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Toxicological Evaluation and Limit Values for 2-Ethylhexyl acrylate, Propylene carbonate, Quaternary ammonium compounds, Triglycidyl isocyanurate, and Tripropyleneglycol diacrylate

Evaluation of health hazards by exposure to

Quaternary ammonium compounds

(Cationic surfactants) and estimation of a limit value in air.

Inger Thorup

The Institute of Food Safety and Toxicology
Danish Veterinary and Food Administration

1 General description

1.1 Identity

Quaternary ammonium compounds (QACs) are cationic surfactants. They are synthetic organically tetrasubstituted ammonium compounds, where the R substituents are alkyl or heterocyclic radicals. A common characteristic of these synthetic compounds is that they have one long-chain hydrophobic alkyl group. The products used in the technical field are normally not distinct individual compounds, but mixtures of homologues, in which the average chain length and the distribution of chain lengths in the lipophilic parts of the molecules may vary according to the starting materials used. The most well investigated compound is benzalkonium chloride.

In 1988, EPA suggested the QACs clustered into four groups, so that the toxicity studies would be facilitated by selecting one representative from each group for testing (Merianos 1991).

Below is given the structural formula for one representative of each of the four groups:

Group I: Straight-chain alkyl or hydroxyalkyl QACs

(e.g. CAS no.124-03-8, Hexadecyl ethyl dimethyl ammonium bromide; CAS no. 1119-97-7 , Tetradecyl trimethyl ammonium bromide; CAS no. 57-09-0, Hexadecyl trimethyl ammonium bromide; CAS no. 112-03-8, Octadecyl trimethyl ammonium chloride; CAS no. 1120-02-1, Octadecyl trimethyl ammonium bromide); CAS no. 1119-94-4, Dodecyl trimethyl ammonium bromide.)

Hexadecyl trimethyl ammonium bromide (CTAB)

Group II: Alkyl dimethyl benzyl ammonium compounds

(e.g. CAS no. 139-08-2, Tetradecyl dimethyl benzyl ammonium chloride (Benzalkonium chloride); CAS no. 122-18-9, Hexadecyl dimethyl benzyl ammonium chloride.)

Tetradecyl dimethyl benzyl ammonium chloride (benzalkonium chloride)

Group III: Alkyl [di- and tri- chlorobenzyl] dimethyl ammonium compounds

Tetradecyl dimethyl dichlorobenzyl ammonium chloride

Group IV: Heterocyclic ammonium compounds

1-Hexadecylpyridinium chloride (cetylpyridinium chloride)

1.2 Physical / chemical properties

QACs are white, crystalline powders. Low molecular weight QACs are very soluble in water, but slightly or not at all soluble in solvents such as ether, petrol and benzene. As the molecular weight and chain lengths increases, the solubility in polar solvents (e.g. water) decreases and the solubility in non-polar solvents increases.

References: Gloxhuber (1974), Gosselin (1984), Kirk-Othmer (1985), Merianos (1991).

1.3 Production and use

QACs are synthesised industrially by alkylation of tertiary amines with alkyl halides or other alkylating species.

QACs are used as antiseptics, bactericides, fungicides, sanitisers, and softeners, but are also used in deodorants and as conditioning agents in hair cosmetics. The compounds are normally applied in concentrations between 0.01 and 1%. Concentrations in the low range are used in pharmaceutical products as topical antiseptics (skin, conjunctivae and mucous membranes). Benzalkonium chloride is a common used preservative in ophthalmic and nasal solutions.

In general, QACs within the field of antiseptics etc. contain alkyl chain lengths in the range C8 to C16 as these show good antimicrobial activities. For the use as softeners and hair conditioning agents chain lengths between C16 to C18 are used. The QACs are most effective against micro-organisms at neutral or slightly alkaline pH and become virtually inactive below pH 3.5. They are incompatible with anionic detergents such as soap, and demonstrate a high degree of binding to non-ionic surfactants.

References: Gosselin (1984), Kirk-Othmer (1985), Merianos (1991), MST (1991).

1.4 Environmental occurrence

QACs are synthetic compounds and therefore not naturally occurring substances.

Levels of 1-5 mg QACs/litre in the water influx at sewage plants have been measured in Europe and USA (MST 1991).

1.5 Environmental fate

A major part of the QACs is discharged into wastewater and removed in the biological processes of sewage treatment plant. A 90% reduction of the QACs in the water phase of sludge has been reported and alkyl di-/ trimethyl ammonium and alkyl dimethyl benzyl ammonium compounds seem almost completely degraded in sewage sludge.

However, the aerobic and anaerobic biodegradability of QACs is not well investigated. Only sparse data are available concerning stability, solubility and biodegradability. In general, it seems that the biodegradability decreases with increasing numbers of alkyl chains: R(CH3)3N+ > R2(CH3)2N+ > R3(CH3)N+ . Within each category the biodegradability seems inversely proportional to the alkyl chain length. Heterocyclic QACs are less degradable than the non-cyclic.

Investigations have shown that bioaccumulation of considerable dimensions will probably not take place. (MST 1991).

1.6 Human Exposure

The general population are exposed to QACs directly through their use in disinfectants, hair conditioning agents and fabric softening agents, and indirectly through food stuffs due to the use to clean food contact surfaces.

 

2 Toxicokinetics

2.1 Absorption, distribution and elimination

Oral intake

Rats received orally 14C-labeled hexadecyl trimethyl ammonium bromide (CTAB, group I). About 80% of the dose of radioactivity was found in the gastrointestinal tract 8 hours after the administration, only small amounts were found in the blood plasma and about 2% of the administrated radioactivity was excreted in the bile during the first 12 hours after treatment. The low levels of radioactivity in the plasma and bile, together with the large amount of radioactivity found in the gastrointestinal tract indicated poor intestinal absorption of CTAB. Only small amounts of radioactivity were found in the liver, kidneys, spleen, heart, lung and skeletal muscles. Within three days of ingestion 92% of the radioactivity was excreted via the faeces and 1% via urine. (Isomaa 1975a).

Intraperitoneal application

Intraperitoneal injections of 14C-labeled CTAB to bile-duct cannulated rats showed that after 24 hours 36% of the radioactivity was excreted in the bile and 1% in the urine. The study indicated that CTAB was subjected to metabolic transformation, but the metabolites were not identified. (Isomaa 1975a).

After i.p. injections to pregnant rats small amounts of the compound could be detected in placenta and foetus (Anon. 1976).

