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Environmental and Health Assessment of Substances in Household Detergents and Cosmetic Detergent Products 8. Preservatives
8.1 IsothiazolinonesIsothizolinones are used in household detergents and cosmetic detergent products. The most frequently used are 2-methyl-4-isothiazolin-3-one (MI) with the CAS No. 2682-20-4 and 5-chloro-2-methyl-4-isothiazolin-3-one (CMI) with the CAS No. 26172-55-4. These two substances are used as a mixture in the preservative product with the commercial name Kathon. 8.1.1 KathonKathon (CAS No. 55965-84-9) is a commercial mixture of MI and CMI in the ratio 1:3. In cosmetic products the maximum allowed concentration is 15 ppm of the mixture of MI and CMI (Directive 97/18/EC and Directive 98/16/EC). The products may include water at levels more than 75% and various kinds of salts, e.g. magnesium salts. Examples of commercial products are Kathon CG (cosmetic grade): 0.35% MI and 1.15% CMI = 1.5% active ingredients + magnesium salts, and Kathon 886: 3.8% MI and 10.1% CMI = 13.9% active ingredients. Ecotoxicology The primary aerobic biodegradability of MI has been examined in a river sediment-water system by use of 14C-labelled model compound. During the 7-day experiment 14C-labelled Primary aerobic biodegradability MI (1 m g/g) was rapidly transformed as only 12.6% of the initial MI was present after 24 hours of incubation at 25° C. The calculated half-life for the parent compound was 9.1 hours (Reynolds 1994a). MI was transformed to several unidentified metabolites. One of the major metabolites reached a level corresponding to 18.2% of the 14C added after 24 hours of incubation. This metabolite decreased to 6.8% after 7 days which indicates further transformation. Other metabolites tended to increase during the 7-day experiment. At the end of the experiment metabolites that were bound in the sediment corresponded to 55%, whereas 14CO2 attained 9% of the added 14C. Most of the formed metabolites have shorter chromatographic retention times than MI which indicates that they are polar compunds. On the basis of the identification of metabolites from transformation of 4,5-dichloro-2-(n-octyl)-4-isothiazolin-3-one, it has been proposed that MI is transformed via N-methyl malonamic acid, N-methyl acetamide, and malonic acid (Madsen 2000). The primary biodegradability of CMI has been examined with the same type of sediment and water as described for MI. The 14C-labelled CMI (1 m g/g) was rapidly transformed as only 30% of the initial CMI remained after 24 hours of incubation at 25° C. The calculated half-life for the intact CMI was 17.3 hours (Reynolds 1994b). At the end of the 7-day experiment, the sediment bound metabolites corresponded to 57.1% of the added 14C whereas 2.8% of the added 14C was released as 14CO2. Due to the structural similarities of MI and CMI, it is suggested that the major metabolites for the transformation of CMI are the same as described for MI. Ultimate aerobic biodegradability The ultimate aerobic biodegradability of MI has been examined in a CO2 evolution test (OECD 301B) which was modified for low concentrations of 14C-labelled compounds (Bashir 1998a). MI was added at initial concentrations of 0.1, 0.03, and 0.01 mg/l. The duration of the test was 29 days and the test was performed at 22° C. At the end of the test the accumulated 14CO2 attained 54.1%, 55.8%, and 47.6% in the respective concentrations (0.1, 0.03 and 0.01 mg/l). During the 10-day window 37%, 30% and 30%, respectively, of the initial MI was mineralized to 14CO2. The ultimate biodegradability of CMI was examined in the CO2 evolution test (OECD 301B) under the same conditions as described for MI (Bashir 1998b). CMI was added at initial concentrations of 0.3, 0.1, and 0.03 mg/l. The 14CO2 formed from the mineralization of CMI during 29 days reached 38.8%, 55.3%, and 62% of the added 14C in the respective concentrations (0.3, 0.1, and 0.03 mg/l). The percentages of 14CO2 attained within the 10-day window were 25%, 40%, and 48% of the added 14C-activity. The ultimate biodegradability of CMI exceeded the 60%-pass level for ready biodegradability at the lowest test concentration of 0.03 mg/l, but the pass level was not reached within the 10-day window. Anaerobic biodegradability The biodegradability of 14C-labelled CMI has been examined under anoxic conditions in a system containing river sediment and water (Liu and Reynolds 1994). During the incubation at 25° C the evolved 14CO2 increased to 16.6% and 55.7% of the added 14C after 30 and 365 days, respectively. The half-life of the parent CMI was calculated to 4.6 h. The level of accumulated 14CO2 from the mineralization of CMI demonstrates that the isothiazolone ring was cleaved and that the metabolites were further oxidized. On the basis of the observed mineralization of CMI and the fate of 14C residuals it has been proposed that the anaerobic degradation of CMI leads to the same type of metabolites as proposed for aerobic degradation of MI and CMI (Liu and Reynolds 1994). Bioaccumulation The high water-solubility and the low log Kow values determined for MI and CMI (0.4 and -0.5, respectively) indicate a low potential for bioaccumulation of both substances. Studies of the bioaccumulation of CMI in bluegill sunfish (Lepomis macrochirus) showed BCF values of 102, 114, and 67 at nominal concentrations of 0.02, 0.12, and 0.8 mg/l (Erikson et al. 1995). These BCF values are based on total accumulated 14C and include both the parent compound and metabolites. The BCF for MI has been determined to 2.3 at a nominal concentration of 0.12 mg/l (Erikson et al. 1995). Aquatic toxicity The toxicity of the formulated product (Kathon) has been investigated towards different aquatic organisms and for all species investigated EC/LC50 values were well below 1 mg/l (Table 8.1). Table 8.1
Interpretation of biodegradability and toxicity Both MI and CMI inhibit the inoculum in biodegradability screening tests which implies that the conditions are very unfavourable in tests aiming at determing the ready biodegradability, even when low contrations are used. MI and CMI may thus be regarded as candidates for an assessment of other available "convincing scientific evidence" to demonstrate that the substances can be degraded (biotically and/or abiotically) in the aquatic environment to a level of > 70% within a 28-day period". Primary biodegradation of MI and CMI occurred with half-lives of less than 24 hours in aerobic and anoxic sediments, and within a period of less than one week the parent compounds were depleted to very low levels that could not be clearly distinguished from analytical artefacts. The ultimate aerobic biodegradability of both MI and CMI attained levels of > 55% within 29 days. Furthermore, the proposed metabolites of MI and CMI are considered to have a low aquatic toxicity on the basis of QSAR estimates and the measured toxicity of the structurally related N-(n-octyl) malonamic acid. Human health As it is Kathon in the MI/CMI ratio of 1:3 which is used in cleaning agents and cosmetics it is this mixture which is assessed in the human health and hazard assessment. Most studies have been carried out with the commercial mixture and not with the pure isothiazolones. Toxicokinetics and acute toxicity After oral administration of Kathon 886 to rats, the majority of MI and CMI was readily excreted in the urine or faeces while storage in the tissues was minimal. Up to 62% of a single percutaneous dose was bound to the site of application 24 hours after exposure (CIRP 1992). N-methyl malonamic acid was detected as the main metabolite in the urine of rats given oral doses of either of the two isothiazolones. Malonamic acid and malonic acid were also identified as metabolites (DFG 1993). Kathon 886 was rapidly distributed to the blood, liver, kidneys, and testes after an intravenous dose (0.8 mg/kg body weight). The chlorinated compound was 14C-labelled and after 24 hours more than 50% of the administered radioactivity had been excreted in the faeces and urine, after 96 hours about 70% (faeces 35%, urine 31%, and CO2 4%) was excreted (Debethizy et al. 1986). The half-life of dermally absorbed compounds was found to be 13.1 day. This suggests an increased potential for accumulation on the skin with repeated application or use (Connor et al. 1996). Isothiazolinones are moderately to highly toxic by oral administration. The major signs of toxicity were severe gastric irritation, lethargy, and ataxia (CIRP 1992) (Table 8.2). Table 8.2
