLNA

Not sensitizing

151-21-3 151-21-3 151-21-3 85586-07-8

C12 ASO4Na C12 ASO4Na C12 ASO4Na C12–14 ASO4Na

Mouse Mouse Mouse Guinea pig

LLNA LLNA LLNA GPMT

Positive Positive Not sensitizing Not sensitizing

90583-18-9 90583-16-7 90583-23-6

C12–14 ASO4TEA C12–14 ASO4MEA C12–14 ASO4Mg

Guinea pig Guinea pig Guinea pig

Not sensitizing Not sensitizing Not sensitizing

68890-70-0

C12–15 ASO4Na

Guinea pig

GPMT OECD TG 406 (Buehler test) FCA test according to Directive 79/831/EEC, Annex V, Part B GPMT

Procter and Gamble (1992) Basketter et al. (1994) Montelius et al. (1994) Ikarashi et al. (1993) Unilever Research (1977f) KGaA (1977a, 1999c) Henkel KGaA (1993) Henkel KGaA (1988b)

90583-12-3

C12–16 ASO4NH4

Guinea pig

Not sensitizing

68955-19-1

C12–18 ASO4Na

Guinea pig

GPMT according to Directive 79/831/EWG, Annex V, Part B OECD TG 406 (Buehler test)

68955-20-4

C16–18 ASO4Na

Guinea pig

GPMT according to Directive 79/831/EWG, Annex V, Part B

Not sensitizing

Guinea pig Guinea pig Guinea pig

GPMT according to OECD TG 406 GPMT according to OECD TG 406 GPMT

Not sensitizing Not sensitizing Not sensitizing

Not sensitizing

Not sensitizing

Unilever Research (1975f) Henkel KGaA (1988a) Henkel KGaA (1996a, 1996b) Henkel KGaA (1986a, 1995)

a-Olefin sulfonates 68439-57-6 93686-14-7 99999-99-9a

C14–16 ¼ /OHASO3 Na C14 ¼/OHASO3Na Mixture (1:1:1) of Sulfonic acids, C14-alkane hydroxyl and C14-alkene, magnesium salts (purity: 93.4%) Sulfonic acids, C16-alkane hydroxyl and C16-alkene, magnesium salts (purity: 97.6%) Sulfonic acids, C18-alkane hydroxyl and C18-alkene, magnesium salts (purity: 92.2%)

Ter Haar (1983) Lion Co. (2004b) Lion Co. (1978c)

Bold¼ HPV chemical; a

Fictitious CAS No for compounds with specific chain length but without a defined CAS-number.

Table 10 Summary of NOAEL and LOAEL values for the alkyl sulfates after repeated oral dosing via gavage or diet. CAS no. Chemical Shorthand

Duration (weeks)

Route

NOAEL (mg a.i./kg bw/day)

LOAEL (mg a.i./kg bw/day)

Reference

151-21-3, C12 ASO4 Na 151-21-3, C12 ASO4 Na 90583-18-9, C12–14 ASO4 68890-70-0, C12–15 ASO4 68890-70-0, C12–15 ASO4 68890-70-0, C12–15 ASO4 86014-79-1, C13–15 ASO4 86014-79-1, C13–15 ASO4 68955-20-4, C16–18 ASO4 68955-20-4, C16–18 ASO4 68955-20-4, C16–18 ASO4

4 13 4 3 13 104 3 13 13 13 3

Gavage Diet Gavage Diet Diet Diet Diet Diet Diet Gavage Diet

90 86 102 252 122 113 199 134 123 55 202

270–540 430 306 503 245 1125 384 253 230 165 417

Henkel KGaA (1987h) Walker et al. (1967) Henkel KGaA (1988e) Unilever Research (1975e) Unilever Research (1976d) Unilever Research (1995a, 1995b) Unilever Research (1976f) Unilever Research (1977e) Unilever Research (1977d) Henkel KGaA (1987f, 1995) Unilever Research (1976e)

TEA Na Na Na Na Na Na Na Na

The a-olefin sulfonate C14–16 ¼ /OHASO3 Na was tested in a 2-year study with Sprague–Dawley derived CFY rats (50 animals/sex/group), where the animals were dosed with 0–5000 ppm via diet (corresponding to up to 259 mg/kg bw/day). The survival rate was in a range of 38–54% and although there was an increase of pancreatic islet cell tumors and adrenal tumors in male rats and thyroid tumors in female rats, these increases were not attributed to the treatment, as there was no dose response (increases were noted in low- and mid-dosed animals, while the incidences in high-dosed rats were comparable with controls). In addition, the incidences of islet cell tumors observed in this study have been recorded among male control CFY rats used in other studies carried out in the same laboratory (Lion Co., 1975; Hunter and Benson, 1976).