Dermal, mucosal and eye application

Benzalkonium chloride was not detected in either venous blood or breast milk from woman using vaginal tampons containing 60 mg benzalkonium chloride (Bleau 1983 - quoted from Anon. 1989).

Following the instillation of a C14 benzalkonium chloride solution onto the corneal surface of rabbits, radioactivity was detected in the corneal epithelium, endothelium and stroma, and in conjunctivae. No radioactive material was found in the aqueous humour or any other tissues, including the blood (Green 1986 - quoted from Anon. 1989).

Although the absorption of QACs through normal skin probably is of less importance (Cutler & Drobeck 1970, Gosselin 1984), studies with excised guinea pig skin have shown that the permeability constants strongly depends on the exposure time and type of skin (Gloxhuber 1974) .

2.2 Toxicological mechanisms

The cationic surface active compounds are in general more toxic than the anionic and non-ionic surfactants. The positively-charged cationic portion is the functional part of the molecule and the local irritation effects of QACs appear to result from the quaternary ammonium cation.

Due to their relative ability to solubilise phospholipids and cholesterol in lipid membranes, QACs affect cell permeability which may lead to cell death. Further QACs denature proteins as cationic materials precipitate protein and are accompanied by generalised tissue irritation.

It has been suggested that the shown decrease in acute toxicity of QACs with chain lengths above C16 is due to decreased water solubility (Cutler & Drobeck 1970, Gloxhuber 1974, Gosselin 1984, Effendy 1995).

In general it appears that QACs with a single long-chain alkyl groups are more toxic and irritating than those with two such substitutions. Only the first mentioned are useful as germicides/detergents (Gosselin 1984).

The straight chain aliphatic QACs have been shown to release histamine from minced guinea pig lung tissue (Cutler & Drobeck 1970). However, studies with benzalkonium chloride have shown that the effect on histamine release depends on the concentration of the solution. When cell suspensions (11% mast cells) from rats were exposed to low concentrations, a decrease in histamine release was seen. When exposed to high concentrations the opposite result was obtained (Anon. 1989).

In addition, QACs may show curare-like properties, a muscular paralysis with no involvement of the central nervous system. This is most often associated with lethal doses (Cutler & Drobeck 1970, Merianos 1991).

 

3 Human toxicity

The toxicity of QACs in general is not well established, although several human fatalities have been ascribed to them. Far from all of the compounds have been put through toxicological investigation and specific investigations are used to characterise the toxicological properties of the QACs. As mentioned before, the QACs has been clustered into four groups (Merianos 1991), so that the toxicity would be facilitated by selecting one member from each group for testing.

The major part of the present data refer to investigation on benzalkonium chloride/alkyl dimethyl benzyl ammonium chloride which belong to group II. In the literature the generic term alkyl dimethyl benzyl ammonium chloride is often used as a general term for benzalkonium chloride.

3.1 Short term/single exposure

At least 10 human fatalities (9 adults and one child) implicating QACs are medically recorded as resulting from alkyl dimethyl benzyl ammonium chloride (C8-C18) solutions of 10 to 15% that were introduced into the victims via oral ingestion, intramuscular, intravenous or intrauterine instillation (Gleason 1969 - quoted from Merianos 1991).

Inhalation

Five deep breaths of benzalkonium chloride (4 mg/ml in 0.9% sodium chloride, nebulised) caused constrictions of the airways in asthmatic persons. The mechanism of this effect is unclear, but it was not considered by the investigators to be an allergic response. (Miszkiel 1988).

Oral intake

Ingestion of 100-400 mg/kg b.w. of alkyl dimethyl benzyl ammonium chloride (10-15% solutions) caused rapid death within a few minutes to three hours in five persons. Superficial necrosis of mucous membranes was seen in the upper alimentary tract and erosion, ulceration and petecchial haemorrhages were seen throughout the small intestine. Severe changes were seen in the liver, kidneys and heart. Even in the case of prompt death lesions were seen in these organs. In addition glottic and pulmonary oedema was reported. (Cutler & Drobeck 1970, Gosselin 1984).

In humans poisoning paralysis is not a well established phenomenon. However, curare-like paralysis was reported in three persons poisoned with dimethyl benzyl ammonium chloride (benzalkonium chloride). (Gosselin 1984).

Dermal application skin irritation

From human testing of different QACs the generalised conclusion is obtained that all the compounds investigated to date exhibit similar toxicological properties.

It has been concluded that the maximum concentration that did not produce irritating effect on intact skin is 0.1%. Irritation became manifest in the 1-10% range. Concentrations below 0.1% have caused irritation in persons with contact dermatitis or broken skin. (Anon. 1989, BIBRA 1989, Cutler & Drobeck 1970, Merianos 1991).

Sensitisation

Topical mucosal application of QACs may produce sensitisation. Reports on case stories and patch test have shown that compounds such as benzalkonium chloride (group II), cetalkonium chloride (group II) and cetrimide (group I) may possibly act as sensitisers (Anon. 1989, BIBRA 1989, Cronin 1980, Cutler & Drobeck 1970, Merianos 1991). However, in general it is suggested that QACs have a low potential for sensitising man (Cronin 1980).

In several studies patients from dermatological clinics have been patch tested with 0.1% benzalkonium chloride (according to standard international procedures). It was shown that the compound was able to induce skin sensitisation in about 0.5-5.5 % of the patients. (Camarasa 1979 - quoted from Anon. 1989, Fuchs et al. 1993, Perrenoud et al. 1994, Schnuch et al.1998).

In patch studies carried out in the general population and in healthy volunteers, no sensitivity to 0,1 % benzalkonium chloride was detected (BIBRA 1989, Lovell 1992 – quoted from Anon. 1989).

It is difficult to distinguish between an allergic and an irritative skin reaction due to the inherent skin irritating effect of QACs.

Mucous membranes and eye

A 0.1% benzalkonium chloride instilled into the eye produced burning and stinging reactions. In general, a 0.02% solution seems without irritating effect. A few cases of unpleasant reactions have been reported at this concentration, however only conjunctival redness and not corneal damage has been described. 0.01% did not cause any damage. (BIBRA 1989, Anon. 1989).

Intrauterine instillation of alkyl dimethyl benzyl ammonium chloride in the range of 5-15 mg /kg/b.w. (10-15% solutions) has lead to death (Gosselin 1984).

Intramuscular or intravenous administration

Intramuscular or intravenous administration of 5-15 mg alkyl dimethyl benzyl ammonium chloride /kg/b.w. (10-15% solutions) caused death.