Aqueous dilutions of Kathon 886 were tested for skin irritation in rabbits. A concentration of 0.056% a.i. was non-irritating, and 5.65% a.i. was corrosive. Kathon CG with an a.i. concentration of 1.5% was severely irritating (CIRP 1992). Solutions which contain more than 0.5% (5000 ppm/active isothiazolones) produce severe irritation of human skin and can cause corrosion of mucous membranes and the cornea. Solutions containing > 100 ppm active isothiazolones can irritate the skin (DFG 1993). Kathon 886 with concentrations of 0.056% a.i. was non-irritating to the eye. Conc of 2.8% and 5.65% a.i. were severely irritating (corrosive) to the eye. Kathon CG with a 1.5% a.i. concentration were corrosive to the eye (CIRP 1992). Instillation of 0.1ml of an aqueous solution containing 560 ppm isothiazolones into the rabbit eye did not produce irritation. Higher concentration caused dose-dependent mild to severe irritation. After instillation into the rabbit eye of a single dose of undiluted Kathon 886 containing 13.9% active ingredients, clouding of the cornea, chemosis, and swelling of the eyelids were observed (DFG 1993). Sensitization The sensitization potential of Kathon CG and Kathon 886 in humans has been studied extensively. There is general agreement among investigators that Kathon CG is a sensitizer (Björkner et al. 1986; Bruze 1987a; Gruvberger 1997). It is primarily CMI which is the sensitizing substance (strong sensitizer) in the product but 2-methyl-4-isothiazolin-3-one also has sensitizing properties (weak sensitizer – moderate allergen) (Bruze 1987a; Gruvberger 1997). Kathon CG is a part of the standard test series at skin clinics. The risk of sensitization depends on how contact with the product occurs. The risk is greater when the skin barrier has been damaged and smaller when the skin is healthy. The sensitizing capacity of the preservatives Kathon CG has been established in both humans and guinea pigs (Bruze 1987b). Several reports on occupational allergic contact dermatitis from MI and CMI have been published (Gruvberger 1997). A large number of patients (8,521) were tested from 1985-1997 for contact allergy to antimicrobials. The MI/CMI mixture was the most common antimicrobial allergen (Goossens et al. 1997). A high frequency (17.6%) of contact allergy to MI and CMI was demonstrated in 51 production workers in a factory handling preservatives with high concentrations of MI and CMI. Four of the workers sensitized to Kathon CG suffered from chemical burns caused by preservatives with high corrosive concentration of MI and CMI (Gruvberger 1997). Dermatological studies have demonstrated that isothiazolone concentrations below 20 ppm may cause sensitization and that allergic reactions can be provoked in sensitized persons even with concentrations in the range of 7-15 ppm active isothiazolones (DFG 1993). Sodium bisulfite and glutathione, (Gruvberger1997), can chemically inactivate MI and CMI. A review of studies of MI/CMI allergic contact potential indicate that the actual sensitization rate observed is extremely dependent on dose and type of exposure. This review of data leads to the conclusion that, under normal use conditions, within the current permitted/recommended use concentration for MI/CMI (up to 15 ppm), the risk of primary sensitization is negligible (Fewings and Menné 1999). Subchronic toxicity Kathon 886 administrated in the drinking water to rats for three months produced slight gastric irritation at a dose of 20 mg/kg/day; the no effects level (NOEL) was 8 mg/kg/day. Dermal application of Kathon 886 at doses up to 0.4 mg/kg/day for three months produced no systemic toxicity in rabbits (CIRP 1992). Mutagenicity and carcinogenicity Kathon CG and Kathon 886 have been evaluated in a number of mutagenicity assays. Although there have been conflicting reports in the literature, it has been reported by several investigators that these biocides are mutagenic in Salmonella typhimurium strains (Ames test) (Monte et al. 1983; Wright et al. 1983; Connor et al. 1996). Negative results were obtained in studies of the DNA-damaging potential of Kathon in mammalian cells in vitro and of cytogenetic effects and DNA-binding in vivo (DFG 1993). The addition of rat liver S-9 (metabolic activation) reduced toxicity but did not eliminate mutagenicity. The compounds bind to the proteins in the S-9. At higher concentrations of Kathon the increase in mutagenicity may be due to an excess of unbound active compounds (Connor et al. 1996). A study of cutaneous application of Kathon CG in 30 months, three times per week at a concentration of 400 ppm (0.04%) a.i. had no local or systemic tumorigenic effect in male mice. No dermal or systemic carcinogenic potential was observed (Scribner et al. 1983; CIRP 1992; DFG 1993). Reprooductive toxicity No adverse effects on fertility, reproduction, fetal survival, or fetal health were observed in rats administrated > 20 mg/kg/day Kathon 886 in the drinking water for 15 weeks prior to mating (CIRP 1992). Reproduction and teratogenicity studies with rats, given isothiazolone doses of 1.4-14 mg/kg/day orally from day 6 to day 15 of gestation, showed no treatment related effects in either the dams or in the foetuses (DFG 1993). Classification MI and CMI are not included in Annex 1 of list of dangerous substances of Council Directive 67/548/EEC. Table 8.3
R23/24/25: Toxic by inhalation, in contact with skin and if swallowed. The highest allowed concentration of Kathon in cosmetics is 15 ppm according to the cosmetic directive (Cosmetic Directive 2000). 8.1.2 1,2-Benzisothiazolin-3-oneEcotoxicology 1,2-Benzisothiazolin-3-one (CAS No. 2634-33-5) is used in specialized cleaning agents, although it is used less frequently than Kathon. There are no experimental data available regarding the biodegradability and bioaccumulation of 1,2-benzisothiazol-3-one. However, QSAR calculations indicate a high probability of aerobic biodegradation and a low potential for bioaccumulation in aquatic organisms (log Kow = 0.64) (EPIWIN 1994). Data describing the acute toxicity of 2-benzisothiazolin-3-one towards algae, crustaceans and fish are given in Table 8.4. Table 8.4
1,2-Benzisothiazolin-3-one is rapidly and totally metabolized in animals. Neither the substance itself nor the metabolites accumulate in the liver or adipose tissue. Excretion is mostly via the kidneys and almost completely within 24 hours. The main metabolites are o-methylsulphonylbenzamide and o-methylsulphinylbenzamide. Rats excreted 96% of an oral dose of 1,2-benzisothiazolin-3-one within 5 days (DFG 1989). Toxicokinetics and acute toxicity 1,2-Benzisothiazolin-3-one has a relatively low toxicity by oral administration (Table 8.5). Table 8.5