For the alkane sulfonates, data concerning carcinogenicity are lacking. However, based on the similar toxicokinetic properties and a comparable metabolism of the alkyl sulfates and alkane sulfonates, carcinogenic effects are not expected. This is supported by a category approach for the sulfonates, where no such effects have been observed (Greim et al., 1994). 3.8.2. Dermal The a-olefin sulfonates were also tested with dermal application in mice and rats. In the first study, groups of mice were treated 3 times weekly with 0.02 ml of C14–16- or C14–18-a-olefin sulfonate at concentrations of 0–25% over 92 weeks and the test material was applied to approximately 1 cm2 of exposed skin.

1098

Table 11 Studies on repeated dose toxicity with oral exposure. Test substance

Species/Strain

Duration

Dosage (mg a.i./ kg bw/day)

NOAEL/LOAEL (mg a.i./kg bw/ day)

Target organs/Main effects

Liver

Kidney

Other

Relative weight m

Relative weight m

Feed intake and weight gain k, water intake m, hematocrit and MCV k, number of leukocytes m, relative weights of adrenals, brain, and gonads m, relative thymus weight k, ulcerations and bleedings in the stomach

Rat, Sprague– Dawley

4w

0–300/600 mg/ kg bw/day

C12 ASO4 Na, CAS 151-21-3

Rat, Carworth Farm ’E’

13 w

Absolute weight m

C12–14 ASO4 TEA, CAS 90583-18-9

Rat, CD

4w

0–5000 ppm in diet ca. 86/ca. 430 (ca. 0–430 mg/ kg bw/day) 0–750 mg/kg bw/day 102/306

C12–15 ASO4 Na, CAS 68890-70-0

Rat, Wistar

3w

0–1.5% in diet (ca. 0– 252/503 2008 mg/kg bw/day)

Parenchymal hypertrophy m, relative weight m

C12–15 ASO4 Na, CAS 68890-70-0

Rat, Wistar

13 w

0–2.25% in diet (ca. 0–2218 mg/kg bw/ day)

Hypertrophy m, weight m, cytoplasmic vacuolation k, cytoplasmic neutral fat / haemosiderin content k

C12–15 ASO4 Na, CAS 68890-70-0

Rat, Wistar

104 w

0–1.5% in diet (ca. 0– ca. 113/ca. 1125 1125 mg/kg bw/day)

C12–15 ASO4 Na, CAS 68890-70-0

Rat, Wistar

104 w

0–1.5% in diet (ca. 0– ca. 113/ ca. 1125 Absolute / relative weight m, 1125 mg/kg bw/day) parenchymal hypertrophy m, pigmented lipid granulomata m, focal necrosis m

C13–15 ASO4 Na, CAS 86014-79-1

Rat, Wistar

3w

0–1.5% in diet (ca. 0– 199/384 1645 mg/kg bw/day)

C13–15 ASO4 Na, CAS 86014-79-1

Rat, Wistar

13 w

0–2.25% in diet (ca. 0–2268 mg/kg bw/ day)

C16–18 ASO4 Na, CAS 68955-20-4

Rat, Wistar

3w

0–1.5% in diet (ca. 0– 202 / 417 1685 mg/kg bw/day)

C16–18 ASO4 Na, CAS 68955-20-4

Rat, Wistar

13 w

0–2.25% in diet (ca. 0–2244 mg/kg bw/ day)

122/245

134 / 253

123/230

Absolute / relative weight m, parenchymal hypertrophy m, pigmented lipid granulomata m, focal necrosis m, extramedullary erythopoiesis k

Henkel KGaA (1987h)

Walker et al. (1967) Hemoglobin m, leukocytes m, forestomach: inflammation, ulceration, acanthosis and papillomatous hyperplasia (reversible, data from satellite group) Absolute weight k Food/water intake k, body weight gain k, terminal body weight k, relative brain weight m, adrenal weight k, relative testes weight m Relative weight m, absolute Food/water intake k, body weight gain k, absolute weight k, incidence/ spleen weight m, relative testes weight m, virtually severity of no abdominal fat / changes in color and nephrocalcinosis k consistency of intestinal contents, lymphatic dilation of small intestine Severity/incidence of Food/water intake and growth rate k, severity / chronic nephropathy, incidence of arterial medial hypertrophy and pelvic nephrocalcinosis and patchy myocardial fibrosis k, haemosiderin pelvic epithetlial deposition in spleen m, myelopoiesis k; stem cell hyperplasia k hyperplasia k, relative brain weights m, relative testes weight m Relative weight k, severity Food/water intake and growth rate k, relative / incidence of chronic spleen weight k, erythropoiesis, haemosiderin nephropathy and pelvic deposition, myelopoiesis and stem cell hyperplasia nephrocalcinosis k k, red pulp haemosiderin m, relative heart weight k, severity / incidence of arterial medial hypertrophy k, relative adrenal weight k, relative testes weight m Relative weight m Food/water intake, body weight gain and terminal body weight k, relative brain weight m, absolute spleen weight k