In total five deaths are reported due to intramuscular, intravenous or intrauterine administration. Three of the persons who received intravenous injections died within 21-46 hours. Another person survived for 15 days (Gosselin 1984).

3.2 Long term/repeated exposure

Inhalation

A group of 196 farmers (with or without respiratory symptoms) were evaluated for the relationship between exposure to QACs (unspecified, exposure levels not given) and respiratory disorders by testing for lung function and bronchial responsiveness to histamine. After histamine provocation statistically significant associations were found between the prevalence of mild bronchial responsiveness (including asthma-like symptoms) and the use of QACs as disinfectant. The association seems even stronger in people without respiratory symptoms. (Vogelzang et al. 1997).

Oral intake

No data have been found.

Dermal application

No data have been found.

3.3 Reproductive / developmental effects

No data have been found.

3.4 Genotoxic effects

No data have been found.

3.5 Carcinogenic effects

No data have been found.

 

4 Toxicity, animal data

The toxicological data available for most of the QACs are limited (see 3 - Human toxicity). However, studies have been performed on some of the widely used compounds. The most investigated QACs belong to group II as particularly benzalkonium chlorides have been studied.

4.1 Short term/single exposure

The acute toxicity of QACs varies with the compound and, especially, the route of administration. For some substances the LD50 value is several hundreds times lower by the i.p. or i.v. than the oral route, whereas toxicities between the congeners only differ in the range of two to five times.

At least some QACs are significantly more toxic in 50% dimethyl sulfoxide than in plain water when given orally (Gloxhuber 1974, Merianos 1991, Gosselin 1984).

Probably all common QAC derivatives produce similar toxic reactions, but as tested in laboratory animals the oral mean lethal dose varies with the compound between the approximate limits given below (Merianos 1991, Gosselin 1984).

Inhalation

Wistar rats were exposed to an alkyl dimethyl ethyl benzyl ammonium compound at a concentration of 5.4 mg/litre (maximum attainable) for one hour. This concentration lead to 100% death. (Levenson 1965- quoted from Cutler & Drobeck 1970).

Recently, a whole-body inhalation study on cetylpyridinium chloride has been reported. This is a heterocyclic QAC belonging to group IV. Groups of five rats per sex were exposed to air containing 0, 0.05, 0.07, 0.13 and 0.29 mg cetylpyridinium chloride dust/l for four hours (equal to 50, 70, 130 and 290 mg dust/m3). The particle size was less than 5 µm. The LC50 was 0.09 mg/l (90 mg/m3) with upper and lower 95% confidence limits at 0.13 and 0.07 mg/l respectively. Deaths occurred in all treated groups (2/10, 1/10, 8/10 and 10/10). No deaths were seen among controls and all the deaths occurred within 4 days of exposure. Nasal discharge and chromodacryorrhoea (red discoloration around the nares) was found in all exposed groups and during the first week transient laboured breathing/respiratory difficulty (most pronounced at the higher exposure levels) was seen. The remaining animals were killed after 14 days. Besides lesions in the eyes (see below), no gross lesions attributed to the treatment were seen in these animals. Histopathological examination of lungs and other major organs were not carried out. (Lin 1991). The author has calculated that the total cetylpyrimidinium chloride exposure at the LC50 level (0.09 mg/l) was about 4-8 mg/kg b.w. and based upon this it was inferred that cetylpyrimidinium chloride could be more toxic by inhalation exposure than by oral or dermal exposure.

Oral administration LD50

LD50 values for QACs have been reported within the range of 250-1000 mg/kg for rats, 150-1000 mg/kg for mice, 150-300 mg/kg for guinea pigs and about 500 mg/kg b.w. for rabbits and dogs (Cutler & Drobeck 1970, Gloxhuber 1974, Anon. 1976). The ranges observed reflect differences in the study designs of these rather old experiments as well as differences between the various QACs.

The oral route of administration was characterised by delayed deaths, gastrointestinal lesions and respiratory and central nervous system depression. It was also found that given into a full stomach, the QACs lead to lower mortality and fewer gastrointestinal symptoms. This support the suggestion of an irritating effect. (Cutler & Drobeck 1970, Gloxhuber 1974, Merianos 1991, Gosselin 1984, BIBRA 1989).

In an attempt to elucidate the relationship between structure and toxicity of QACs, various homologues alkyl dimethyl benzyl ammonium chloride (C8-C19) were investigated with respect to LD50 in mice. The results indicated that increasing chain length beyond C16 decreased the acute toxicity markedly and that even numbered members appeared to be more toxic than those with odd numbered carbon chains. It was suggested that the decrease in toxicity above C16 was due to decreased water solubility. (Cutler & Drobeck 1970).

Dermal application LD50

Only a very few LD50 data are available. For benzalkonium unspecified (group II) a LD50 at about 1500 mg/kg b.w. for rats has been reported. In mice a LD50 value at 1600 mg/kg b.w. for octadecyl trimethyl ammonium chloride (group I) and in rabbits a LD50 at 7700 mg/kg b.w. for cetylpyridinium chloride (group IV) have been obtained.

CTAB (group I) given subcutaneously to rabbits and guinea pigs lead to a LD50 at about 100 mg/kg. Unspecified alkyl dimethyl benzyl ammonium chloride (group II) applicated subcutaneously gave rise to values in the range of 60 (mice) to 400 (rats). (BIBRA 1989, RTECS 1998).

0.1, 1.5, 6.5 and 50% solutions of benzalkonium chloride were applied on the fur (0.05 ml and then rubbed in) of two strains of mice. Each dilution was applied to 8 mice. 29 of 96 mice receiving 6.5 and 50% solutions (approximately 160 and 1250 mg/kg b.w./day) died within 72 hours after the application. Weight reduction was seen in the 6.5 and 50% groups, but not at lower levels. Necropsy of animals which died revealed discoloration of the subcutis on application site and absence of content in the gastrointestinal tract. The cause of death was not apparent. (Serrano 1972 - quoted from Anon. 1989).

skin irritation

From animal testing (rabbits, guinea pigs, rats and mice) of different QACs within groups I and II the generalised conclusion is obtained that all the QACs investigated to date exhibit similar skin irritating properties. In general, the maximum concentration that did not produce effect on intact skin is 0.1%. Solutions of 0.3-5% induces reactions ranging from skin irritation (erythema) to necrosis. (Gosselin 1984, BIBRA 1989, Merianos 1991).

