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The cumulative action of triphenyltin
Fd Cosmet. Toxicol. Vol. 5, pp. 285--287.Pergamon Press 1967. Printed in Great Brttain
LETTERS TO THE EDITOR T H E C U M U L A T I V E A C T I O N OF T R I P H E N Y L T I N Sir,--In previous experiments on the fungicide triphenyltin acetate (Stoner, Br. J. ind. Med. 1966, 23, 222) it was found that the effects of this compound in guinea-pigs were cumulative, i.e. the amounts consumed by those dying on diets containing 25 and 50 ppm were similar to the acute oral LDs0 and the logarithmic mean survival time on 25 ppm was twice that on 50 ppm. Striking evidence of accumulation has also been presented by Scholz (Nature, Lond. 1965, 207, 870). From our previous results it was calculated that if triphenyltin acetate was completely cumulative in the guinea-pig, a diet containing 12 ppm should lead to death after 86--106 days. This proposition has now been tested. Six male guinea-pigs obtained from AUington Farm, Porton, Wiltshire were kept separately and fed on powdered R.G.P. diet (Dixon & Sons (Ware) Ltd.), containing 12 ppm triphenyltin acetate obtained from Dr. G. J. M. Van der Kerk, T.N.O., Utrecht. These were compared with six pair-fed controls. The body weight ( m e a n + S D ) at the be~nning of the experiment was 308-4-29 g. At the end of 1 yr, only one of the treated guinea-pigs was still alive. All the pair-fed controls gained weight during the period of pair-t:eeding. After the death of the treated member of the pair the control was fed ad lib. and all the control guinea-pigs were alive and well at the end of the year. The treated guinea-pigs grew more slowly than their pair-fed controls and the toxic signs before death were the same as in the previous experiments. At autopsy it was noteworthy that in three of these animals (Nos 22, 24 and 32) fluid was found in the pericardial sac and in one of them it was blood-stained (No. 32). Some fluid was also found in this site in one of the controls but the amount was less. On histological examination increased lipid was seen in the parenchymal cells of the liver in all the treated animals which died. Degenerative changes were seen in the myocardium in Nos 24 and 32. The survival times, the total dose of triphenyltin acetate and its rate of consumption are shown in Table 1. During the first month of the experiment the daily dose of the compound was approximately half that consumed by guinea-pigs on a diet containing 25 ppm (previous experiment S 43; Stoner, loc. cit.). As the experiment proceeded, the amount of the compound taken per day fell. Table. 1.
Surviva•timeandd•serateinguinea-pigsgivenadietc•ntaining12ppmtripheny•tinacetatef•rup
lyr Approximate average daffy dose (mg/kg body welght/day)
Ammal Survivaltime no. (days) 29 22 22 248 27 259 24 294 32 306 28 S S=Alive at end of expertment.
1-28 days -0-83 1"15 1"10 1"22 1-23
200-228days -0"45 0"73 0.76 0.93 0"77 285
Overall 0"89 0-81 0.87 0.96 0"80 0"98
to
Total dose consumed (mg/kg body weight) 19 196 247 277 279 352
286
LIz-IIERS TO THE EDITOR
It is clear from the survival times and the total amounts consumed that at this dosage level triphenyltin is not completely cumulative. If guinea-pig No. 29 is excluded these and previous results (Stoner, loc. cit.) are consistent with a half-life of triphenyltin at the site of action of about 50 days. It is possible, however, that the compound is more cumulative than this and that guinea-pigs develop some degree of tolerance when repeated small doses are given for long periods. H. B. STONEg and D. F. HEATH,
Medical Research Council Laboratories, Woodmansterne Road, Carshalton, Surrey, England Acknowledgements--Our t h a n k s
are due to Mrs. A K e t t e m a n a n d Mrs. M. Blyth for their careful technical
assistance.