Parenchymal hypertrophy m, cytoplasmic vacuolization / cytoplasmic neutral fat content k, relative weight m absolute / relative weight m, Absolute weight k, relative Feed/water intake, weight gain and terminal parenchymal hypertrophy m weight m, nephrocalcinosis weight k, absolute spleen weight m, virtually no k abdominal fat, relative brain weight m, relative testes weight m, lymphatic dilation of the intestine m parenchymal hypertrophy m, Absolute weight k, Feed/water intake, weight gain and terminal relative weight m, neutral fat intensity of renal lesions k weight k, adrenal weight k, body fat depots k, content of parenchymal cells m absolute heart weight k, relative brain weight m, absolute spleen weight k, relative testes weights m, haemopoietic activity k, no ovarian activity or endometrial stimulation and only minimal endometrial hyperplasia Weight mk, parenchymal Weight mk, incidence / Feed/water intake, weight gain and terminal hypertrophy m, glycogenic severity of weight k, brain weight mk, heart weight mk, vacuolation, cytoplasmic nephrocalcinosis k relative testes weight m, absolute spleen

Henkel KGaA (1988e)

Unilever Research (1975e) Unilever Research (1976d)

Unilever Research (1995a)

Unilever Research (1995b)

Unilever Research (1976f) Unilever Research (1977e)

Unilever Research (1976e)

Unilever Research (1977d)

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Alkyl sulfates C12 ASO4 Na, CAS 151-21-3

ca. 90/ca. 270– 540

Reference

Kitasato University (1968) Mortality m, feed intake and body weight gain k, adrenal weights m, slight hemorrhages in spleen

3.9. Reproductive toxicity 3.9.1. Fertility For alkyl sulfates and alkane sulfonates, there are no studies available that have been performed according to standard protocols. In one older study (Hemsworth, 1981), groups of 10 male Swiss albino mice were dosed orally with either 1% of C12 ASO4 Na for 2 weeks or with 0.1% of C12 ASO4 Na for 6 weeks and 1–3 weeks after dosing the animals of each group were mated. The treatment caused no adverse effects on epididymal spermatozoa, and from this study a NOAEL for male fertility of 1000 mg active ingredient/kg bw/day can be derived. The results of several repeated oral dose 13-week studies with C12–15 ASO4 Na, C16–18 ASO4 Na, and C13–15 ASO4 Na gave no indication for adverse effects on reproductive organs at the histopathological examinations (see also Section 3.6.1; Unilever Research, 1976d, 1977d, 1977e). Although at very high doses ( Z1000 mg/kg bw/day) increases in relative (but not absolute) testes weights were noted, this effect is not considered as adverse but can be attributed to a decrease in body fat and body weight. Therefore, adverse effects on fertility caused by the alkyl sulfates and also alkane sulfonates are not to be expected. For a-olefin sulfonates, a reliable two generation reproductive toxicity study comparable to OECD TG 416 with male and female CD rats was performed with a mixture of C14:C16:C18 blend (1:1:1 ratio) of a-olefin sulfonate, Mg salt (Lion Co., 1980). Two batches with an active ingredient content of ca. 95% were used and the animals were continuously dosed with 0–5000 ppm (up to about 1040 mg a.i./kg bw/day) in the diet (see Table 16). Even at the highest dose tested there were no adverse effects concerning general health, food and water intake, food utilization, weight gain, reproductive performance and fertility. Also, at terminal necropsy of adults and offspring there were no treatment-related abnormalities and the histopathological examination of tissues from the F2 generation gave no adverse treatmentrelated effects.

Slight hemorrhages

Lion Co. (1975); Hunter and Benson (1976) Slight body weight depression between weeks 14 and 26 of treatment, minor depression of food intake during the first year of treatment

Feed/water intake, weight gain and terminal Henkel KGaA weight k, changes in several hematological and (1987f; 1995) clinical chemistry parameters, relative brain weight m, absolute heart weight k, absolute / relative thymus weight k, absolute / relative spleen weight m, relative adrenal weight m, forestomach: acanthosis, hyperkeratosis, inflammation and proliferative changes, satellite group: no significant effects on liver, thymus or spleen and partial regeneration of the forestomach

0, 100, 250 or 500 mg/kg bw/day 26 w

Bold¼ HPV chemical.