Sensitisation

Various protocols involving repeated dermal or intradermal applications of benzalkonium chloride and challenge with 0.01-0.3% solutions have shown that benzalkonium chloride is able to induce sensitisation in guinea pigs and mice (Anon. 1989, BIBRA 1989). Older studies performed on other QACs did not reveal any signs of sensitising effect (Cutler & Drobeck 1970).

Mucous membranes and eye

Various studies concerning toxic effect of benzalkonium chloride to the eye have been performed. Instillation of different concentrations of benzalkonium chloride solutions in the rabbit eye have revealed that microscopic changes in the corneal epithelium can be induced at levels 0.01% or more. 0.001% is without damaging effect. (Anon. 1989).

Examination of five groups I or II QACs showed that 0.063-0.125% was the "threshold irritant concentration" range. (Cutler & Drobeck 1970).

Investigation of two QACs -alkyl dimethyl benzyl ammonium chloride and cetylpyridinium chloride- showed that instillation of a 330 ppm (0.033%) solution was the maximum concentration which did not produce irritation in rabbit eyes (Whitehall 1945 - quoted from Merianos 1991).

Eye irritation due to airborne cetylpyridinium chloride (group IV) has been reported once (see 4.1, inhalation above). Groups of five rats per sex were exposed to air containing 0, 0.05, 0.07, 0.13 and 0.29 mg cetylpyridinium chloride dust/l for four hours (equal to 50, 70, 130 and 290 mg dust/m3). Eye irritation was found in one or more animals per sex in all groups, except the controls. Lesions of the cornea, iris and/or conjunctiva were found in 4/10, 4/10, 6/10 and 6/10, respectively. All the ocular lesions were reversible (Lin 1991). In general, the longer chain alkyl trimethyl ammonium compounds are less irritating to the eye than the shorter chain homologues (C18<C12) and the dialkyl dimethyl ammonium compounds are less irritating than the corresponding mono alkyl trimethyl ammonium compounds.

Other tests for mucous membrane irritation occasionally applied to study the QACs include a penile irritation test. Seven group I QACs were tested (alkyl trimethyl ammonium compounds) in such assay. Irritating effect were seen after application of a 1-10% solutions. (Cutler & Drobeck 1970).

Others

Benzalkonium chloride or benzethonium chloride (group II) was instilled in the middle ear of guinea pigs. A single application of a 0.1% the respective solutions were placed in the tympanic cavity for 10-60 minutes. After two or 9 weeks the animals were killed. For both compounds severe lesions were seen in both the middle and inner ear. The extent of the damages were related to both the duration of exposure and the length of survival after the exposure. (Aursnes 1982).

A curare-like paralysis of skeletal muscles have been ascribed to QACs, specifically benzalkonium chloride and cetyl pyrimidinium chloride. Parenteral injections in rats, rabbits and dogs have resulted in prompt but transient limb paralysis and sometimes fatal paresis of the respiratory muscles. This effect seems to be transient. (Gosselin 1984).

4.2 Long term/repeated exposure

Inhalation

An inhalation toxicity study of an aerosolised hair conditioner containing an effective benzalkonium chloride concentration at 0.1% has been carried out in rats and hamsters. 12 CD rats and 12 golden hamsters were exposed to 9.9 mg conditioner/m3 five days a week, four hours/day, for 14 weeks (9.9 mg conditioner corresponds to 9.9 µ g benzalkonium chloride/m3). Body weights, haematological and biochemistry data were recorded, and gross and histopathological examination were conducted. No changes related to inhalation of the benzalkonium chloride conditioner were seen in any of the species. (CFTA 1979 - quoted from Anon. 1989).

Oral administration rat

The most widely investigated group is the alkyl dimethyl benzyl ammonium chlorides, particularly benzalkonium chloride. Many long term studies have been carried out, however, they are all of a very old date and do not meet the requirements of today’s quality guidelines.

Osborn-Mendel rats were fed 0.063, 0.125, 0.25 and 0.5% alkyl dimethyl benzyl ammonium chloride (group II) in the diet for two years. The measured toxicity parameters were growth rate, food consumption, mortality, and gross and microscopic (at least ten tissues) pathological examination. Suppression of growth occurred even at the lowest concentration (about 63 mg/kg b.w./day). For the remaining parameters toxic effects were seen at the 0.25% level. At about this level (250 mg/kg b.w./ day) pathologic changes were reported including diarrhoea and bloating of the abdomen, brown syrupy material in the intestine, distension of the coecum and foci of haemorrhagic necrosis in the gastro-intestinal tract. All rats at the 0.5% level died within 10 weeks. (Fitzhugh 1948 – quoted from Cutler & Drobeck 1970 and BIBRA 1989).

In another two years study, however, using a larger number of animals (12/sex), levels of 0.015, 0.031, 0.062, 0.125, 0.25 and 0.5% alkyl dimethyl benzyl ammonium chloride in the diet were tested. This study revealed that alkyl dimethyl benzyl ammonium chloride at 0.125% (125 mg/kg b.w./day) in the diet did not affect the growth, food consumption, blood picture or histopathology of the treated animals. At the 0.5% level only 50% of the animals survived 50 days. The pathological findings at this level were in agreement with Fitzhugh (1948) in that diarrhoea, brown viscid contents in the upper intestinal tract and acute gastritis were observed. Histopathological investigation revealed mucosal necrosis of the gastrointestinal tract. (Alfredson 1951 - quoted from Cutler & Drobeck 1970 ).

In these long-term studies the alkyl dimethyl benzyl ammonium chloride were fed in the diet. To obviate the difficulties concerning calculation of the exact doses administered to the animals, studies with benzalkonium chloride given by gavage were carried out. Rats were given the compound at 50 and 100 mg/kg b.w./day for 12 weeks with water or milk as vehicle. The compound was well tolerated at 50 mg/kg b.w./day, but depression of weight gain was seen at 100 mg/kg b.w./day when water was used as vehicle. (Coulston 1961 - quoted from Cutler & Drobeck 1970). It is not clear if tissue examination was performed in this study.

In a rat study doses of 5, 12.5 and 25 mg benzalkonium chloride /kg b.w./day given by gavage for two years lead to decrease in body weight at the highest dose level and increased cell growth in the gastric mucosa (probably at all dose levels) (Shelanski 1949 - quoted from Cutler & Drobeck 1970 and BIBRA 1989).

