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Paraben sensitivity
PRESERVATIVES
147
The development of adverse effects in the cat thus seems to depend on a single dose of more than 0.45 g/kg or repeated daily doses above about 0.2 g/kg. In view of the ease with which BA overdosage can occur and the alleged inefficiency of this preservative at pH 5-6, it is suggested that the continued use of BA in cat meat should be seriously questioned.
2451. The effects of high-speed benzyl alcohol Baker, N. & Huebotter, R. J. (1971). Immobilizing and hyperglycemic effects of benzyl alcohol, a common preservative. Life Sci. 10 (Part I), 1193. Benzyl alcohol (I), when used at a level of 0.9 ~ as a preservative in commercial isotonic saline and other solutions for parenteral administration, has been shown to be free from hazard on slow intravenous infusion (Cited in F.C.T. 1971, 9, 908), but the study cited above describes certain untoward effects produced by large doses given intraperitoneally (ip). Mice given an ip injection of a 0.9 or 4 ~o solution of I in saline, in amounts equivalent to 900 or 700 mg I/kg, respectively, were totally immobilized within 2 min and remained unresponsive for about 30 min. I also induced marked hyperglycaemia in mice fasted for 1 or 6 hr, but it had no effect on liver glycogen levels. Tracer studies using radioactivelylabelled glucose suggested that the hyperglycaemic effect may have resulted from increased gluconeogenesis, although diminished peripheral uptake of glucose was not ruled out. The authors warn that investigators using commercial saline should be aware of the possible effect that the presence of this preservative may have on their experimental results, and suggest that further studies on the action of I on the nervous system would prove of interest.
2452. Paraben sensitivity Braun, W. (1971). Die allergologische Bedeutung der p-Hydroxybenzoes/iureester als Konservierungsmittel in kosmetischen und dermatologischen Externa. Hautarzt 22, 531. Esters of p-hydroxybenzoic acid (parabens) used as preservatives in cosmetics and pharmaceutical preparations have already been implicated in cases of dermatitis and sensitization. The paper cited above describes the results of tests carried out in 1968-1970 on a total of 2497 subjects believed to be suffering from some contact allergy. A mixture of the methyl, ethyl and propyl esters (1 ~o of each in vaseline) was used, and some of the patients who reacted positively were also tested with the individual esters (1 ~o in vaseline). The patients were also tested with seven other organic and inorganic compounds of known allergenic potential. A 24-hr exposure to the paraben mixture was followed by examination after 24 and 48 hr and, if necessary, at 72 hr and thereafter. Paraben sensitization was detected in 59 subjects. Of these 59, 26 also gave positive reactions to at least one of thep-aminobenzene derivatives, p-(aminomethyl)benzenesulphonamide,p-phenylenediamine and ethyl aminobenzoate, and 31 reacted to Peruvian balsam. Tests with the individual methyl, ethyl and propyl parabens carried out in 19 of the paraben-positive subjects were positive in 10, 3 and 11 subjects, respectively. In the light of these results, the author comments on the apparent importance of p-substitution in the development of sensitization. Of 913 cases of contact eczema examined in 1970, 48 ~o were traced either to the paraben
148
MISCELLANEOUS DIRECT ADDITIVE
esters or to one of the seven other known allergens tested. The 2.9 % incidence of paraben sensitization compared, for example, with a figure of 10.4 % for p-phenylenediamine, 6-2 7o for nickel sulphate, 7.9% for Peruvian balsam and 8.3 % for potassium dichromate. An incidence of 2.9 % was also found the previous year for paraben-sensitivity among 720 patients tested. This incidence compares closely with values quoted by other authors and its significance must be considered in the light of the known value of these parabens as preservatives in cosmetics and pharmaceuticals.
