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Chlorhexidine—percutaneous penetration
loo
Cosmetics.
toiletries
and
household
products--Fr/
and pairs of the animals were killed after 2. 4, 8 and 24 hr. the survivor being killed at 48 hr. Blood was collected at 30-min intervals initially and later every 2 hr, and lung-tissue samples were taken at autopsy from the treated goats and from three untreated controls. There was a steady rise in plasma 3MI concentration and peaks were reached between 1 and 2 hr after treatment, returning to zero after I2 and 15 hr respectively, in the two goats examined beyond 8 hr. The animals developed pulmonary oedema and laboured breathing at 4 hr and this became increasingly severe up to I5 hr. One animal with a peak 3MI concentration of 13,8pg/ml died at 8 hr with severe dyspnoea. Electron-microscope studies of the lungs revealed extensive degeneration and necrosis of alveolar membranous pneumocytes and bronchiolar epithelium. Necrosis of the pneumocytes was followed by a repair process involving proliferation of granular pneumocytes. 3MI also induced proliferation of the smooth endoplasmic reticulum in the remaining membranous pneumocytes and non-ciliated columnar epithelium of the small airways, indicating that these two types of cell are involved in the foreign-compound metabolism effected by the lung. The results suggest that cigarette smoke, which may contain 04-1.4mg 3MI/lOO cigarettes as a product of tryptophan pyrolysis, could play an important role in the pathogenesis of small airway disease and emphysema. In addition, patients with a severe liver disease or portacaval shunt may be predisposed to diffuse alveolar damage by 3MI produced in the intestinal tract. Pat&n
ingestion
by monkeys
Garza, H. C., Swanson, B. G. & Branen, A. L. (1977). Toxicological study of patulin in monkeys. J. Fd Sci. 42, 1229. Patulin is a heterocyclic lactone produced by various species of Penicillium and Aspergillus, which may contaminate bread and pastry, fruits and cereals. It has been reported to inhibit lactic dehydrogenase, alcohol dehydrogenase and muscle aldolase (Ashoor & Chu. Fd Comet. To.ltico/. 1973, II, 617 & 995; Cited
in F.C.T.
1977.
IS, 495).
Pig-tail monkeys (Macaca nemestrina) were given daily oral doses of 5, 50 or 500 pg patulin/kg for 4 wk. Those given 500 gg/kg were subsequently given 5 mg/ kg/day for a further 2 wk. Blood samples were taken weekly for haematology and biochemical determinations. The only statistically significant effect of patulin was a decrease in serum alkaline phosphatase, a finding probably meaningless in isolation. Serum proteins showed their normal electrophoretic patterns, and blood counts were unaltered. There was a slight increase in blood urea nitrogen during wk 2 and 3,
COSMETICS, Chlorhexidine-percutaneous
TOILETRIES
AND
penetration
Chow, C. P., Buttar, H. S. & Downie, R. H. (1978). Percutaneous absorption of chlorhexidine in rats. Toxicology
Left.
I,
213.
Coswr.
Tauicol.
Vol.
17. No.
I
but this was of no clear biochemical significance. The monkeys showed no signs of toxicity during the 4-wk treatment period or in the extended highdose period that followed. Those transferred to the 5-mg/kg/day dose rejected the freeze-dried bananas that were used throughout the experiment for administration of the patulin, presumably either because they found the flavour of the lactone or the citrate buffer unpleasant or because these Ravours had become associated with stress. The low toxicity of patulin by the oral route, compared with its effects when given parenterally. is possibly due to the rapid absorption and metabolism of the toxin, and to its prompt excretion.
Tree
pollution?
Boyd, M. R.. Statham, C. N.. Franklin, R. B. & Mitchell, J. R. (1978). Pulmonary bronchiolar alkylation and necrosis by 3-methylfuran, a naturally occurring potential atmospheric contaminant. Name. Lond. 272, 270. 3-Methylfuran (3MF) was found to be a major contaminant of the smog that occurred in Washington, DC, during the summer of 1973. As it has been postulated that 3MF is a photo-oxidation and degradation product of terpenes and other volatile hydrocarbons released in large amounts by vegetation such as deciduous forest, this compound may be a common environmental factor. The results of a preliminary study of the inhalation toxicity of 3MF have now been reported. A high degree of covalent binding of [Me-3H]3MF to the microsomes of mouse lung occurred in vitro. As the binding reaction required an NADPH-generating system and was inhibited by an atmosphere enriched with carbon monoxide or by addition of piperonyl butoxide to the medium, it appeared that the lung microsomes were converting 3MF to an alkylating metabolite by means of a cytochrome P-450-dependent oxidation. A similar metabolic activation occurred in uiuo. If mice were exposed to atmospheric concentrations of 0.23 mmol C3H]3MF/ litre for 1 hr, the 3MF became covalently bound to the lung macromolecules and induced severe bronchial necrosis. Histologically ‘it was shown that the metabolites accumulated preferentially in the terminal pulmonary bronchioles. Both the degree of covalent binding and the extent of bronchial necrosis was markedly reduced in mice pretreated with an ip injection of piperonyl butoxide (1.6 g/kg). The observed effects were produced by high concentrations of 3MF. Nevertheless, these preliminary findings, incriminating 3MF as a possible cause of bronchiolar disease in man and raising the question of its possible carcinogenic potential, suggest that further investigation is warranted.