250

0, 1000, 2500 or 96-132 / 1955000 ppm in diet (ca. 259 0–259 mg/kg bw/ day) 104 w

a-Olefin sulfonates C14–16 ¼/OHASO3 Na, Rat, Spraguemixture of Dawley alkenyl sulfonate and hydroxyalkane sulfonate, (60.4:39.6% w/w), CAS 68439-57-6 rat, Wistar C14 ¼ /OHASO3 Na, CAS 93686-14-7

55/165 0, 100, 300 or 900 mg/kg bw 13 w Rat, SpragueDawley C16–18 ASO4 Na, CAS 68955-20-4

1099

At the final necropsy performed at a mean survival of 30% per group (at ca. 19 months), the histopathological examination gave no indication for carcinogenic effects (International Alpha Olefin Sulfonate Group, 1980). In another study, Long-Evans rats (50 animals/sex/group) were treated twice weekly with 1 ml C14–16 ¼/OHASO3 Na/kg bw at a concentration of 10% in deionized water (ca. 100 mg a.i./kg bw). Also in this study, there was no indication for carcinogenic effects and apart from decreased relative kidney weighs in dosed males, no adverse effects concerning mortality, mean body weights, food consumption, hematology, urinalysis, and post-mortem observations were found (SDA, 1979).

basophilia, neutral fat content and haemosiderin content of parenchymal and Kupffer cells k Weight m

Absolute weight k

weightkabsolute pituitary weight k, absolute adrenal weight k, loss of abdominal fat depots, lymphatic dilation of the intestine m

A. Wibbertmann et al. / Ecotoxicology and Environmental Safety 74 (2011) 1089–1106

3.9.2. Developmental toxicity The developmental toxicity of various alkyl sulfates (C12 ASO4 Na, C12–14 ASO4 Na, C12–15 ASO4, C13–15 ASO4 Na, C15–16 AS Na, C16–18 ASO4 Na) was tested on rats, rabbits and mice. Principally, effects on litter parameters were restricted to doses causing significant maternal toxicity such as anorexia, weight loss, and death (doses between 300 and 500 mg active ingredient/kg bw for rats and 300 mg active ingredient/kg bw/day for mice and rabbits) and principal effects such as higher fetal loss and increased incidences of total litter losses. Apart from a higher incidence of delayed ossification or skeletal variation seen in mice at Z500 mg active ingredient/kg bw/day, which is indicative for a delayed development, the incidences of malformations and visceral and skeletal anomalies were unaffected. The lowest reliable

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Table 12 Studies on repeated dose toxicity of alkyl sulfates with dermal exposure. Test Species/ Duration substance Strain

C12–15 ASO4 Na, CAS 6889070-0 C12–15 ASO4 Na, CAS 6889070-0

Dosage

NOAEL

10% (ca, 400 mg/ kg bw/ day)

LOAEL

15% (ca, 600 mg/ kg bw/ day)

Mouse, C57B1

Twice weekly with 3 day intervals for a total of 3 weeks

0.2 ml of a 0–18% aqueous solution per application (ca. 0– 720 mg a.i./kg bw/day)

Mouse, C57B1

Twice weekly with 3 day intervals for a total of 13 weeks

10% (ca. 12.5% 0.2 ml of a 0–15% 400 mg/ (ca. aqueous solution per kg bw) 500 mg/ application (ca. 0– kg bw) 600 mg a.i./kg bw/day)

Target organs/Main effects

Reference

Skin

Liver

Kidney

Other

Edema, hyperkeratosis, hypergranulosis, acanthosis, necrosis and ulceration Necrosis and ulceration

Relative weight m

Relative weight m

Unilever Relative heart weight Research (1976c) m

Hepatic glycogen k, parenchymal cytoplasmic basophilia k, relative weight m

Relative weight m

Hemoglobin k, heart weight m

Unilever Research (1977c)

Bold¼ HPV chemical.

Table 13 Studies on dermal absorption. Test substance

Species

Applied dose

Absorption

Reference

14

Guinea pig Guinea pig Rat

3 mmol 3 mmol (1) 0.5 ml of a 0.2% aqueous solution. (2) 0.5 ml of a 0.2% aqueous solution (wiping 0.5 h p.a.)

0.35% of the applied dose 0.2% of the applied dose (1) 0.6% of the applied dose. (2) 0.2% of the applied dose

Prottey and Ferguson (1975) Prottey and Ferguson (1975) Minegishi et al. (1977)

C-labeled C12 ASO4Na C-labeled C12 ASO3Na C-labeled C14-a-olefin sulfonate (C14 ASO3Na + C14 ¼ /OHASO3Na)

14 14

NOAEL for maternal toxicity is about 200 mg active ingredient/ kg bw/day in rats, while the lowest NOAELs in offspring were 250 mg active ingredient/kg bw/day in rats and 300 mg active ingredient/kg bw/day for mice and rabbits. For a-olefin sulfonates, no adverse effects were reported in rats (dams and offspring) dosed with up to 600 mg active ingredient/kg bw/day of C14–16 ¼ /OHASO3 Na during days 6–15 of gestation, i.e. this value is the NOAEL both for maternal and developmental toxicity. From a parallel study performed with mice and rabbits, no clear NOAEL can be derived due to unusual intervals of the applied dose sizes (0, 0.2, 2, 300 and 600 mg active ingredient/kg bw/day). At 2 mg active ingredient/kg bw/day, no adverse effects were found, while at 300 mg active ingredient/ kg bw/day adverse effects both in dams and offspring were observed. For alkane sulfonates, no data are available for developmental toxicity. However, due to similar toxicokinetic properties and a comparable metabolism of the alkyl sulfates and alkane sulfonates, the alkane sulfonates are not considered to be developmental toxicants (Table 17).