MISCELLANEOUS DIRECT ADDITIVES
2453. 1,3-Butanediol gives food for thought Mehlman, M. A., Tobin, R. B., Hahn, H. K. J., Kleager, L. & Tate, R. L. (1971). Metabolic fate of 1,3-butanediol in the rat: Liver tissue slices metabolism. J. Nutr. 101, 1711. Tate, R. L., Mehlman, M. A. & Tobin, R. B. (1971). Metabolic fate of 1,3-butanediol in the rat: Conversion to/3-hydroxybutyrate. J. Nutr. 101, 1719. Interest has centred on the potential use of butane-l,3-diol (BD) as a synthetic food substance, and investigations have been made into the usefulness of BD to rats as a source of dietary energy (Cited in F.C.T. 1967, 5, 727). Rats fed for 4 wk with 20 % BD in isocaloric substitution for carbohydrate grew more slowly than controls, because of reduced food intake not of reduced utilization, and the epididymal fat pad was reduced in size. These rats were less able than controls to survive extreme cold, probably because of their relative lack of adipose tissue. The first paper cited above reports the effect of feeding rats on a diet containing 30 % fat together with 25 % BD as a substitute for carbohydrate for 3 and 7 wk. Animals fed BD failed to gain weight normally and food consumption was reduced, as was the weight of the epididymal fat pad in relation to body weight. Concentrations of acetoacetate and /3-hydroxybutyrate in the blood rose, the level of total ketone bodies being approximately trebled. At wk 7, rats showed a significant reduction in the blood level of pyruvate. In vitro studies on liver slices indicated a great decrease in pyruvate and a significantly increased lactate/pyruvate ratio when BD was added to glucose in the substrate. With BD and glucose as substrates there was a marked increase in total ketone formation and with BD alone, ketone bodies were also formed. These results indicate that BD is converted to ketone bodies prior to its oxidation in the tricarboxylic acid cycle. The second paper cited above illustrates in more detail the metabolic fate of BD in the rat. Rat-liver homogenates were found to oxidize BD and ethanol at pH 10 in the presence of NAD ÷. Liver slices and homogenates from rats previously treated with pyrazole or n-butyraldoxime to inhibit alcohol dehydrogenase failed to produce ketone bodies from BD. These findings indicate that BD is catabolized to ]3-hydroxybutyrate in the rat liver, the initial oxidation to aldol being catalysed by alcohol dehydrogenase and taking place in the cytosol. Once formed,/3-hydroxybutyrate follows the known metabolic pathway. [Perhaps the conclusion to be drawn from these studies is that, regarded as a possible foodstuff to take place of carbohydrates, 1,3-butanediol closely resembles ethanol in its metabolism. In contrast to the finding, mentioned elsewhere in this issue (p. 145), that
147
The development of adverse effects in the cat thus seems to depend on a single dose of more than 0.45 g/kg or repeated daily doses above about 0.2 g/kg. In view of the ease with which BA overdosage can occur and the alleged inefficiency of this preservative at pH 5-6, it is suggested that the continued use of BA in cat meat should be seriously questioned.
2451. The effects of high-speed benzyl alcohol Baker, N. & Huebotter, R. J. (1971). Immobilizing and hyperglycemic effects of benzyl alcohol, a common preservative. Life Sci. 10 (Part I), 1193. Benzyl alcohol (I), when used at a level of 0.9 ~ as a preservative in commercial isotonic saline and other solutions for parenteral administration, has been shown to be free from hazard on slow intravenous infusion (Cited in F.C.T. 1971, 9, 908), but the study cited above describes certain untoward effects produced by large doses given intraperitoneally (ip). Mice given an ip injection of a 0.9 or 4 ~o solution of I in saline, in amounts equivalent to 900 or 700 mg I/kg, respectively, were totally immobilized within 2 min and remained unresponsive for about 30 min. I also induced marked hyperglycaemia in mice fasted for 1 or 6 hr, but it had no effect on liver glycogen levels. Tracer studies using radioactivelylabelled glucose suggested that the hyperglycaemic effect may have resulted from increased gluconeogenesis, although diminished peripheral uptake of glucose was not ruled out. The authors warn that investigators using commercial saline should be aware of the possible effect that the presence of this preservative may have on their experimental results, and suggest that further studies on the action of I on the nervous system would prove of interest.