* A Proxel product. Skin and eye irritation 1,2-Benzisothiazolin-3-one has strong irritating or corrosive properties in animals. These properties are related to its alkaline reaction in water solutions. Solutions of 1,2-benzisothiazolin-3-one (> 5%) in water have a pH of 10-12 (ICI 1990). A solution of 1% 1,2-benzisothiazolin-3-one has been reported to cause strong irritation of the guinea pig skin (Alomar et al. 1985). In routine patch testing 1% 1,2-benzisothiazolin-3-one in alcohol gave weak irritant reaction in 30% of a total of 404 patients tested (Andersen and Hamann 1984). Concentrations from 0.1% 1,2-benzisothiazolin-3-one have been found irritating to the skin in clinical studies of 56 subjects (Chew and Maibach 1997). 1,2-Benzisothiazolin-3-one in 0.08 and 0.16% aqueous solutions produced some irritant responses when patch tested on a group of 25 healthy volunteers (Damstra et al. 1992). In the rabbit eye 12.5% 1,2-benzisothiazolin-3-one was a strong and severe irritant (DFG 1989). Sensitization The allergenic potential of 1,2-benzisothiazolin-3-one has been assessed in very few animal studies, but there are numerous reports about humans being sensitized due to handling products containing small amounts of 1,2-benzisothiazolin-3-one. The sensitizing potential of 1,2-benzisothiazolin-3-one was evaluated using the guinea pig maximization test of Magnusson and Kligman and was found to be a week sensitizer. Three of 20 guinea pigs exhibited sensitizaton with 0.2% 1,2-benzisothiazolin-3-one in aqueous propylene glycol (Andersen and Hamann 1984). Using the murine local lymph node assay the lowest concentration at which 1,2-benzisothiazolin-3-one were able to induce a significant proliferative response was at 10% 1,2-benzisothiazolin-3-one. The murine local lymph node assay assesses contact sensitization potential by measuring T cell activation and, in particular, T lymphocyte proliferation in the lymph nodes (Botham et al. 1991). In several published case reports 1,2-benzisothiazolin-3-one has induced allergic dermatitis. The allergic effects appear from 0.01% 1,2-benzisothiazolin-3-one and have been confirmed in a series of patch test studies. The majority of cases are occupational exposure to 1,2-benzisothiazolin-3-one in cutting oils, paper, gum arabic, air fresheners, water softeners and paints (Freeman 1984; Alomar et al. 1985; DeBoer et al. 1989; Damstra et al. 1992; Diaz et al. 1992; Sanz-Gallen et al. 1992; Cooper and Shaw 1999). According to Hopkins (1994) 1,2-benzisothiazolin-3-one possesses a fairly high sensitizing potential in man and it is significantly more active in the workplace than in the test laboratory in guinea pigs or mice. One case story from a detergent formulation factory has been reported on occupational astma or rhinitis after exposure to 1,2-benzisothiazolin-3-one (Moscato et al. 1997). Mutagenicity and carcinogenicity 1,2-Benzisothiazolin-3-one (94% solution) was nonmutagenic in an Ames test when tested in Salmonella strain TA98 (Riggin et al. 1983). In the in vivo micronucleus test, where a solution of 73.4% 1,2-benzisothiazolin-3-one was given orally to mice, no evidence of mutagenicity was observed. This method involves the use of polychromatic erythrocyte stem cells of mice. The bone marrow is collected and an increase in micronucleated cells over the controls is considered as a positive mutagenic effect (DGF 1989). An UDS test (unscheduled DNA synthesis) in cultures of rat hepatocytes also gave no mutagenic effects at a concentration of 73.4% 1,2-benzisothiazolin-3-one. This test is a measure of DNA repair capability after direct damage to DNA (DGF 1989). Finally, the mouse lymphoma cell mutation test showed no mutagenic potential of 1,2-benzisothiazolin-3-one at a concentration of 73.1% 1,2-benzisothiazolin-3-one. This mutation assay is used to determine the ability of chemicals to cause gene mutations in cultured mamalian cells (DGF 1989). Reproductive toxicity Female rats were given a product containing 73.4% 1,2-benzisothiazolin-3-one by gavage from day 7 to 16 after mating in doses of 10, 40, or 1,009 mg product/kg/day. The rats were sacrificed shortly before expected day of delivery. The dose 40 mg/kg/day were neither embryotoxic, fetotoxic nor teratogenic. The dose 100 mg/kg/day was considered to be slightly fetotoxic because the fetuses were on average 4% lighter and that ossification was sometimes slightly delayed. No teratogenic effect at this concentration was seen but it caused moderate maternal toxicity (DFG 1989). Classification 1,2-Benzisothiazolin-3-one is included in Annex 1 of list of dangerous substances of
Council Directive 67/548/EEC and classified as follows: 1,2-Benzisothiazolin-3-one is not allowed as preservative in cosmetics according to the cosmetic directive (Cosmetic Directive 2000). 8.2 ParabensThe parabens are all esters of 4-hydroxybenzoic acid, only differing in the ester group, which may be a methyl-, an ethyl-, a propyl- or a butyl group giving methylparaben (CAS No. 99-76-3), ethylparaben (CAS No. 120-47-8), propylparaben (CAS No. 94-13-3), or butylparaben (CAS No. 94-26-8). The most frequently used parabens are methylparaben and propylparaben. Methylparaben is used as a preservative in foods, beverages and cosmetics. Propylparaben is used as a preservative in food and antifungal agents. In shampoos/conditioners methyl paraben is preferred, frequently in combination with propyl paraben and/or ethyl paraben. The concentration used is below 0.2% (Rastogi and Johansen 1993). Parabens are stable in acidic solutions. Hydrolysis occurs above pH 7. In strong alkaline solutions parabens hydrolyze to the corresponding carboxylic acid. As the carbon number of the alkyl chain increases, anti-microbial activity increases but water solubility decreases. The individual esters differ in their relative anti-microbial activities. For this reason, optimum effectiveness is usually obtained with combinations of two or more paraben esters (of different chain lengths). Ecotoxicology The tests that were conducted in the present study showed that methyl-, ethyl-, and propylparaben are readily biodegradable under aerobic conditions. The parabens were only partially degraded in anaerobic screening tests (ISO 11734) as illustrated by an ultimate biodegradability in the range of 18 to 40% of the theoretical gas production (Table 8.6). Of the three parabens examined, methylparaben attained the highest biodegradability in the anaerobic screening test. It is possible that the parabens inhibit the anaerobic bacteria at the applied test concentration (20 mg of C/l) and that ethyl- and propylparaben were more toxic than methylparaben. The potential for bioaccumulation is low to moderate as judged from the QSAR estimated log Kow values that range between 1.96 and 3.57 (Table 8.6). Table 8.6
Table 8.7