CTAB (group I) was offered to 10 SD rats of each sexes in concentrations of 0.007, 0.014 and 0.032% in drinking water for one year. These concentrations were calculated to deliver doses of approximately 10, 20 and 45 mg/kg b.w./day. The compound was well tolerated at the two lowest dose levels. At the highest dose level reduction in body weight, wetting and discoloration of the fur in the ventral region, decreased relative liver weight and increased relative coecum weight were seen. No compound related haematological or gross pathologic changes were seen and no microscopic alterations were found in the wall of stomach and small intestine of treated rats. No other tissues were histopathological examined. (Isomaa 1976).

dog

Dogs fed alkyl dimethyl benzyl ammonium chloride in the diet for 15 weeks at levels of 0.031, 0.062, 0.125, 0.25, 0.5 and 1.0% showed that 0.125% (approximately 30 mg/kg b.w./day) was the level without toxic effect. At the 0.25% level decreased body weight and food consumption were seen. Dogs fed the 0.5 and 1% levels died. As in the rats, the pathological changes were restricted to the gastrointestinal tract and included haemorrhage and necrosis in the gastrointestinal mucosa. (Alfredson 1951 - quoted from Cutler & Drobeck 1970).

In another study dogs (6 animals/dose) were given doses of 12.5, 25 and 50 mg benzalkonium chloride/kg b.w./day by gavage for 52 weeks with water or milk as vehicle. The benzalkonium chloride was given as a 10% solution. Deaths occurred among dogs at the two highest dose levels, but only when water was used as vehicle. The toxic effects seen at these levels - salivation, emesis and enteritis - were most intense in the dogs given the compound in water. When water was used as vehicle, intestinal congestion and inflammation was seen even in the dogs receiving 12.5 mg/kg b.w./day. These observations were, however, regarded as minor changes. (Coulston 1961 - quoted from Anon. 1989).

guinea pig

Groups of 20 guinea pigs were given 5, 12.5 or 25 mg alkyl dimethyl benzyl ammonium chloride by gavage for one year. No overt adverse effects or cellular changes in the major organs (not further specified) were seen. (Shelanski 1949 - quoted from Anon. 1989).

The above mentioned repeated toxicity studies do not cover all the studies carried out on group I and II QACs, but include the data which seems most pertinent. For the remaining studies not described above, the reported non-toxic (unspecified) levels are within the same range -or even higher- than those stated above. (Cutler & Drobeck 1970).

Dermal application

Application (probably uncovered) of benzalkonium chloride at 10 mg/kg b.w./day or more five times per week for three months to rats caused changes in the blood picture, liver and kidney damage and changes in certain organ weights (Berezovskaya 1978 - quoted from BIBRA 1989).

In a dermal study involving 100 female Swiss mice and ten New Zealand rabbits (both males and females), half of the mice and rabbits were treated with 8.5% benzalkonium chloride and the remaining half with 17% for about 80 weeks. An untreated group consisting of 100 mice and 19 rabbits served as controls. The solutions were applied uncovered twice a week (0.02 ml) on shaved dorsal skin (mice) or ear (rabbit). The highest dose level corresponds to approximately 85 mg/kg b.w./day for mice and 0.85 mg/kg/day for rabbits. Complete necropsy was performed on each animal. Skin samples and lesions in the lung, liver, kidneys were examined microscopically. Benzalkonium chloride caused ulceration, inflammation and scarring at the application site at both dose levels. No effects were seen on survival. The study indicated lack of systemic toxicity. (Stenbäck 1977).

4.3 Reproductive / developmental effects

The toxicological data available are primarily related to benzalkonium salts. Only a few studies on other relevant QACs have been found.

Oral intake

There were no overt adverse effects on reproduction in groups of 15 rats and 10 guinea pigs given up to 25 mg benzalkonium chloride/kg b.w./ day by gavage for two generations (Shelanski 1948 - quoted from BIBRA 1989).

Pregnant rats given up to 50 mg benzalkonium chloride/kg/day by gavage from days 6-15 of pregnancy showed no evidence of foetal malformations or decrease in litter size (FDRL 1977 - quoted from BIBRA 1989).

A brief review reported maternal and embryo toxicity (unspecified) when pregnant rabbits were fed 30 mg/kg b.w./day or more of an unspecified benzalkonium salt by gavage on days 7-19 of pregnancy. No malformations were seen. (CEC 1987 - quoted from BIBRA 1989).

Dermal application

Benzalkonium chloride (0.5 ml) in concentrations up to 6.6% was applied (uncovered) to the shaved skin of rats on days 6-15 of pregnancy (6.6% corresponds to approximately. 150 mg /kg/day). The doses induced local adverse maternal reaction (skin reactions), but not systemic toxicity. No effects on litter size, post-implantation loss, litter and mean foetal weights were seen. No signs of embryotoxicity or foetal abnormalities. (Palmer et al. 1983).

Dermal exposure to up to 120 mg /kg/day of an unspecified benzalkonium salt on days 6-15 of pregnancy apparently caused no adverse effects on the foetus in rats. No further details available. (CEC 1987 - quoted from BIBRA 1989).

Dimethyl distearyl ammonium chloride (group I) (0.5 ml) in concentrations up to 9.9% or 0.5 ml trimethyl stearyl ammonium chloride in concentrations up to 2.5% was applied (uncovered) to the shaved skin of rats on days 6-15 of pregnancy (2.5 and 9.9% corresponds to approximately 60 and 250 mg /kg/day, respectively). The doses induced local adverse maternal reaction (skin reactions), but not systemic toxicity. No effects on litter size, post-implantation loss, litter and mean foetal weights were seen. No signs of embryotoxicity or foetal abnormalities. (Palmer et al. 1983).

Mucous membranes

Single doses of 0, 25, 50, 100 and 200 mg benzalkonium chloride/kg b.w. were instilled into the vagina of pregnant rats. No adverse effects on pregnancy outcome at the lowest dose level. At 50 mg/kg b.w. and above, there were decreases in the number of live pups per litter and in litter size and weight. No visceral anomalies were seen, however abnormal bone development (sternal defects), increases in early embryo/foetal death (resorptions), reduced foetal growth and slight decreases in pregnancy rate were seen at 100 mg/kg b.w. In all rats given 100 mg/kg b.w. or more vaginal inflammation was seen at necropsy. (Buttar 1985 - quoted from BIBRA 1989).

Intraperitoneal application

I.p. administration of 10.5 or 35 mg CTAB /kg b.w. to pregnant mice as a single dose increased the incidence of dead implantations and malformations, principally cleft palate and minor skeletal defects in the skull and sternum. At the high dose CTAB increased foetal mortality. As QACs are able to alter the cell permeability it was suggested by the authors, that the embryotoxic and teratogenic effects of CTAB was due to a disturbance of the functional integrity of the placenta. (Isomaa & Ekman 1975b).