2452. Paraben sensitivity Braun, W. (1971). Die allergologische Bedeutung der p-Hydroxybenzoes/iureester als Konservierungsmittel in kosmetischen und dermatologischen Externa. Hautarzt 22, 531. Esters of p-hydroxybenzoic acid (parabens) used as preservatives in cosmetics and pharmaceutical preparations have already been implicated in cases of dermatitis and sensitization. The paper cited above describes the results of tests carried out in 1968-1970 on a total of 2497 subjects believed to be suffering from some contact allergy. A mixture of the methyl, ethyl and propyl esters (1 ~o of each in vaseline) was used, and some of the patients who reacted positively were also tested with the individual esters (1 ~o in vaseline). The patients were also tested with seven other organic and inorganic compounds of known allergenic potential. A 24-hr exposure to the paraben mixture was followed by examination after 24 and 48 hr and, if necessary, at 72 hr and thereafter. Paraben sensitization was detected in 59 subjects. Of these 59, 26 also gave positive reactions to at least one of thep-aminobenzene derivatives, p-(aminomethyl)benzenesulphonamide,p-phenylenediamine and ethyl aminobenzoate, and 31 reacted to Peruvian balsam. Tests with the individual methyl, ethyl and propyl parabens carried out in 19 of the paraben-positive subjects were positive in 10, 3 and 11 subjects, respectively. In the light of these results, the author comments on the apparent importance of p-substitution in the development of sensitization. Of 913 cases of contact eczema examined in 1970, 48 ~o were traced either to the paraben
148
MISCELLANEOUS DIRECT ADDITIVE
esters or to one of the seven other known allergens tested. The 2.9 % incidence of paraben sensitization compared, for example, with a figure of 10.4 % for p-phenylenediamine, 6-2 7o for nickel sulphate, 7.9% for Peruvian balsam and 8.3 % for potassium dichromate. An incidence of 2.9 % was also found the previous year for paraben-sensitivity among 720 patients tested. This incidence compares closely with values quoted by other authors and its significance must be considered in the light of the known value of these parabens as preservatives in cosmetics and pharmaceuticals.
MISCELLANEOUS DIRECT ADDITIVES
2453. 1,3-Butanediol gives food for thought Mehlman, M. A., Tobin, R. B., Hahn, H. K. J., Kleager, L. & Tate, R. L. (1971). Metabolic fate of 1,3-butanediol in the rat: Liver tissue slices metabolism. J. Nutr. 101, 1711. Tate, R. L., Mehlman, M. A. & Tobin, R. B. (1971). Metabolic fate of 1,3-butanediol in the rat: Conversion to/3-hydroxybutyrate. J. Nutr. 101, 1719. Interest has centred on the potential use of butane-l,3-diol (BD) as a synthetic food substance, and investigations have been made into the usefulness of BD to rats as a source of dietary energy (Cited in F.C.T. 1967, 5, 727). Rats fed for 4 wk with 20 % BD in isocaloric substitution for carbohydrate grew more slowly than controls, because of reduced food intake not of reduced utilization, and the epididymal fat pad was reduced in size. These rats were less able than controls to survive extreme cold, probably because of their relative lack of adipose tissue. The first paper cited above reports the effect of feeding rats on a diet containing 30 % fat together with 25 % BD as a substitute for carbohydrate for 3 and 7 wk. Animals fed BD failed to gain weight normally and food consumption was reduced, as was the weight of the epididymal fat pad in relation to body weight. Concentrations of acetoacetate and /3-hydroxybutyrate in the blood rose, the level of total ketone bodies being approximately trebled. At wk 7, rats showed a significant reduction in the blood level of pyruvate. In vitro studies on liver slices indicated a great decrease in pyruvate and a significantly increased lactate/pyruvate ratio when BD was added to glucose in the substrate. With BD and glucose as substrates there was a marked increase in total ketone formation and with BD alone, ketone bodies were also formed. These results indicate that BD is converted to ketone bodies prior to its oxidation in the tricarboxylic acid cycle. The second paper cited above illustrates in more detail the metabolic fate of BD in the rat. Rat-liver homogenates were found to oxidize BD and ethanol at pH 10 in the presence of NAD ÷. Liver slices and homogenates from rats previously treated with pyrazole or n-butyraldoxime to inhibit alcohol dehydrogenase failed to produce ketone bodies from BD. These findings indicate that BD is catabolized to ]3-hydroxybutyrate in the rat liver, the initial oxidation to aldol being catalysed by alcohol dehydrogenase and taking place in the cytosol. Once formed,/3-hydroxybutyrate follows the known metabolic pathway. [Perhaps the conclusion to be drawn from these studies is that, regarded as a possible foodstuff to take place of carbohydrates, 1,3-butanediol closely resembles ethanol in its metabolism. In contrast to the finding, mentioned elsewhere in this issue (p. 145), that