Phenoxyethanol (CAS No. 122-99-6) and benzyl alcohol (CAS No. 100-51-6) have some structural similarities with parabens. These preservatives are readily biodegradable and the few data indicate a low aquatic toxicity. Phenoxyethanol attained > 90% ThOD in a BOD test and the log Kow of 1.16 indicates that the substance is not expected to bioconcentrate in aquatic organisms. The toxicity of phenoxyethanol to fish has been determined in studies with fathead minnow (Pimephales promelas; LC50: 344 mg/l) and golden orfe (Idus idus melanotus; NOEC: 200 mg/l (Bayer 1997). Benzyl alcohol reached a level of more than 70% ThOD in a BOD test and has a log Kow of 1.1. The anaerobic biodegradability of a mixed product containing 55-80% benzyl alcohol, 15-30% methylparaben, and 5-15% propylparaben attained 66% of ThGP in the ISO 11734 screening test after 56 days (Appendix; Table A19, Figure A19). The aquatic toxicity of benzyl alcohol has been determined in test with Daphnia magna (24 h-EC50: 55 mg/l) and fish (Idus idus melanotus; LC50: 646 mg/l) (CETOX 2000). Endocrine disrupting effects The estrogenic effects of parabens have been investigated in juvenile rainbow trout (Oncorhynchus mykiss) where the induction of yolk protein (vitellogenin) was used as an estrogen-specific endpoint after repeated injections of the parabens (ethyl-, propyl-, and butylparaben (Petersen et al., in press). All of the tested parabens showed estrogenic activity in doses between 100 and 300 mg/kg with propyl- and butylparaben being the most active. The major metabolite of the parabens, p-hydroxybenzoic acid, was tested as well but showed no estrogenic activity. In a receptor-binding assay, it was shown that butylparaben was able to compete with 3H-estradiol for binding to the rat estrogen receptor with an affinity approximately 5 orders of magnitude lower than that of diethylstilbestrol (DES) and between 1 and 2 orders of magnitude less than nonylphenol (Routledge et al. 1998). In an in vitro yeast-based estrogen assay, methyl-, ethyl-, propyl-, and butylparaben were all found to be weakly estrogenic with butylparaben as the most potent with an estrogenic activity which was 10,000 fold less than that of 17b -estradiol. Oral administration of parabens to immature rats showed no activity, however, subcutaneous administration of butylparaben produced a positive uterotrophic response in vivo 100,000 times less potent than 17b -estradiol. When parabens are applied to skin they are known to be metabolised by four carboxyl esterases capable of hydrolysing, the different parabens to p-hydroxybenzoic acid (Lobemeier et al. 1996). However, in vitro studies on penetration of rat skin by butylparaben and propylparaben have indicated that 4% of butylparaben and 30% of propylparaben were not hydrolysed (Bando et al. 1997). If parabens in the concentrations used in household products and cosmetics will have endocrine disrupting effects in the environment or in humans is unknown. For such an evaluation the rapid biodegradation and metabolization of the parabens should be taken into account. Human health After oral administration parabens are quickly absorbed from the gastrointestinal tract. They are hydrolyzed to p-hydroxybenzoic acid, conjugated, and the conjugate is excreted in the urine. Parabens do not accumulate in the body. Most of an administered dose can be recovered within 5 to 72 hours as p-hydroxybenzoic acid or its conjugates (CIRP 1984; Rastogi and Johansen 1993). Propylparaben was readily hydrolysed when administered orally to dogs, with peak tissue concentration 6 hrs after administration. After 48 hrs the compound was completely eliminated. The hydrolyses occurs in the liver, kidney and muscle, but not in other tissues. The metabolites excreted were 4-hydroxybenzoic acid, 4-hydroxyhippuric acid, ester glucuronides and ester sulphates (Richardson 1992-1994). Parabens are rapidly absorbed through intact skin (CIRP 1984). Toxicokinetiics and acute toxicity The lower paraben homologues have minimal acute and chronic toxicity and are therefore cleared as human diet additives (WHO 1974; Clayton and Clayton 1993; Positivlisten 1998) (Table 8.8). Table 8.8
The parabens have a low irritant potential (Clayton and Clayton 1993). The sodium salt, however, may be strongly alkaline and lead to severe irritation and corrosion damage. Undiluted methylparaben was tested with the Draize skin irritation technique using rabbits. Mild skin irritation was observed (CIRP 1984). A 5% concentration of butylparaben caused mild irritation in guinea pigs (Richardson 1992-1994). Pure methylparaben was slightly irritating when instilled into the eyes of rabbits (CIRP 1984). Sensitization Parabens are not strong sensitizers. The incidence of sensitivity induced primarily by parabens is extremely small (Cronin 1980). The skin allergenic qualities of parabens appear to be apparent primarily if they come into contact with damaged skin by e.g. eczema. Normal skin is affected to a lesser degree (Fisher 1986; Rastogi and Johansen 1993). Particularly medicinal liniments and creams preserved with parabens cause a certain frequency of contact eczema. This is due to the fact that the products are applied to damaged skin which is more vulnerable to sensitizing substances. However, the number of cases of contact allergic eczema in relation to the widespread exposure is low. Many paraben-sensitive individuals tolerate paraben-containing cosmetics provided the product is applied to normal skin not subjected to a dermatitis in the past. This is called the "paraben paradox" (Fisher 1979). Paraben hypersensitivity has been reported in a number of cases (Schamberg 1967; Henry et al. 1979; De Groot et al. 1986; Cooper and Shaw 1998; Carradorri et al. 1990). In a period from 1985-1997, a total of 8,521 patients were tested in a contact allergy clinic. Anti-microbials were tested for allergic contact dermatitis and sensitivity to parabens had a frequency 0.8% and was thus the seventh most frequent anti-microbial allergen in this study (Goossens et al. 1997). In another study a paraben mixture in 5% petrolatum was used in a comparison between the frequency of sensitization in healthy subjects and in patients with dermatitis. In 2,150 patients, 1.01% were sensitized with the paraben-mix, and 0.67% of 593 healthy volunteers were sensitized (Seidenari et al. 1990). Chronic toxicity The chronic toxicity of methylparaben and propylparaben was tested in white rats. The rats were fed diets containing 2 and 8% each of methylparaben or propylparaben for 96 weeks. Only mild growth retardation was observed at 8% levels (Furia 1972). Dogs fed 700 mg propylparaben /kg body weight/day for 90 days suffered no ill effects. Growth retardation occurred when rats were fed 1,600 mg propylparaben/kg/day (Richardson 1992-1994). Mutagenicity and carcinogenicity Numerous in vitro mutagenicity studies indicate that parabens are non-mutagenic (CIRP 1984). Butyl paraben and ethylparaben were tested in Salmonella/microsome assay (Ames test) and chromosomal aberrations assay in vitro using a Chinese hamster fibroblast cell line. No mutagenic potential was observed in either of the tests (Ishidate et al. 1984). Methylparaben was tested for mutagenic activity in Salmonella typhimurium strains and was found negative (Prival et al. 1982). No evidence of tumorigenic effects were seen in a 2 year study at doses up to 0.06% of butylparaben by oral administraton to mice (Inai et al. 1985). Reproductive toxicity Teratogenic studies on methylparaben were negative (CIRP 1984). Classification Parabens are not included in Annex 1 of list of dangerous substances of Council Directive 67/548/EEC. The highest allowed concentration of parabens in cosmetics is 0.4% for one type of paraben and 0.8% for paraben mixtures (Cosmetic Directive 2000). 8.3 Nitrosubstituted compoundsTwo nitrosubstituted substances were included in this review: 2-bromo-2-nitropropane-1,3-diol (BNPD) with the CAS No. 52-51-7 and 5-bromo-5-nitro-1,3-dioxane (CAS No. 30007-47-7). Both preservatives are used in cosmetic products, liquid soaps and cleaning agents. 