4.4 Genotoxic effects

Primarily benzalkonium chloride, but also other QACs have been investigated for mutagenicity in microbial test systems.

In Ames tests using Salmonella typhimurium with and without metabolic activation no signs of mutagenicity has been observed. Negative results were also obtained in E. coli reversion and B. subtilis rec assays. However, for benzalkonium chloride also positive and equivocal results were seen in the B. subtilis rec assays. In an E. coli DNA polymerase assay benzalkonium chloride induced repairable DNA damage, which points towards a genetic damage. (Yam 1984, BIBRA 1989, Anon. 1989).

QACs have been tested in hamster and mouse cell-transformation tests with negative results (Yam 1984, BIBRA 1989, Anon. 1989).

In vivo (i.p., micronucleus test) and/or in vitro tests (mouse and hamster cell cultures) carried out with unspecified benzalkonium salts did not lead to sister chromatid exchanges or any chromosomal aberrations (BIBRA 1989, NTP – quoted from Toxline, 1995-1998).

4.5 Carcinogenic effects

A few oral and dermal carcinogenicity studies on representative QACs (from groups I and II) are available. However, they are of an earlier date and do not meet the requirements of today’s quality guidelines.

Oral intake

In a two years study rats (12-24/group) were given an alkyl dimethyl benzyl ammonium chloride in dietary levels of 0.015 to 0.5%. Only the highest level showed signs of toxic effect. The incidence of neoplasms among the treated groups was not significantly different from that observed in the control group. Only a limited number of organs were examined. (Alfredson 1951 – quoted from Cutler & Drobeck 1970 and BIBRA 1989).

Dermal contact

The tumorigenicity of benzalkonium chloride was evaluated in a dermal study involving 100 female Swiss mice and ten New Zealand rabbits (both males and females). Half of the mice and rabbits were treated with 8.5% benzalkonium chloride and the remaining half with 17% for about 80 weeks. An untreated group consisting of 100 mice and 19 rabbits served as controls. The solutions were applied uncovered twice a week (0.02 ml) on shaved dorsal skin (mice) or ear (rabbit). Complete necropsy was performed on each animal. Skin samples, grossly observed tumours, and other lesions in the lung, liver, kidneys were examined microscopically. Neither local skin tumours or systemic tumours were induced. (Stenbäck 1977).

In a well performed NTP study (1995) benzethonium chloride (group II) was investigated in rats and mice. Groups of 60 animals of each sex and species were topically administered up to 1.5 mg benzethonium chloride/kg b.w. 5 days/week for 103 weeks. The doses were administered in ethanol. There were no evidence of carcinogenic activity of benzethonium chloride in neither rats nor mice. (NTP - quoted from Toxline, 1995-1998).

 

5 Regulations, limit values

Ambient air

-

Drinking water

-

Soil

-

OELs

-

Classification

QACs in the category benzyl-C8-18-alkyldimethyl chloride are classified for acute toxicity (Xn;R21/22 - harmful in contact with skin or if swallowed), for corrosive properties (C;R34 - causes burns); and for environmental toxicity (N;R50 - dangerous for the environment; very toxic to aquatic organisms) (MM 1999).

Cosmetics

Denmark: The content of alkyl (C8-C18) dimethyl benzyl ammonium chloride and alkyl trimethyl ammonium chloride/bromide in cosmetics must not exceed 0.1% (MEM 1998).

IARC/WHO

-

USA

FDA has concluded for some QACs, that the food additive regulations should be amended to provide for the safe of use on food equipment and food contact surfaces, if the solution does not exceed 200 ppm. In this instance, safe use does not require potable water rinse (Federal Register 1969 & 1974 - quoted from Merianos 1991).

 

6 Summary

Description and use

Quaternary ammonium compounds (QACs) are cationic surfactants. They are synthetic organically tetrasubstituted ammonium compounds, where the R substituents are alkyl or heterocyclic radicals.

A common characteristic of these synthetic compounds is that one of the R’s is a long-chain hydrophobic aliphatic residue. The most well investigated compound is benzalkonium chloride.

QACs are used as antiseptics, bactericides, fungicides, sanitisers, and softeners, but are also used in deodorants and as conditioning agents in hair cosmetics. Benzalkonium chloride is a common used preservative in ophthalmic and nasal solutions. The compounds are normally applied in concentrations between 0.01 and 1%.

Environment

QACs are synthetic compounds and therefore not naturally occurring substances. A major part of the QACs is discharged into wastewater and removed in the biological processes of sewage treatment plant. A 90% reduction of the QACs in the water phase of sludge has been reported and alkyl di/trimethyl ammonium and alkyl dimethyl benzyl ammonium compounds seem almost completely degraded in sewage sludge.

Investigations indicate that bioaccumulation of considerable dimensions will not take place.

The general population are exposed to QACs directly through their use in disinfectants, hair conditioning agents and fabric softening agents, and indirectly through food stuffs due to the use as sanitising food contact surfaces.

Toxicokinetics

Studies in rats have indicated poor intestinal absorption of QACs. For CTAB 92% of the radioactivity was excreted via the faeces and 1% via urine within three days of ingestion.

Toxicity

The mammalian toxicity of QACs in general is not well established and far from all of the compounds have been put through toxicological investigations.

The major part of the present data refer to investigations on benzalkonium chloride/alkyl dimethyl benzyl ammonium chloride.

Human toxicity

A few deep breaths benzalkonium chloride (4 mg/ml in 0.9% sodium chloride, nebulised) has caused constrictions of the airways in asthmatic persons.

A group of 196 farmers were evaluated for the relationship between exposure to QACs and respiratory disorders. Associations were found between the prevalence of mild bronchial responsiveness and the use of QACs as disinfectant.

Human fatalities implicating QACs are recorded as resulting from alkyl dimethyl benzyl ammonium chloride (C8-C18) solutions of 10 to 15% (100-400 mg/kg b.w.). Erosion, ulceration and necrosis of mucous membranes was seen in the alimentary tract. Severe changes were seen in the liver, kidneys and heart.

From human dermal testing of different QACs it is concluded that all the compounds investigated to date exhibit similar toxicological properties. The maximum concentration that did not produce irritating effect on intact skin is 0.1%. Irritation became manifest in the 1-10% range. Concentrations below 0.1% have caused irritation in persons with contact dermatitis or broken skin. Concerning eye and mucosa, the level which did not cause any damage is 0.01%.