HOUSEHOLD
PRODUCTS
Chlorhexidine is now widely used in place of hexachlorophene as an antimicrobial agent in cosmetics and toiletries. In this application it produces only rare cases of sensitization (Cited in F.C.T. 1974, 12, 799),
Cosmetics. toiletries and household products--Ft/ although eye irritation may result from its use as a soft-lens sterilant (ibid 1975, 13, 288). Most of an oral dose administered to a number of species was excreted in the faeces, and (except in the mouse) less than l:/, appeared in the urine, while after iv injection some 50-70% appeared in the bile within 48 hr (ibid 1974, 12, 587). Its fate after skin application has now been similarly quantified. When 296 pg “C-labelled chlorhexidine in aqueous acetone was applied to shaved rat skin under a nonocclusive plastics guard, a mean total of 1.1% of the radioactivity had appeared in the faeces after 5 days. The urine contained a total of only 0.07%, and the carcass (after excision of the application site) a further 3.2%. The skin application site contained approximately 987: on average. After iv injection of the same quantity in saline some SOY/, had been excreted in the faeces and 3.39” in the urine after 5 days, and the carcass contained a residual 22.5%. When the ratio of urinary excretion after topical and after iv application was expressed as a percentage, to give an estimate of the total percutaneous absorption (a method recommended by Feldmann & Maibach, J. invest. Derm. 1970, 54, 399) a value of 2.0% was reached. The total absorbed through the skin in 5 days was thus in the range 2.&4.3%. This compared with a value of 76.6:~: from an equimolar dose of hexachlorophene administered in the same way (Chow et al. Toxicology 1978. 9, 147) a difference which could be attributed to the greater lipid-solubility and lower molecular weight of the latter compound.
Decline and fall of a sensitizer Smith, S. Z. & Epstein, J. H. (1977). Photocontact dermatitis to halogenated salicylanilides and related compounds. Arch Dew. 113, 1372. The halogenated salicylanilides and related compounds have been widely used ?r.santibacterial agents in soaps, cleansers and medicated toilet preparations. However, over the period 196@1970, many cases of photosensitization to these materials were reported (Cited in F.C.T. 1969,7,690). In the USA, from where
Cosmer.
Toxicol.
Vol. 17, No. I
101
many of the reports emanated, bithionol was officially excluded from incorporation into cosmetic and antibacterial preparations in June 1968. Subsequently, the dibrominated compounds (1972) and tribomosalicylanilide (1974) were eliminated from such use. The above-cited study examines experience with these compounds at the University of California’s San Francisco clinic over the period June 1967 to October 1975. The subjects involved were 434 patients who had either a history suggestive of a photosensitivity problem or an eruption involving sun-exposed areas at least in part. Age, sex and racial distribution were tabulated and the numbers of patients with positive photopatch tests, positive patch tests and completely negative tests were compared. The majority of patients tested and the majority of patients with positive photopatch tests were in their fifth to sixth decade. None were children, and men were more commonly involved than women, the ratio being approximately 8:5. No racial trends could be detected in those tested or in those with positive phototests. Over the period of study there was a distinct decline in the numbers of patients with positive patch and photopatch test reactions and in the number tested. Almost three times as many were tested and four times as many had positive photopatch tests in the last 6 months of 1967 as in the first 9 months of 1975. There were also 16 positive non-irradiated patch tests in the 1967 period and only one in 1975. The most striking reduction of patients with positive tests occured in 1971, although the total number of positive photopatch tests dropped. most notably after 1968. In 1967 the compounds that elicited the greatest number of positive photopatch tests were 3,5-dibromosalicylanilide, 3,4’,5-tribromosalicylanilide, bithionol, 3,3’,4’,5-tetrachlorosalicylanihde and polybromosalicylanilide. The general reduction after this date resulted from a lower incidence of reactivity to these brominated salicylanilides and to 3,3’,4’,Stetrachlorosalicylanilides. Although the primary reason for the decline was probably the removal of the more potent photosensitizers from deodorant soaps, it is also believed that a greater awareness among physicians played a role in reducing referrals to the clinic.