8.3.1 2-Bromo-2-nitropropane-1,3-diol (Bronopol)The highest concentration allowed in cosmetics is 0.1%. Formation of nitrosamines in the presence of amines should be avoided (Cosmetic Directive 2000). BNPD reacts with iron and aluminium with some loss of microbial activity. It is quite stable about pH 5.5 and can be used with good effect at low pH values. BNPD is one of the most frequently used preservatives in cosmetics and cleaning agents in concentrations of about 0.1% or less. It is a broad spectrum preservative with a wide range of antimicrobial properties. It is active against gram positive bacteria, gram negative bacteria, fungi and yeast, and has a special effect on Pseudomonas aeruginosa. The antibacterial activity of BNPD relates to its interaction with essential thiols within the cell. In the presence of air, BNPD acts as a catalyst for the oxidation of thiol-groups to disulfides, with the rapid consumption of oxygen (DFG 1989). BNPD is a formaldehyde-releasing compound, also called a formaldehyde donor. In alkaline solution and at increasing temperature, it dissociates to form formaldehyde, bromide and nitrite. BNPD acts as an antibacterial and antifungal agent because of its intrinsic properties and not through release of formaldehyde. 0.02% BNPD in an emulsion has been reported to release up to 15 ppm formaldehyd (Storrs and Bell 1983; Ford and Beck 1986). Ecotoxicology According to the OECD criteria BNPD is not readily biodegradable. BNDP was not readily biodegradable in a closed bottle test (OECD 301D) at concentrations of 3 and 6 mg/l (Knoll MicroCheck 1996). The low biodegradability is not unexpected as BNPD inhibits the inoculum at the applied concentration in standard biodegradability tests. 14C-Labelled BNPD at 1 mg/l was partially mineralized by an inoculum, which was probably a mixture of activated sludge and soil, as indicated by a 14CO2 evolution of approximately 40% during 17 days. At day 21 over 80% of the 14C was present either as CO2 or in the biomass. BNPD was completely transformed by day 3 and one major metabolite (probably trishydroxynitromethane or 2-nitropropane-1,3-diol) was formed. However, this substance was a transient metabolite as its concentration had decreased to negligible levels by day 17 (Knoll MicroCheck 1996). No evidence confirming an ultimate biodegradation of BNPD under anoxic conditions was found in the literature. Bioaccumulation No experimental data describing the bioaccumulation potential of BNPD were found in the literature. However, due to the low log Kow value of 0.18 (Knoll MicroCheck 1996), BNPD is unlikely to accumulate in aquatic organisms. Aguatic toxicity BNPD is very toxic to aquatic organism with effect concentrations below 1 mg/l for algae and crustaceans. BNPD was not particularly toxic towards the examined fish as indicated by LC50 values between 20 and 59 mg/l (Table 8.9). Table 8.9
BNDP and its breakdown products administrated intravenously to rats and rabbits were excreted in the urine and expired air. BNPD did not accumulate in the organism. Metabolic breakdown products included 2-nitropropane-1,3-diol, which may be further metabolized to glycerol and CO2 (CIRP 1984a). When 14C –labelled BNPD was administered either orally or intravenously to rats a rapid elimination of radioactivity occurred from the body. 70-80% was excreted in urine and 6-10% in expired air during 24 hours. The highest concentration of radioactivity, 24 hours after the percutaneous application, was found in kidneys, liver and lung. No unchanged BNPD was detected in the urine samples examined. Within 24 hours approx 40% of topically applied dose of 14C-labelled BNPD was absorbed through the skin of rats. About 19% of the applied radioactivity were excreted in the urine, faeces and expired air at the end of 24 hours. The 24 hour recoveries of 14C were about 15% in the urine and about 2% in expired air of the dose applied to the skin (Buttar and Downie 1980). When BNPD was applied orally the maximum body burden was reached after 60 min. The muscle, liver and blood had the highest levels. About 86% of the applied dose is excreted during 24 hours, about 75% in the urine and about 9% as CO2 (Kujawa et al. 1987). BNPD causes gastrointestinal lesions after oral administration to rodents. BNPD is moderately toxic by oral administration (Table 8.10). Table 8.10
23 patients of 129 showed irritant reactions in patch test to 1% BNPD. 3 patients showed irritant reaction to 0.5% and 2 patients to 0.25% BNPD (Peters et al. 1983). A study of 149 eczematous patients determined that 0.25% BNPD in soft yellow paraffin caused mild irritation (Richardson 1992-1994). A 20% aqueous solution was moderately to severely irritating to abraded and nonabraded rabbit skin. Primary irritation score was 6.75 of 8.0 (maximum possible score). A 0.5% emulsion and a 0.5% solution of BNPD were not irritating after four daily applications. The irritation to nonabraded rabbit skin depends to some extent on the vehicle (CIRP 1984a). Solid BNPD and 10% and 20% aqueous solutions of BNPD placed in the eye of rabbits produced severe ocular damage, washing after application either did not reduce the reaction, or reduced it only slightly. 2% BNPD in solution and in emulsion was irritating to the rabbit eye. 4 daily applications of a 0.5% solution and emulsion or a 0.5% solution in saline was nonirritating to the eyes (CIRP 1984a; DFG 1989). Skin Sensitization After repeated intradermal injection of a 0.02% solution of BNPD followed by an application of a 15% aqueous solution of BNPD, no sensitization was observed in the guinea pig maximization test (DFG 1989). Contact sensitization was not demonstrated in any of 93 normal subjects on whose skin 5% BNPD in yellow paraffin was applied 10 times in 3 weeks (induction phase) followed by a 2 week rest period prior to challenge with 0.25% BNPD (Maibach 1977). Acute allergic contact dermatitis was reported in patients using Eucerin cream preserved with BNPD in concentration above 0.05%. The patients were BNPD patch test-positive. Eucerin is a cream used by many dermatologist in USA to patients with abnormal skin (Storrs and Bell 1983). Patients with suspected allergic contact dermatitis were tested with 13 preservatives. 2,295 patients were included. BNPD was one of the preservatives with the lowest sensitization rate of 1.2% (Perrenoud et al. 1994). 8,149 patients were patch tested with BNPD (0.5%). Reactivity was quite low, with 38 allergic reactions, corresponding to 0.47% (Frosch et al. 1990). In some cases there were indications of cross-sensitization between BNPD and formaldehyde and in others no cross-reactions were observed (Storrs and Bell 1983). Subchronic toxicity Rats tolerated oral doses (by intubation) of 20 mg BNPD/kg /day for 90 days. No other symtoms than occasional vomiting were seen. A dose of 160 mg/kg/day for six weeks in the drinking water caused reduced water intake by rats and slightly enlarged kidneys. Some deaths (2 of 80) occurred at a dose level of 300 mg/kg/day (CIRP 1984a). In 72 day feeding trial, rats receiving up to 100 mg/kg diet (corresponding to 5-10 mg/kg body weight/day) showed no ill-effects (DFG 1989). Mutagenicity and carcinogencity BNPD was not considered mutagenic in the Ames test with Salmonella typhimurium with and without metabolic activation (Bryce et al. 1978; DFG 1989). Oral administration of BNPD to rats in drinking water at doses 160 mg/kg/day for 2 years did not affect the incidence of tumors (Bryce et al. 1978). No carcinogenic effect was observed in concentration of up to 0.5% applied