It cannot be excluded that topical mucosal application of certain QACs may produce sensitisation. 0.1 % benzalkonium chloride has been shown to lead to positive skin reaction, but in general it is suggested that QACs have a low potential for sensitising man.

Animal toxicity

Exposure to a dimethyl ethyl benzyl ammonium compound for one hour in concentrations of 5.4 mg/l air lead to 100% dead. In a study rats were exposed to air containing 0, 0.05, 0.07, 0.13 and 0.29 mg cetylpyridinium chloride dust/l for four hours (equal to 50, 70, 130 and 290 mg dust/m3) and the LC50 was estimated to 0.09 mg/l (90 mg/m3). Deaths within 4 days of exposure occurred in all treated groups. Eye irritation, nasal discharge and discoloration around the nares and transient laboured breathing/respiratory difficulty was seen in all exposed groups.

The oral LD50 values for QACs have been reported within the ranges of 250-1000 mg/kg for rats, 150-1000 mg/kg for mice, 150-300 mg/kg for guinea pigs and about 500 mg/kg b.w. for rabbits and dogs. The administration lead to deaths, gastrointestinal lesions and respiratory and central nervous system depression. Only a very few dermal LD50 data are available and the reported values are in the ranges of 1500-7700 mg/kg b.w. for mice, rats and rabbits.

From animal testing (rabbits, guinea pigs, rats and mice) of different QACs within group I and II it can be concluded that all the QACs investigated to date exhibit similar skin irritating properties. The maximum concentration that does not produce effect on intact skin is 0.1%. Solutions of 0.3-5% induces reactions ranging from skin irritation to necrosis. Studies have shown that benzalkonium chloride is able to induce sensitisation in guinea pigs and mice.

Many studies concerning toxic effect of benzalkonium chloride to the eye have been performed. Instillation of different concentrations of benzalkonium chloride solutions in the rabbit eye have revealed that microscopic changes in the corneal epithelium can be induced at levels 0.01% or more. 0.001% is without damaging effect. Eye irritation may also be induced via exposure to QACs in the air.

A 14 weeks inhalation study with an aerosolised hair conditioner containing 0.1% benzalkonium chloride (corresponding to 9.9 m g benzalkonium chloride/m3) has been carried out in rats and hamsters. No changes related to inhalation of the benzalkonium chloride conditioner were seen in any of the species.

Long term studies in rats (one and two years duration) showed that QACs in doses as low as 0.032% in drinking water (45 mg/kg b.w./day) or 0.063% in the diet (63 mg/kg b.w./day) may affect the growth of rats and cause slight gastro-intestinal disturbances. In dogs severe gastro-intestinal lesions were seen after administration of 0.25% QAC in the diet (60 mg/kg b.w./day) for 15 weeks. Concentrations at 0.5% lead to deaths among both rats and dogs. The effects observed is primarily of local nature due to irritation of surface tissues. Based upon the available studies a NOAEL at about 0.01% in drinking water/diet can be established (roughly corresponding to 15 mg/kg b.w.). Long term dermal studies in rats showed that application of a 8.5% benzalkonium chloride solution twice a week lead to local skin inflammation and ulceration. No systemic toxic effect was observed.

Reproductive and developmental effects

No developmental toxicity was observed in oral studies causing local, but not systemic, maternal toxicity. Toxic effect was observed when QACs have been applied locally near the developing foetus (i.p. application or instillation into vagina). This could be due to a disturbance of the functional integrity of the placenta.

Genotoxicity

The results of the genotoxicity tests were in the vast majority of the cases negative, indicating that QACs have negligible potential to cause genetic damage.

Carcinogenicity

The results of the carcinogenicity tests were negative, indicating that QACs have no carcinogenic potential.

 

7 Evaluation

As the QACs are solid substances (which are used in form of solutions) the exposure in form of vapour is irrelevant whereas dust as well as aerosol exposure is relevant. No data with respect to dust exposure is available and for aerosol exposure, only one relevant animal study has been carried out.

The toxicity profile of QACs is primarily based upon data from studies with benzalkonium chloride. Other QACs have only been more or less sparsely investigated. However, it seems that the various QACs exhibit similar toxicological properties.

Oral, dermal and few inhalation toxicity studies on representative QACs are available. However, they are of an earlier date and do not meet the requirements of today’s quality guidelines.

The studies have shown that QACs may induce adverse effect, including death, in humans as well as animals. From the available studies it can be concluded that the critical toxic effect of QACs apparently can be ascribed to the local irritating effects on surface tissues (skin, gastro-intestinal mucosa, eye, and respiratory system). These effects of QACs can be induced at levels not causing systemic effect. Therefore, the threshold for induction of oral toxic effect seems more related to the concentration of the solution than the daily amount of compound ingested.

Studies have shown that 0.001% solutions are without adverse effect even on the most sensitive membranes (eye).

It has been shown that benzalkonium chloride is able to induce sensitisation in guinea pigs and mice at concentrations not leading to skin irritation. In humans, it has been difficult to distinguish between an allergic and an irritative skin reaction due to the inherent skin irritating effect of QACs. However, it is suggested that QACs have a low potential for sensitising man (Andersen 1999).

Only a few studies reflect of QACs after inhalation. In a human study, a group of farmers were investigated for a possible relationship between exposure to QACs and respiratory disorders. Associations were found between the prevalence of mild bronchial responsiveness and the use of QACs as disinfectant. The design of the study does not allow the use for setting a N/LOAEL.

The most pertinent study for setting a N/LOAEL seems to be the four hours rat study on cetylpyrimidinuim chloride in dust form. A NOAEL cannot be estimated from this experiment as effects (death as well as irritating effect) were seen even at the lowest dose level at 0.05 mg/l. This is only about 6 times lower than the dose level, which caused 100% death. Cetylpyrimidinuim chloride seems to cause adverse effects at dose levels similar to other QACs after application on surfaces and after repeated oral intake. Based upon calculations from the cetylpyrimidinium chloride inhalation study it could be inferred that the compound is more toxic by inhalation exposure than by oral or dermal exposure. This may be the case for other QACs too.

A repeated animal inhalation study performed with a hair conditioner containing a very low concentration of benzalkonium chloride (9.9 mg/m3) was without adverse effect.

The results from the reprotoxicity studies do not indicate developmental toxicity. Effects have only been observed when QACs have been applied locally near the developing foetus (i.p. or instillation into vagina). This could be due to a disturbance of the functional integrity of the placenta.