Cosmetics.
toiletries
and
household
products--Fr/
and pairs of the animals were killed after 2. 4, 8 and 24 hr. the survivor being killed at 48 hr. Blood was collected at 30-min intervals initially and later every 2 hr, and lung-tissue samples were taken at autopsy from the treated goats and from three untreated controls. There was a steady rise in plasma 3MI concentration and peaks were reached between 1 and 2 hr after treatment, returning to zero after I2 and 15 hr respectively, in the two goats examined beyond 8 hr. The animals developed pulmonary oedema and laboured breathing at 4 hr and this became increasingly severe up to I5 hr. One animal with a peak 3MI concentration of 13,8pg/ml died at 8 hr with severe dyspnoea. Electron-microscope studies of the lungs revealed extensive degeneration and necrosis of alveolar membranous pneumocytes and bronchiolar epithelium. Necrosis of the pneumocytes was followed by a repair process involving proliferation of granular pneumocytes. 3MI also induced proliferation of the smooth endoplasmic reticulum in the remaining membranous pneumocytes and non-ciliated columnar epithelium of the small airways, indicating that these two types of cell are involved in the foreign-compound metabolism effected by the lung. The results suggest that cigarette smoke, which may contain 04-1.4mg 3MI/lOO cigarettes as a product of tryptophan pyrolysis, could play an important role in the pathogenesis of small airway disease and emphysema. In addition, patients with a severe liver disease or portacaval shunt may be predisposed to diffuse alveolar damage by 3MI produced in the intestinal tract. Pat&n
ingestion
by monkeys
Garza, H. C., Swanson, B. G. & Branen, A. L. (1977). Toxicological study of patulin in monkeys. J. Fd Sci. 42, 1229. Patulin is a heterocyclic lactone produced by various species of Penicillium and Aspergillus, which may contaminate bread and pastry, fruits and cereals. It has been reported to inhibit lactic dehydrogenase, alcohol dehydrogenase and muscle aldolase (Ashoor & Chu. Fd Comet. To.ltico/. 1973, II, 617 & 995; Cited
in F.C.T.
1977.
IS, 495).
Pig-tail monkeys (Macaca nemestrina) were given daily oral doses of 5, 50 or 500 pg patulin/kg for 4 wk. Those given 500 gg/kg were subsequently given 5 mg/ kg/day for a further 2 wk. Blood samples were taken weekly for haematology and biochemical determinations. The only statistically significant effect of patulin was a decrease in serum alkaline phosphatase, a finding probably meaningless in isolation. Serum proteins showed their normal electrophoretic patterns, and blood counts were unaltered. There was a slight increase in blood urea nitrogen during wk 2 and 3,
COSMETICS, Chlorhexidine-percutaneous
TOILETRIES
AND
penetration
Chow, C. P., Buttar, H. S. & Downie, R. H. (1978). Percutaneous absorption of chlorhexidine in rats. Toxicology
Left.
I,
213.
Coswr.
Tauicol.
Vol.
17. No.
I
but this was of no clear biochemical significance. The monkeys showed no signs of toxicity during the 4-wk treatment period or in the extended highdose period that followed. Those transferred to the 5-mg/kg/day dose rejected the freeze-dried bananas that were used throughout the experiment for administration of the patulin, presumably either because they found the flavour of the lactone or the citrate buffer unpleasant or because these Ravours had become associated with stress. The low toxicity of patulin by the oral route, compared with its effects when given parenterally. is possibly due to the rapid absorption and metabolism of the toxin, and to its prompt excretion.
Tree
pollution?
Boyd, M. R.. Statham, C. N.. Franklin, R. B. & Mitchell, J. R. (1978). Pulmonary bronchiolar alkylation and necrosis by 3-methylfuran, a naturally occurring potential atmospheric contaminant. Name. Lond. 272, 270. 3-Methylfuran (3MF) was found to be a major contaminant of the smog that occurred in Washington, DC, during the summer of 1973. As it has been postulated that 3MF is a photo-oxidation and degradation product of terpenes and other volatile hydrocarbons released in large amounts by vegetation such as deciduous forest, this compound may be a common environmental factor. The results of a preliminary study of the inhalation toxicity of 3MF have now been reported. A high degree of covalent binding of [Me-3H]3MF to the microsomes of mouse lung occurred in vitro. As the binding reaction required an NADPH-generating system and was inhibited by an atmosphere enriched with carbon monoxide or by addition of piperonyl butoxide to the medium, it appeared that the lung microsomes were converting 3MF to an alkylating metabolite by means of a cytochrome P-450-dependent oxidation. A similar metabolic activation occurred in uiuo. If mice were exposed to atmospheric concentrations of 0.23 mmol C3H]3MF/ litre for 1 hr, the 3MF became covalently bound to the lung macromolecules and induced severe bronchial necrosis. Histologically ‘it was shown that the metabolites accumulated preferentially in the terminal pulmonary bronchioles. Both the degree of covalent binding and the extent of bronchial necrosis was markedly reduced in mice pretreated with an ip injection of piperonyl butoxide (1.6 g/kg). The observed effects were produced by high concentrations of 3MF. Nevertheless, these preliminary findings, incriminating 3MF as a possible cause of bronchiolar disease in man and raising the question of its possible carcinogenic potential, suggest that further investigation is warranted.