topically to mice 3 times pr week for 80 weeks (CIRP 1984a). BNPD is a known nitrosating agent for secondary and tertiary amines or amides. Model assays have indicated that, in the presense of secondary and tertiary amines and amides, nitrite is released during the breakdown of BNPD. This may lead to N-nitrosation of diethanolamin and formation of the carcinogenic compound N-nitrosodiethanolamine (Scmeltz and Wenger 1979; Ong and Rutherford 1980). Reproductive toxicity No effects on reproduction were observed when male rats were given 40 mg/kg body weight BNPD orally for 63 days prior to mating, or when female rats were given the same dose level 14 days prior to mating (CIRP 1984a). Dermal application of up to 2% BNPD to rats from day 6 –15 of pregnancy had no adverse effect other than local skin reactions (Bryce et al. 1978). Classification BNPD is included in Annex 1 of list of dangerous substances of Council Directive 67/548/EEC and classified as follows: Harmful (Xn) with R21/22 (Harmful by inhalation and if swalloved) and Irritant (Xi) with R37/38 (Irritating to respiratory system and skin)- R41(Risk of serious damage to eyes), N; R50/53 (Very toxic to aquatic organisms, may cause long-term adverse effects). The highest allowed concentration of BNPD in cosmetics is 0.1% according to cosmetic directive (Cosmetic Directive 2000). 8.3.2 5-Bromo-5-nitro-1,3-dioxaneEcotoxicology Information regarding degradation, bioaccumulative potential and aquatic toxicity is not available for 5-bromo-5-nitro-1,3-dioxane (CAS No. 30007-47-7). However, due to the structural similarity to 2-bromo-2-nitropropane-1,3-diol, the ecotoxicological properties of 5-bromo-5-nitro-1,3-dioxane are expected to be similar to those of 2-bromo-2-nitropropane-1,3-diol (Section 8.3). Human health 5-Bromo-5nitro-1,3-dioxane is moderately toxic for rats and mice. Significant skin and eye irritation was observed in animal studies at 0.5%, but not at 0.1% (Table 8.11). Table 8.11
1: Numbers marked with asterisk (*) are mg/kg body weight (bw). Other numbers are %. NOEC: No Observed Effect Concentration. LOEC: Lowest Observed Effect Concentration. 5-Bromo-5-nitro-1,3-dioxane was neither a sensitiser nor a photosensitiser in guinea pig studies. This ingredient was neither mutagenic nor teratogenic. Sensitisation was observed in clinical patients at 0.1 and 0.5%, but not in a study on nonclicical volunteers. 5-Bromo-5-nitro-1,3-dioxane may react with amines and amides to form nitrosamines or nitrosamides, which are considered as carcinogenic substances. Concerning cosmetic products, there are special conditions laid down for the use of this preservativ, stating that formation of nitrosamines must be avoided. As a consequence, 5-bromo-5-nitro-1,3-dioxane must not be mixed with amines and amides in cosmetic products. Further this preservative must only be used in rinse-off products, which are products intended not to remain on skin. The highest allowed concentration of 5-bromo-5-nitro-1,3-dioxane in cosmetics is 0.1%, and it is only allowed in cosmetic products which are rinsed away after use (Cosmetic Directive 2000). 8.4 Halogenated compounds8.4.1 ChloroacetamideChloroacetamide (CAS No. 79-07-2) is used as a preservative in cosmetics, pharmaceutical products, paints, glues, emulsions and as a wood preservative. It is used in concentrations of less than 1% and most often 0.2 – 0.5%. Ecotoxicology The environmental properties of chloroacetamide are scarcely described. There are no data available on the biodegradability and the potential for bioaccumulation. The log Kow was calculated to – 0.582 (EPWIN 1994) which indicates that chloroacetamide will not bioconcentrate in aquatic organisms. The 48 h-EC50 of chloroacetamide has been determined to 55.6 mg/l for Daphnia magna (CETOX 2000). Human health There are no data available on the toxicokinetics of chloroacetamide. The data concerning acute oral toxicity indicate high acute toxicity (Table 8.12). Toxicokinetics and acute toxicity Table 8.12
The skin irritancy response of a 0.2% solution of chloroacetamide in water was tested in 25 patients. The solution did not cause any reaction (Damgård Nielsen 1983). No irritation was observed when a 9% solution of chloroacetamide was applied to guinea pig as part of a sensibilization study (CIRP 1991b). Instillation of 0.1 ml of a 5% solution of chloroacetamide into the eyes of albino rabbits caused no irritation (CIRP 1991b). Skin sensitization Using a test to determine the potential to induce a sensitization reaction in humans (the Draize test) with 1.25% chloroacetamide, 35 of 205 (17%) human volunters were sensitized (Nord 1991). Several case reports have been published where sensitization to chloroacetamide is described. These reports show a strong sensitizing potential (Bang Pedersen and Fregert 1976; Wahlberg et al. 1978; Doom-Goossens 1981; DeGroot and Weyland 1986; Lama et al. 1986; Detmar and Agathos 1988; Jones and Kennedy 1988; Jelen et al. 1989; Wantke et al. 1993). Several animal studies with Guinea pigs were performed, and no sensitization was observed. The concentration range was 0.07 – 9% (CIRP 1991b). Subchronic toxicity Four groups of rats were exposed to 0, 20, 100 or 500 ppm chloroacetamide in the diet for 90 days. Effects were observed at the highest dose. Increase in leucocytes, decrease in female liver weight and decrease in testicular weight were seen (CIRP 1991b). Mutagenecity and carcinogenecity Chloroacetamide in solution (70% and 30% sodium benzoate) was nonmutagenic in gene mutation and chromosomal aberration assays (CIRP 1991b). Reproductive toxicity Pregnant rats were tested at dose levels of 20 mg/kg chloroacetamide on single days (7th, 11th or 12th ) and no effects on litter size or fetuses and no effect on dams were observed (Thiersch 1971; Shepard 1995). A subacute study indicate that chloroacetamide with a dose level of 50 mg/kg body weight has an effect on the male reproductive function, when dosed orally repeatedly in a 90 days study (CIRP 1991b). Dosing 50 mg/kg chloroacetamide to rats on day 13 and 14 of gestation resulted in the postnatal death of approx. half of the embryos. Surviving offspring developed normally (Kreybig et al. 1969). Classification Chloroacetamide is included in Annex 1 of list of dangerous substances of Council Directive 67/548/EEC and classified as follows: Reprotoxic category 3 (Rep 3) with R62 (Possible risk of impaired fertility), Toxic (T) with R25 (Toxic if swallowed) and Irritant with R43 (May cause sensitization by skin contact). 0.1% < C < 3%: Xi; R43 The highest allowed concentration of chloroacetamide in cosmetics is 0.3% and the mandatory warning text on the label is "contains chloroacetamide" (Cosmetic Directive 2000). 