The results of the genotoxicity tests were in the majority of the cases negative, indicating that QACs have negligible potential to cause genetic damage. This is in accordance with the results from the carcinogenicity studies, although these do not meet today’s quality guidelines.

Based on the available data, the critical effect in humans following exposure to QACs is considered to be the irritative effect on skin, mucosal membranes and eye and respiratory system. The effect may be induced following exposure to QACs in solutions or as aerosols. For the purpose of estimating a limit value in air, an exposure level of 50 mg cetylpyrimidinuim chloride/m3 (as aerosols, particle size less than 5 µm) is considered a LOAEL for death and irritative effects in rats.

 

8 Limit value in air

Limit value in air

The limit value is calculated based on an acute inhalation study in rats (cetylpyrimidinuim chloride as aerosols, particle size less than 5 µm). A NOAEL could not be established as effect was seen even at the lowest dose level of 50 mg/m3. At this concentration irritative effect and even death was seen.

LOAEL 50 mg/m3

4_formel1.gif (1768 bytes)

= 0.005 mg/m3

The safety factor SFI is set to 10 assuming that humans are more sensitive than animals. The SFII is set to 10 to protect the most sensitive individuals in the population. The SFIII is set to 100 since deaths were recorded even at the lowest dose level and the calculations were based upon a four hour exposure study.

 

9 C-value

A limit value of 0.005 mg/m3 has been calculated for the sum of QACs. For substances having acute or subchronic effects, but for which activity over a certain period of time is necessary before the harmful effect occurs, the C-value is set at the limit value. A C-value of 0.005 mg/m3 and placing in Main Group 2 is proposed (MST 1992).

C-value

0.005 mg/m3 (sum of QACs), Main Group 2.

 

10 References

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Anon. (1989). Final Report on the Safety Assessment of Benzalkonium Chloride. J Am Coll Toxicol 8, 589-625.

Anon. (1976). Raad van Europa Werkgroep Cosmetica: Alkyltrimethylammoniumbromide; Alkyltrimethylammoniumchloride;. Dialkyldimethylammoniumchloride; Alkyldimethyl benzylammoniumchloride.

Aursnes J (1982). Ototoxic effect of quaternary ammonium compounds. Acta Otolarylgol 93, 421-433.

BIBRA Working Group (1989). Benzalkonium chloride. Toxicity profile. The British Industrial Biological Research Association.

Cronin E (1980). Cont Derm, 692-695. Churchill Livingstone.

Cutler RA and Drobeck HP (1970). Toxicology of Cationic Surfactants. In: Cationic Surfactants. Vol. 4 (Chap. 15). Jungermann E (Ed.) Marcel Dekker, Inc., New York.

Effendy I and Maibach HI (1995). Surfactants and experimental irritant contact dermatitis. Cont derm 33, 217-225.

Fuchs T, Meinert A, Aberer W, Bahmer FA, Peters KP, Lischka GG, Schulze Dirks A, Enders F and Frosch PJ (1993). [Benzalkonium chloride- a relevant contact allergen or irritant? Results of a multicenter study of the German Contact Allergy Group] In German. Hautarzt 44, 699-702.

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Gloxhuber C (1974). Review articles. Toxicological Properties of Surfactants. Arch Toxicol 32, 245-270.

HSDB (through 1998). Tetradecylbenzyl-dimethyl-ammonium-chloride. Alkyl-dimethyl-benzyl-ammonium-chloride In: Hazardous Substances Database.

Isomaa B, Reuter J and Djupsund BM (1976). The Subacute and Chronic Toxicity of Cetyltrimethylammonium Bromide (CTAB), a Cationic Surfactant, in the Rat. Arch Toxicol 35, 91-96.

Isomaa B (1975a). Absorption, distribution and excretion of [14C]CTAB, a quaternary ammonium surfactant, in the rat. Fd Cosmet Toxicol 13, 231-237.

Isomaa B and Ekman K (1975b). Embryotoxic and teratogenic effects of CTAB, a cationic surfactant, in the mouse. Fd Cosmet Toxicol 13, 331-334

Kirk-Othmer (1985). Quaternary ammonium compounds. In: Concise Encyclopedia of Chemical Technology. John Wiley & Sons. A Wiley-Interscience Publication, 162-63.

Lin GHY (1991). Acute inhalation toxicity of Cetylpyridinium chloride. Fd Chem Toxic 29, 851-854.

Lægemiddelkataloget. København 1996. Danmarks Apotekerforening, Foreningen af danske Medicinfabrikker og Medicinindustriforeningen. ISSN 0105-287X.

MEM (1998). Bekendtgørelse om kosmetiske produkter. Miljø- og Energiministeriets bekendtgørelse nr. 303 af 18. maj 1998.

Merianos JJ (1991). Quaternary Ammonium Antimicrobial Compounds. In: Disinfection, Sterilisation, and Preservation (Chap. 13). Block S. (Ed.) Fourth edition. Lea & Febiger, USA.

Miskiel KA, Beasly R, Rafferty P and Holgate ST (1988). The contribution of histamine release to bronchoconstriction provoked by inhaled benzalkonium chloride in asthma. Br J Clin Pharmacol 25, 157-163.

MM (1999). Danish Environment and Energy Ministry Standing Order No. 510 af 18th.June, 1999.

MST (1992). Industrial Air Pollution Control Guidelines. Vejledning fra Miljøstyrelsen nr. 9 1992.

MST (1991). Overfladeaktive stoffer - spredning og effekter i miljøet. Miljøprojekt nr. 166. Miljøstyrelsen.

Palmer AK, Bottomley AM, Edwards JA and Clark R (1983). Absence of embryotoxic effects in rats with three quarternary ammonium compounds (cationic surfactants). Toxicology 26, 313-315.

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Preller L, Doekes G, Heederik D, Vermeulen R, Vogelzang PF and Boleij JS (1996). Disinfectant use as a risk factor for atopic sensitization and symptoms consistent with asthma: an epidemiological study. Eur Resp J. 9, 1407-13.

RTECS (1998). Hexadecyl trimethyl ammonium bromide. In the data base: Registry of Toxic Effects of Chemical Substances.

Schnuch A, Geier J, Uter W and Frosch PJ (1998). Patch testing with preservatives, antimicrobials and industrial biocides. Results from a multicentre study. Br J Dermatol 138, 467-76.

Stenbäck F (1977). Local and Systemic Effects of Commonly Used Cutaneous Agents: Lifetime Studies of 16 Compounds in Mice and Rabbits. Acta Pharmacol Toxicol 41, 417-431.

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