HOUSEHOLD
PRODUCTS
Chlorhexidine is now widely used in place of hexachlorophene as an antimicrobial agent in cosmetics and toiletries. In this application it produces only rare cases of sensitization (Cited in F.C.T. 1974, 12, 799),
Cosmetics. toiletries and household products--Ft/ although eye irritation may result from its use as a soft-lens sterilant (ibid 1975, 13, 288). Most of an oral dose administered to a number of species was excreted in the faeces, and (except in the mouse) less than l:/, appeared in the urine, while after iv injection some 50-70% appeared in the bile within 48 hr (ibid 1974, 12, 587). Its fate after skin application has now been similarly quantified. When 296 pg “C-labelled chlorhexidine in aqueous acetone was applied to shaved rat skin under a nonocclusive plastics guard, a mean total of 1.1% of the radioactivity had appeared in the faeces after 5 days. The urine contained a total of only 0.07%, and the carcass (after excision of the application site) a further 3.2%. The skin application site contained approximately 987: on average. After iv injection of the same quantity in saline some SOY/, had been excreted in the faeces and 3.39” in the urine after 5 days, and the carcass contained a residual 22.5%. When the ratio of urinary excretion after topical and after iv application was expressed as a percentage, to give an estimate of the total percutaneous absorption (a method recommended by Feldmann & Maibach, J. invest. Derm. 1970, 54, 399) a value of 2.0% was reached. The total absorbed through the skin in 5 days was thus in the range 2.&4.3%. This compared with a value of 76.6:~: from an equimolar dose of hexachlorophene administered in the same way (Chow et al. Toxicology 1978. 9, 147) a difference which could be attributed to the greater lipid-solubility and lower molecular weight of the latter compound.
Decline and fall of a sensitizer Smith, S. Z. & Epstein, J. H. (1977). Photocontact dermatitis to halogenated salicylanilides and related compounds. Arch Dew. 113, 1372. The halogenated salicylanilides and related compounds have been widely used ?r.santibacterial agents in soaps, cleansers and medicated toilet preparations. However, over the period 196@1970, many cases of photosensitization to these materials were reported (Cited in F.C.T. 1969,7,690). In the USA, from where
Cosmer.
Toxicol.
Vol. 17, No. I
101
many of the reports emanated, bithionol was officially excluded from incorporation into cosmetic and antibacterial preparations in June 1968. Subsequently, the dibrominated compounds (1972) and tribomosalicylanilide (1974) were eliminated from such use. The above-cited study examines experience with these compounds at the University of California’s San Francisco clinic over the period June 1967 to October 1975. The subjects involved were 434 patients who had either a history suggestive of a photosensitivity problem or an eruption involving sun-exposed areas at least in part. Age, sex and racial distribution were tabulated and the numbers of patients with positive photopatch tests, positive patch tests and completely negative tests were compared. The majority of patients tested and the majority of patients with positive photopatch tests were in their fifth to sixth decade. None were children, and men were more commonly involved than women, the ratio being approximately 8:5. No racial trends could be detected in those tested or in those with positive phototests. Over the period of study there was a distinct decline in the numbers of patients with positive patch and photopatch test reactions and in the number tested. Almost three times as many were tested and four times as many had positive photopatch tests in the last 6 months of 1967 as in the first 9 months of 1975. There were also 16 positive non-irradiated patch tests in the 1967 period and only one in 1975. The most striking reduction of patients with positive tests occured in 1971, although the total number of positive photopatch tests dropped. most notably after 1968. In 1967 the compounds that elicited the greatest number of positive photopatch tests were 3,5-dibromosalicylanilide, 3,4’,5-tribromosalicylanilide, bithionol, 3,3’,4’,5-tetrachlorosalicylanihde and polybromosalicylanilide. The general reduction after this date resulted from a lower incidence of reactivity to these brominated salicylanilides and to 3,3’,4’,Stetrachlorosalicylanilides. Although the primary reason for the decline was probably the removal of the more potent photosensitizers from deodorant soaps, it is also believed that a greater awareness among physicians played a role in reducing referrals to the clinic.