8.4.2 5-Chloro-2-(2,4-dichlorophenoxy) phenol (Triclosan)5-Chloro-2-(2,4-dichlorophenoxy) phenol (Triclosan) with the CAS No. 3380-34-5 is used in surgical scrub preparations, medicated cosmetics, deodorants, body, and hand preparations, moisturing preparations, cleansing products, bath soaps, detergents, skin care preparations, powders, eye makeup, aftershave etc. (Wenninger and McEwen 1997) Ecotoxicology Residues of methyl triclosan (4-Chloro-1-(2,4-dichlorophenoxy)-2-methoxybenzene) have been reported in rivers, industrial wastewater, and aquatic biota. The concentrations of methyl triclosan ranged from 1-38 m g/kg body weight in the freshwater fish topmouth gudgeon in Tama River, whereas 1-2 m g/kg body weight was found in the goby fish (A. flavimanus) and 3-20 m g/kg body weight was found in clam, oyster, and mussels in Tokyo Bay. The highest levels reported in Tokyo Bay (20 ppb) were measured in the blue mussel Mytilus edulis (Miyazaki et al. 1984). Triclosan was not biodegraded (0% ThOD) after 4 weeks in a standard test for ready biodegradability at concentrations of 30 and 100 mg/l (MITI 1992). Triclosan would be expected to bioaccumulate in aquatic organisms on the basis of its log Kow of 4.76. However, a bioaccumulation study over 8 weeks with fish has shown relatively low BCF values between 2.7 and 90 (MITI 1992). The acute aquatic toxicity of Triclosan has been determined to 0.39 mg/l for Daphnia magna (48 h-EC50) and to 0.25 mg/l for fathead minnow (Pimephales promelas) (96 h-LC50) (Office of Pesticide Programs 1995). Human health Triclosan has shown not to be toxic by oral administration, and has not acted as a carcinogen, mutagen or teratogen (Table 8.13). Direct contact with the material under exaggerated exposure conditions has been reported to cause dermal irritation in laboratory animals. Triclosan has rarely been associated with skin irritation or sensitisation in humans in formulated products (Bhargava and Leonard 1996). Table 8.13
1: Numbers marked with * are mg/kg body weight (bw). Other numbers are %. NOEC: No Observed Effect Concentration, LOEC: Lowest Observed Effect Concentration A few investigations of allergic contact dermatitis to Triclosan have been reported when used in cosmetic products (e.g., deodorants). Daize testing showed a low sensitising potential to Triclosan (Fisher 1986). The highest allowed concentration of Triclosan in cosmetics is 0.3% according to the cosmetic directive (Cosmetic Directive 2000). 8.4.3 MethyldibromoglutaronitrileMethyldibromoglutaronitrile (CAS No. 35691-65-7) is used in hair shampoos, hair conditioners, hair preparations, bubble baths, indoor tanning preparations, face and neck preparations, permanent waves and all types of blushers. Ecotoxicology Methyldibromoglutaronitrile has been shown to be readily biodegradable in a standard OECD screening test (CTFA 1997). The log Kow was determined to 1.022 and the potential for accumulation of methyldibromoglutaronitrile in aquatic organisms is thus regarded as low. The toxicity of methyldibromoglutaronitrile has been determined towards algae, crustaceans, and fish with the following effect values determined: Fish (96 h-LC50), 1.75-8.3 mg/l; daphnia (48 h-EC50), 2.2 mg/l; and algae (72 h-EC50), 0.15 (CTFA 1997). The highest allowed concentration of methyldibromoglutaronitrile in cosmetics is 0.1% according to the cosmetic directive (Cosmetic Directive 2000). 8.5 Other preservatives8.5.1 1,3,5-Triazine - 1,3,5 (2H,4H,6H)-triethanol (THT) (Grotan)1,3,5-Triazine - 1,3,5 (2H,4H,6H)-triethanol (THT) with the CAS No. 4719-04-4 is a formaldehyde-releasing preservative which is primarily used for industrial applications, e.g. as a bacteriocide in cooling oils. The triazine-group releases formaldehyde. Ecotoxicology The environmental fate and effect of THT are only sparsely described. There were no experimental data that describe the biodegradation and bioaccumulation potential of THT. However, on the basis of a log Kow value of –4.67 which was calculated by use of QSAR estimation (EPWIN 1994), the potential for bioaccumulation in aquatic organism is considered to be low. The toxicity of THT towards aquatic organisms has been described for crustaceans and fish where the following LC50 values have been reported: Bluegill sunfish (Lepomis macrochirus) adults, 44.8 mg/l and fingerlings, 27.0 mg/l; rainbow trout (Oncorhynchus mykiss); 67.3 mg/l; mud crab; 72.6 mg/l; and grass shrimp (Palaemonidae sp.), 147.0 mg/l. The duration of the exposure periods was not indicated (RTECS 1997). Human health There were no data on the toxicokinetics available. By oral administration THT is of moderate acute toxicity (Table 8.14). Toxicokinetics and acute tixicity Table 8.14
Higher concentration of THT can cause irritation, as is demonstrated by the results of Danish dermatologists. Of 694 patients who underwent a skin test with a 2% or 5% aqueous solution of THT, 13% developed skin irritation (Roed Pedersen 1977). Skin irritation or other skin changes are generally not observed during occupational exposure with THT. Irritation may develop at higher concentrations (> 1%), especially in persons with sensitive skin or eczema. Prolonged and frequent skin contact can result in skin damage and even eczema. The severity of the reaction seems to depend on the concentration, and the high pH seems to be important in this context (MAK 1995). THT caused transient irritation in rabbit eye, but eyes recovered after 96 hours (Rossmoore 1981). Skin sensitization There is disagreement as to the sensitizing potential of THT, if it is a strong or weak sensitizer. Numerous studies with concentrations up to 1% and more yielded negative results, but some revealed positive reactions, mostly on persons with eczema - at concentrations below 0.5% (Rycroft 1978; Ketel and Kirch 1983; De Groot et al. 1986; Fisher 1986; Veronesi et al. 1987). 4 of 19 men with occupationally derived soluble oil dermatitis reacted positively to patch testing with 0.2% Grotan BK. However, when re-patch tested about a year later, with no contact with the allergen occurred, only 1 reacted to 0.2%, 1 reacted to 1% and the last 2 men did not react to 0.1-5% (Keczkes and Brown 1976). 230 metal workers with occupational dermatitis were patch tested with 1% THT. 16 subjects (6.9%) were sensitized (Alomar et al. 1985). In studies on sensitization with THT using the guinea pig maximization test it has been observed that the sensitization frequency increases with increasing concentration. THT was applied in 3 concentrations: 1.0, 0.5 and 0.1%. Four of twenty animals were sensitized at 1% THT (Andersen et al. 1984). Mutagenicity and carcinogenicity THT was tested for mutagenicity (chromosome abnormalities) in micronucleus test. THT was administered by intragastric intubation, dermal application or subcutaneous injection. Bone marrow preparations were screened for the presence of micronucleated cells in polychromatic erythrocytes. Doses administered were 15, 60, 240 or 960 mg/kg body weight. THT did not show any detectable mutagenic activity in the micronucleus test (Urwin et al. 1976). As part of a testing programme this component was tested in the Ames test with S. typhimurium strains. A positive response was observed in some of the strains (Mortelmans et al. 1986). No carcinogenicity studies were available. Classification THT is included in Annex 1 of list of dangerous substances of Council Directive 67/548/EEC and classified as follows: Harmful (Xn) with R22 (Harmful if swalloved) and Irritant (Xi) with R43 (May cause
sensitization by skin contact). 8.5.2 FormaldehydeFormaldehyde (CAS No. 50-00-0) is a colourless gas and mostly marketed as aqueous solution with typical content of 37-50%, stabilized with 10-15% methanol to prevent polymerisation (Flyvholm 1997). Formaldehyde is frequently used as preservative in concentrations of about 0.1% in cosmetics and cleaning agents. Formaldehyde is added to the product or generated in the product from formaldehyde releasers. BNPD is an example of a formaldehyde releaser, with concentrations in cosmetics of 0.01-0.1%, and it can release up to 75 ppm formaldehyde in the product. Quaternium 15 (methanamine –3-chloroallylochloride) is another formaldehyde releaser. The concentrations of Quaternium-15 in products are between 0.02-0.3% and it can release up to 300 ppm formaldehyde in the product (Flyvholm and Menné 1992). The use of formaldehyde as a preservative is small in amounts compared with other applications of formaldehyde (Flyvholm 1997). Ecotoxicology The biodegradability of formaldehyde has been determined according to BOD5 methods (DIN 38409) by which a degradation of 97.4% and > 60% was determined (IUCLID 2000). The log Kow of formaldehyde has been reported to -0.78 (IUCLID 2000), and hence, the potential for accumulation in aquatic organism is considered to be low. A number of studies have been performed for determination of the toxicity of formaldehyde towards aquatic organisms. Some of the effect concentrations are given in Table 8.15. Table 8.15