4. Exposure assessment Within the HERA Initiative4 (HERA, 2002), an extensive exposure assessment for the alkyl sulfates covering several exposure scenarios has been performed. Consumers can be exposed to these chemicals due to the use of household laundry and cleaning products mainly via direct dermal contact, but also via the oral route by residues deposited on dishes after manual washing or due to indirect exposure via drinking water. 4 HERA is a voluntary industry program to carry out Human and Environmental Risk Assessments on ingredients of household cleaning products. This European voluntary initiative launched in 1999 by A.I.S.E. representing the formulators and manufacturers of household cleaning products and Cefic representing the suppliers and manufacturers of the raw materials.

The estimated values for the different scenarios are summarized in the following Table 18. According to HERA, the calculated body burden taking into account all routes of exposure and using highly conservative or worst-case assumptions, is 5.93 mg a.i./kg bw/day. This value is about 10,000 times lower than the determined NOAEL values in experimental animals, so that adverse effects in consumers caused by substances of the ANS category can be excluded.

5. Results and discussion The ANS category consists of three structurally related classes of anionic surfactants, i.e., alkyl sulfates, primary alkane sulfonates, and the a´-olefin sulfonates. A total of 61 anionic surfactants have been assessed within this category approach performed under the HPV chemicals program of the OECD. Most chemicals of this category are not defined substances, but mixtures of homologs with different alkyl chain lengths, and the most important common structural feature is the presence of a predominantly linear aliphatic hydrocarbon chain with a polar sulfate or sulfonate group, neutralized with a counter ion (i.e. Na + , K + , NH4+ , or an alkanolamine cation). Reliable data are not available for the different toxicological endpoints for all members of this category. However, using read-across based on physicochemical and toxicological data, a comparable behavior of these closely related category members can be demonstrated. Overall, the common physical and/or biological pathways result in structurally similar breakdown products, which are responsible for an essentially identical hazard profile with regard to human health. The available toxicological data support the common properties of the compounds of the substances comprising the whole category. Alkyl sulfates of various chain lengths show a very similar profile of oral absorption, excretion and metabolite formation. Butyric acid-4-sulfate and sulfate are the main metabolites irrespective of chain length for the even numbered alkyl sulfates and propionic acid-3 sulfate, pentanoic acid-5-sulfate and sulfate

A. Wibbertmann et al. / Ecotoxicology and Environmental Safety 74 (2011) 1089–1106

are the main metabolites for the odd numbered alkyl sulfates. Compared to compounds with other chain lengths, C12 ASO4 shows a higher oral absorption and faster metabolism and excretion. The acute oral toxicity for most compounds is relatively low and only unspecific signs of intoxication are observed. In longer-term studies with oral dosing, all compounds are showing a strikingly similar pattern of effects with the liver as the only target organ and with similar NOAEL and LOAEL ranges. There is no difference between mixtures with even or odd chain lengths. In Ames tests with various different mixtures as well as with eukaryotic test systems, consistently negative results are obtained. Also, several in vivo studies (i.e. micronucleus test and chromosome

1101

aberration tests) with compounds of different chain lengths provided negative results. Also, negative results are obtained in oral carcinogenicity studies. There is no indication that alkyl sulfates will cause adverse effects on reproduction or development. As the salts will dissociate in aqueous environments, the counter ions will not fundamentally alter pathways of tissue disposition, metabolism, excretion, or target organs of toxicity. Accordingly, no major differences are found in most of the endpoints between the compounds with different counter ions. Chemicals of this category are used in consumer cleaning and personal care products, which may be used as is, or diluted prior to or during use. The main potential exposure includes dermal contact as well as eye contact

Table 14 Genetic toxicity in vitro. Test substance

Protocol/Test system

Result

Reference

Alkyl sulfates C8 ASO4 Na, CAS 142-31-4 C8–14 ASO4 NH4, CAS 90583-10-1 C8–14 ASO4 TEA, CAS 85665-45-8 C8–16 ASO4 Na, CAS 90583-27-0 C10 ASO4 Na, CAS 142-87-0 C12 ASO4 Na, CAS 151-21-3 C12 ASO4 Na, CAS 151-21-3 C12 ASO4 TEA, CAS 139-96-8 C12–14 ASO4 Na, CAS 85586-07-8 C12–14 ASO4 MEA, CAS 90583-16-7 C12–14 ASO4 TEA, CAS 90583-18-9 C12–14 ASO4 Mg, CAS 90583-23-6 C12–15 ASO4 Na, CAS 68890-70-0 C12–15 ASO4 Na, CAS 68890-70-0 C12–16 ASO4 Na, CAS 73296-89-6 C12–16 ASO4 NH4, CAS 90583-12-3 C12–18 ASO4 Na, CAS 68955-19-1 C12–18 ASO4 NH4, CAS 90583-13-4 C14 ASO4 Na, CAS 1191-50-0 C14 ASO4 Na, CAS 1191-50-0 C16 ASO4 Na, CAS 1120-01-0 C16 ASO4 Na, CAS 1120-01-0 C16 ASO4 Na, CAS 1120-01-0 C16–18 ASO4 Na, CAS 68955-20-4 C14–18 and C18 ¼ ASO4 Na, CAS 90583-31-6

OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 Ames test, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 476, L5178Y tk + /tk  cells Ames test, S. typhimurium TA 98, TA 100 OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 Ames test, Salmonella typhimurium TA 1535, TA 1538 Ames test, S. typhimurium TA 1535, TA 1538 OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 476, L5178Y tk + /tk  cells OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 476, L5178Y tk + /tk  cells OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 OECD TG 471, S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538

Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative

Henkel KGaA (1989b) Henkel KGaA (1981) Henkel KGaA (1991i) Henkel KGaA (1991e) Henkel KGaA (1992c) Henkel KGaA (1988d) McGregor et al. (1988) Sunakawa et al. (1981) Henkel KGaA (1991j) Henkel KGaA (1991h) Henkel KGaA (1987j) Henkel KGaA (1987d) Unilever Research (1975k) Unilever Research (1975k) Henkel KGaA (1992d) Henkel KGaA (1987b) Henkel KGaA (1991f) Henkel KGaA (1991c) Procter and Gamble (1979) Procter and Gamble (1981) Procter and Gamble (1979) Procter and Gamble (1976c) Procter and Gamble (1981) Henkel KGaA (1992a, 1995) Henkel KGaA (1991b)

OECD OECD OECD OECD OECD OECD OECD

Negative Negative Negative Negative Negative Negative Negative

Kao Co. (1996) Hoechst AG (1988a) Hoechst AG (1988a) Hoechst AG (1989) Lion Co. (2004a) Lion Co. (2004a) Lion Co. (2004c)

a-Olefin sulfonates C14–16 ¼/OHASO3 Na, CAS 68439-57-6 C14–16 ¼/OHASO3 Na, CAS 68439-57-6 C14–16 ¼/OHASO3 Na, CAS 68439-57-6 C14–16 ¼/OHASO3 Na, CAS 68439-57-6 C14 ¼/OHASO3 Na, CAS 93686-14-7 C14 ¼/OHASO3 Na, CAS 93686-14-7 C14 ¼/OHASO3 Na, CAS 93686-14-7

TG TG TG TG TG TG TG

471, 471, 471, 473, 471, 471, 473,

S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 S. typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 E. coli WP2uvrA Chinese hamster V79 cells S. typhimurium TA 98, TA 100, TA 1535, TA 1537 E. coli WP2uvrA Chinese hamster CHL cells

Bold ¼HPV chemical; S. typhimurium ¼ Salmonella typhimurium; E. coli¼Escherichia coli.

Table 15 Genetic toxicity in vivo. Test substance

Protocol, Test system

Species

Application

Result

Reference

Alkylsulfates C12 ASO4 Na, CAS 151-21-3 C12 ASO4 Na, CAS 151-21-3 C12–14 ASO4 TEA, CAS 90583-18-9 C12–15 ASO4 Na, CAS 68890-70-0 C12–15 ASO4 Na, CAS 68890-70-0 C12–15 ASO4 Na, CAS 68890-70-0 C12–15 ASO4 Na, CAS 68890-70-0 C12–15 ASO4 Na, CAS 68890-70-0 C16–18 ASO4 Na, CAS 68955-20-4

Chromosome aberration assay OECD TG 478, Dominant lethal assay OECD TG 474, Micronucleus assay Chromosome aberration assay Chromosome aberration assay Chromosome aberration assay OECD TG 478, Dominant lethal assay OECD TG 478, Dominant lethal assay OECD TG 474, Micronucleus assay

Rat Mouse Mouse Hamster Rat Rat Mouse Mouse Mouse

Diet Gavage Gavage Gavage Diet Diet Gavage Gavage Gavage

Negative Negative Negative Positivea Negative Negative Negative Negative Negative

Unilever Research (1976a); Hope (1977) Unilever Research (1976h, 1976l) Henkel KGaA (1987k) Unilever Research (1977b) Unilever Research (1976a, 1976h); Hope (1977) Unilever Research (1976a, 1976h); Hope (1977) Unilever Research (1976h, 1976l) Unilever Research (1976h, 1976l) Henkel KGaA (1986b)

Bold¼ HPV chemical; a Significant increase in the number of aberrations only in high-dosed females (no increase in males); this isolated positive result is not considered to be of biological relevance, as all other in vivo studies gave no indication of a clastogenic potential.

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during handling and use. Alkyl sulfates are usually used in conjunction with other surfactants when formulated in consumer products. These mixed surfactant systems form micelles that typically lead to a reduction in irritation potential of the mixture, compared to the irritation potential of the individual ingredients.