Formaldehyde can enter the body through skin and by ocular contact, inhalation and ingestion. It does not accumulate in the body. Formaldehyde disappears rapidly in the bloodstream because of condensation reactions with DNA, protein, amino acids, as well as by oxidation to CO2. The liver and erythrocytes appear to be primary sites of rapid oxidation of formaldehyde to the nontoxic chemical formate, which is excreted in the urine, and to CO2, which is exhaled. Almost every tissue in the body has the ability to break down formaldehyde. Numerous enzymes (e.g. formaldehyde dehydrogenase) can catalyze conversion to formate, which is further metabolized to CO2 and water. Formate is a normal metabolite in mammalian systems (CIRP 1984b; Richardson 1992-1994). Formaldehyde is characterized by a high acute toxicity by oral administration (Table 8.16). Table 8.16
No significant irritant effects on the skin were noted following exposure to a 1% aqueous solution of formaldehyde. Liquid formaldehyde may irritate the skin, causing a rash or burning feeling on contact. It can also cause severe burns, leading to permanent damage, depending on the concentration (CIRP 1984b). Formaldehyde may in some individuals be mildly irritating to the eyes in airborne concentrations down to 0.01 ppm (Arbejdstilsynet 1991). Aqueous solutions of formaldehyde accidentally splashed into the eyes have caused severe injuries. Ocular irritation is observed in animals exposed to formaldehyde vapour at concentrations of 15 ppm (CIRP 1984b). The most important exposure of formaldehyde is through inhalation. Upper airway irritation to formaldehyde vapour occurs at 0.1-25 ppm. Lower airway irritation is reported at 5-30 ppm (CIRP 1984b). Sensitization Formaldehyde may cause allergic asthma. Formaldehyde is a relatively strong contact allergen and contact allergy may develop after contact with products, which contain less than 1% formaldehyde (Arbejdstilsynet 1991). Subchronic and chronic toxicity Chronic studies with rats given formaldehyde in drinking water showed adverse effects in the animals receiving the highest dose (about 100 mg/kg of body weight). The effects were a.o. low body weight and pathological changes in the stomach (Til et al. 1989; Tobe et al. 1989). Reproductive toxicity No teratogenic effects were seen in mice given formaldehyde orally, in an aqueous solution containing about 0.2% formaldehyde, on day 6-15 of gestation. The oral doses were 74, 148, 185 mg/kg body weight. No effects on fetus size and no skeletal or visceral abnormalities were observed. Neither was any teratogenic effect of formaldehyde observed in mice in inhalation studies (Marks et al. 1980). No effects on reproductive performance or on the health of the offspring were observed in beagle dogs exposed to formaldehyde via the diet on day 4-56 after mating. The concentration administered was 125 or 375 ppm formaldehyde (Hurni and Ohder 1977). Sperm abnormalities and inhibition of spermatogenesis has been observed in rat studies with doses administrated 100-200 mg/kg body weight (WHO 1996). Pregnant hamsters were treated with a 37% aqueous formaldehyde solution to evaluate the embryotoxic effects of topical exposure on day 8, 9,10, and 11 of gestation. No treatment related malformation or significant effects on fetal weight and length were seen (Overman 1985). Mutagenicity and carcinogenicity Formaldehyde increased the number of micronuclei and nuclear anomalies in epithelial cells in rats by oral administration (Migliore et al. 1989). There is little evidence that formaldehyde is carcinogenic by oral route. Though exposure to formaldehyde by inhalation gives an increased incidence of carcinomas of the nasal cavity in rats and mice at doses that caused irritation of the nasal epithelium (WHO 1996; Kerns et al. 1983). The International Agency for Research on Cancer (IARC) concluded that there is limited evidence for the carcinogenicity to humans and sufficient evidence for carcinogenicity in experimental animals. IARC has placed formaldehyde in group 2A (probably carcinogenic to humans) (IARC 1995). Epidemiologic studies of cancer risk and formaldehyde have shown no convincing evidence of a relationship (ECETOC 1995). Formaldehyde is included in the list of carcinogenic components of the Executive Order on precautions to prevent cancer risk issued by the National Working Environment Authority (Executive Order 1999). Classification Formaldehyde is included in Annex 1 of list of dangerous substances of Council Directive 67/548/EEC and classified as follows: Toxic (T) with R23/24/25 (Toxic by inhalation, in contact with skin, and if swallowed), Corrosive (C) with R34 (Causes burns) and Carc3, R40 (Possible risk of irreversible effects) and R43 (May cause sensitization by skin contact). 0.2% < C < 1% Xi; R43 The highest allowed concentration of formaldehyde in cosmetics is 0.2%, except for products for dental hygiene where the concentration allowed is 0.1%. The concentration is expressed as free formaldehyde. The mandatory warning text "contains formaldehyde" must be placed on the label if the content of formaldehyde is more than 0.05% in the product (Cosmetic Directive 2000). The Danish occupational threshold limit value is 0.4 mg/m3 (Arbejdstilsynet 2000). 8.5.3 DiazolidinylureaEcotoxicology The environmental fate and effect of diazolidinylurea (CAS No. 78491-02-8) has only been scarcely examined. Diazolidinylurea is not readily biodegradable as only 24% ThCO2 was attained in a standard laboratory test, OECD 301B (CETOX 2000). According to a QSAR estimation (EPIWIN 1994) the log Kow of diazolidinyl urea is –7.49 which implies that the potential bioaccumulation in aquatic organisms is expected to be low. The toxicity of diazolidinylurea has been examined in test with fish (species not indicated) and Daphnia magna where LC50 and EC50 (48-h) were determined to > 100 mg/l and 35 mg/l, respectively (CETOX 2000). The highest allowed concentration of diazolidinglurea in cosmetics is 0.5% according to cosmetic directive (Cosmetic Directive 2000). 8.5.4 Sodium hydroxymethylglycinateEcotoxicology Only very few data were found describing the fate and effects of sodium hydroxymethylglycinate (CAS No. 70161-44-3). There are no data available describing the biodegradability of sodium hydroxymethylglycinate. According to a QSAR estimation (EPIWIN 1994) log Kow is –3.41. The potential of bioaccumulation in aquatic organisms is thus regarded as being low. The toxicity of sodium hydroxymethylglycinate has been examined in tests with fish (species not indicated) and Daphnia magna where LC50 and EC50 (48-h) were determined to 94-100 mg/l and 26.5 mg/l, respectively (CETOX 2000). The highest allowed concentration of sodium hydroxymethylglycinate in cosmetics is 0.5% according to cosmetic directive (Cosmetic Directive 2000).
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