Table 16 Dosage regimen for the two generation reproductive toxicity study performed with a mixture of C14:C16:C18 blend (1:1:1 ratio) of a-olefin sulfonate, Mg salt (Lion Co., 1980). Generation

Sex

Test material consumption (mg a.i./kg bw/day) Week 1

F0 F1 F2

Males Females Males Females Males Females

0, 0, 0, 0, 0, 0,

189, 186, 232, 232, 248, 242,

357 350 458 462 474 492

Week 13 or or or or or or

727 679 891 871 1040 961

0, 0, 0, 0, 0, 0,

63, 79, 68, 85, 66, 82,

127 160 131 165 131 165

or or or or or or

250 320 261 338 266 370

The database for alkyl sulfonates is more limited. These substances may be viewed as being structurally in-between the two other groups, as they share the saturated alkyl chain with the alkyl sulfates and the sulfonic acid group with the a-olefin sulfonates. As for the alkyl sulfates and a-olefin sulfonates, the acute oral toxicity is low. If data from the alkyl sulfates and a-olefin sulfonates are taken into account, it can be assumed that the alkyl sulfonates also will cause skin and eye irritation, but will not have sensitizing or genotoxic effects. Longer-term studies as well as data concerning carcinogenicity or reproduction toxicity are missing. However, the sulfonates have been subject of a category approach, which shows similarities for all members of the group irrespective of their structure. They are quickly eliminated, the acute and repeated dose toxicity is low, there is no indication for genotoxic effects and the results of teratogenicity studies are negative. This is consistent with the data obtained for the alkyl sulfates and a-olefin sulfonates. Therefore, based on the similar toxicokinetic properties and a comparable metabolism of the alkyl sulfates and alkane sulfonates, effects after long-term exposure or adverse effects on reproduction and development are not to be expected.

Table 17 Results of developmental toxicity studies. Test substance

Species/ Strain

Duration

Dosage

NOAEL (mg a.i./ kg bw/day)

LOAEL (mg a.i./ kg bw/day)

Reference

Alkyl sulfates C12 ASO4 Na, CAS 151-21-3

Rat CD

C12 ASO4 Na, CAS 151-21-3

Mouse CD-1

C12 ASO4 Na, CAS 151-21-3

Rabbit NZW

C12 ASO4 Na, CAS 151-21-3

Rat Wistar

Day 6–15 of gestation, termination on gd 20 Day 6–15 of gestation termination on gd 17 Day 6–18 of gestation termination on gd 29 Day 6–15 of gestation termination on gd 21 or to weaning day 21 Day 6–15 of gestation termination on gd 21 or to weaning day 21 day 6–15 of gestation termination on gd 21 or to weaning day 21 Day 6–15 of gestation termination on gd 21 or to weaning day 21 day 6–15 of gestation termination on gd 21 or to weaning day 21 Day 6–15 of gestation termination on gd 21 or to weaning day 21 Day 6–15 of gestation termination on gd 21 or to weaning day 21

up

Gavage, 0–600 mg/ kg bw/day Gavage 0–600 mg/ kg bw/day Gavage 0–600 mg/ kg bw/day Gavage 0–500 mg/ kg bw/day

Maternal: 2, Offspring: 600 Maternal: 2, Offspring: 300 Maternal:2, Offspring:300 Maternal: 250, Offspring: 500

Maternal: 300, Offspring: 4600 Maternal: 300, Offspring: 600 Maternal: 300, Offspring: 600 Maternal: 500, Offspring: 500

Palmer et al. (1975a, 1975b) Palmer et al. (1975a, 1975b) Palmer et al. (1975a, 1975b) Unilever Research (1976i)

up

Gavage 0–500 mg/ kg bw

Maternal: 250, Offspring: 250

Maternal: 500, Offspring: 500

Unilever Research (1987)

up

Gavage 0–563 mg/ kg bw/day

Maternal: 375, Offspring: 375

Maternal: 563, Offspring: 563

Unilever Research (1977g)

up

Gavage 0–500 mg/ kg bw

Maternal: 250, Offspring: 500

Maternal: 500, Offspring: 4500

Unilever Research (1976g)

up

Gavage 0–390 mg/ kg bw/day

Maternal: 195, Offspring: 390

Maternal: 390, Offspring: 4390

Unilever Research (1979)

up

Gavage 0–1000 mg/ kg bw/day

Maternal: 250, Offspring: 750

Maternal: 500, Offspring: 1000

Unilever Research (1986)

up

Gavage 0–675 mg/ kg bw

Maternal: 225, Offspring: 675

Maternal: 450, Offspring: 4675

Unilever Research (1978)

C12–14 ASO4 Na, CAS 85586-07-8

C12–15 ASO4 Na, CAS 68890-70-0

C12–15 ASO4 Na, CAS 68890-70-0

C13–15 ASO4 Na, CAS 86014-79-1

Rat Wistar

Rat Wistar

Rat Wistar

Rat Wistar

C15–16 ASO4 a.i.: 31.6%, CAS 99999-99-9n

Rat Wistar

C16–18 ASO4 Na, CAS 68955-20-4

Rat Wistar

a-Olefin sulfonates C14–16 ¼ /OHASO3 Na mixture of alkenyl sulfonate and hydroxyalkane sulfonate (60.4:39.6% w/w) CAS 6843957-6 C14–16 ¼ /OHASO3 Na mixture of alkenyl sulfonate and hydroxyalkane sulfonate (60.4:39.6% w/w) CAS 6843957-6 C14–16 ¼ /OHASO3 Na mixture of alkenyl sulfonate and hydroxyalkane sulfonate (60.4:39.6% w/w) CAS 6843957-6

Rat CD

Day 6–15 of gestation termination on gd 20

Gavage 0–600 mg/ kg bw/day

Maternal: 600, Offspring: 600

Maternal: 4 600, Offspring: 4600

Palmer et al. (1975a, 1975b)

Mouse CD-1

Day 6–15 of gestation termination on gd 17

Gavage 0–600 mg/ kg bw/day

Maternal: 2, Offspring: 2

Maternal: 300, Offspring: 300

Palmer et al. (1975a, 1975b)

Rabbit NZW

Day 6–18 of gestation termination on gd 29

Gavage 0–600 mg/ kg bw/day

Maternal: 2, Offspring: 2

Maternal: 300, Offspring: 300

Palmer et al. (1975a, 1975b)

Bold¼ HPV chemical; * Fictitious CAS No for compounds with specific chain length but without a defined CAS-number.

A. Wibbertmann et al. / Ecotoxicology and Environmental Safety 74 (2011) 1089–1106

Table 18 Results of the exposure assessment for the alkyl sulfates performed by HERA (2002). Exposure scenario

Estimated update (lg a.i./kg/day)

Direct skin contact – Hand-wash laundry – Laundry pre-treatment – Hand dishwashing – Hard surface cleaning

0.64 2.27 0.47 0.41

Indirect skin contact – Wearing clothes

0.73

Exposure by inhalation – Dust – Aerosols

0.001 0.06

Oral exposure – Indirect via the environment – Indirect via dishwashing residues

0.53 0.82

For the a-olefin sulfonates, several studies are available and the chain lengths investigated cover C14–18 with sodium as the counter ion. The observed effects are very similar compared with the alkyl sulfates, and no difference is seen between the different substances. These substances are eliminated mainly in the urine, the acute oral toxicity is low and all mixtures show irritating properties without a sensitizing potential. The a-olefin sulfonates are not mutagenic in vitro and no increased tumor rates are found in dermal or oral carcinogenicity studies. There is no indication for adverse effects on reproduction. For consumers, the calculated body burden for the alkyl sulfates taking into account all routes of exposure is about 6 mg/ kg bw/day, which is about 10,000 times lower than the lowest NOAEL value in experimental animals. Therefore, adverse effects in consumers caused by substances of the ANS category can be excluded.

Acknowledgments This work was supported by the SDA Alkylsulfates Consortium. The authors as well as the Consortium Members would like to acknowledge comments received from the German Federal Institute for Risk Assessment (BfR) as well as The Advisory Committee on Existing Chemicals of Environmental Relevance (BUA) during the review of the documents within the OECD/ICCA peer review process. References Basketter, D.A., 2002. Sodium dodecyl (lauryl) sulphate—allergen or irritant. Personal communication to SDA/ CESIO. 3 p. Basketter, D.A., Scholes, E.W., Kimber, I., 1994. The performance of the local lymph node assay with chemicals identified as contact allergens in the human maximization test. Food Chem. Toxicol. 32, 543–547. Black, G.J., Howes, D., 1980. Absorption, metabolism, and excretion of anionic surfactants. In: Gloxhuber, C. (Ed.), Surfactant Science Series, vol. 10: Anionic Surfactants—Biochemistry, Toxicology, Dermatology. Dekker, New York, pp. 51–85. Blank, I.H., Gould, E., 1961. Penetration of anionic surfactants (surface active agents) into skin. J. Invest. Dermatol. 33, 327–336. Brown, V.K.H., Muir, C.M.C., 1970. The toxicities of some coconut alcohol and Dobanol 23 derived surfactants. Tenside 7, 137–139. Burke, B., Olavesen, A.H., Curtis, C.G., Powell, G.M., 1975. The biodegradation of some anionic detergents in the rat. A common metabolic pathway. Xenobiotica 5, 573–584. Burke, B., Olavesen, A.H., Curtis, C.G., Powell, G.M., 1976. The biodegradation of the surfactant undecyl sulphate. Xenobiotica 6, 667–678. Carson, S., Oser, B.L., 1964. Dermal toxicity of sodium lauryl sulfate. J. Soc. Cosmet. Chem. 15, 137–147.

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