FREE F O R M A L D E H Y D E FROM PLASTICS DISHES Sir,--A query was raised concerning the possibility of free formaldehyde being extracted from dishes made from urea or melamine resins if hot liquids were poured into them. Since information on this subject was not readily available, two plastics dishes were obtained for testing from a local retail outlet. One was a small brown bowl, the other was a flatter, white dish; both were made of thermosetting plastics. Boiling water was used in the first test. Approximately i00 ml boiling water was poured into each dish; after 30 rain the water had returned to room temperature and triplicate 2-ml samples were taken for the determination of formaldehyde by the method of Nash (Biochem. J. 1953, 55, 416). Both distilled water and tap water were used. All samples gave a very small positive response, less than 0.1 ppm formaldehyde. (Here and throughout, ppm are based on the 100 ml solution used.) Three additional extractants (3 Yo sodium chloride, 3 ~o acetic acid and 3 ~o sodium bicarbonate) were used in a second test, following the lines suggested in "Information Required for the Consideration of Packaging Materials" (Internal Memorandum of Food and Drug Directorate, Ottawa, Canada, 1961). As before, I00 ml boiling solution was poured into each bowl, and tested for formaldehyde after it had cooled. Again, trace amounts were found in each case (less than 0.2 ppm). Since plastics dishes become scratched in use, an extreme test was devised. Boiling solvent (100 ml of each of those used before) was poured into beakers containing 8 g of pieces of the broken dishes, each piece being approximately 3 c m × 1.5 cm. The eight beakers (four solvents on two plastics) were covered with watch-glasses and placed in an oven maintained at 57°C. Samples were taken for analysis at I, 2, 4, 6, 24 and 28 hr. In general, all solvents gave similar results. Less than 2 ppm formaldehyde was extracted in the first hour, with the amount gradually rising to an average of 2.3 ppm at 2 hr, 3-5 ppm at 4 hr, 4.8 ppm at 6 hr and 19 ppm at 28 hr. Exceptions were (1) the water extract from the white pieces which was consistently low, reaching only 10 ppm at 28 hr, and (2) the acetic acid extract from the brown pieces which was consistently high, reaching 33 ppm at 28 hr. The results at 24 hr are not quoted, as the sample sizes used were such as to make the results only very approximate. They did, however, indicate the ranges subsequently found at 28 hr.
LETTERS TO THE EDITOR T H E C U M U L A T I V E A C T I O N OF T R I P H E N Y L T I N Sir,--In previous experiments on the fungicide triphenyltin acetate (Stoner, Br. J. ind. Med. 1966, 23, 222) it was found that the effects of this compound in guinea-pigs were cumulative, i.e. the amounts consumed by those dying on diets containing 25 and 50 ppm were similar to the acute oral LDs0 and the logarithmic mean survival time on 25 ppm was twice that on 50 ppm. Striking evidence of accumulation has also been presented by Scholz (Nature, Lond. 1965, 207, 870). From our previous results it was calculated that if triphenyltin acetate was completely cumulative in the guinea-pig, a diet containing 12 ppm should lead to death after 86--106 days. This proposition has now been tested. Six male guinea-pigs obtained from AUington Farm, Porton, Wiltshire were kept separately and fed on powdered R.G.P. diet (Dixon & Sons (Ware) Ltd.), containing 12 ppm triphenyltin acetate obtained from Dr. G. J. M. Van der Kerk, T.N.O., Utrecht. These were compared with six pair-fed controls. The body weight ( m e a n + S D ) at the be~nning of the experiment was 308-4-29 g. At the end of 1 yr, only one of the treated guinea-pigs was still alive. All the pair-fed controls gained weight during the period of pair-t:eeding. After the death of the treated member of the pair the control was fed ad lib. and all the control guinea-pigs were alive and well at the end of the year. The treated guinea-pigs grew more slowly than their pair-fed controls and the toxic signs before death were the same as in the previous experiments. At autopsy it was noteworthy that in three of these animals (Nos 22, 24 and 32) fluid was found in the pericardial sac and in one of them it was blood-stained (No. 32). Some fluid was also found in this site in one of the controls but the amount was less. On histological examination increased lipid was seen in the parenchymal cells of the liver in all the treated animals which died. Degenerative changes were seen in the myocardium in Nos 24 and 32. The survival times, the total dose of triphenyltin acetate and its rate of consumption are shown in Table 1. During the first month of the experiment the daily dose of the compound was approximately half that consumed by guinea-pigs on a diet containing 25 ppm (previous experiment S 43; Stoner, loc. cit.). As the experiment proceeded, the amount of the compound taken per day fell. Table. 1.
Surviva•timeandd•serateinguinea-pigsgivenadietc•ntaining12ppmtripheny•tinacetatef•rup
lyr Approximate average daffy dose (mg/kg body welght/day)
Ammal Survivaltime no. (days) 29 22 22 248 27 259 24 294 32 306 28 S S=Alive at end of expertment.
1-28 days -0-83 1"15 1"10 1"22 1-23
200-228days -0"45 0"73 0.76 0.93 0"77 285
Overall 0"89 0-81 0.87 0.96 0"80 0"98
to
Total dose consumed (mg/kg body weight) 19 196 247 277 279 352
286
LIz-IIERS TO THE EDITOR
It is clear from the survival times and the total amounts consumed that at this dosage level triphenyltin is not completely cumulative. If guinea-pig No. 29 is excluded these and previous results (Stoner, loc. cit.) are consistent with a half-life of triphenyltin at the site of action of about 50 days. It is possible, however, that the compound is more cumulative than this and that guinea-pigs develop some degree of tolerance when repeated small doses are given for long periods. H. B. STONEg and D. F. HEATH,
Medical Research Council Laboratories, Woodmansterne Road, Carshalton, Surrey, England Acknowledgements--Our t h a n k s
are due to Mrs. A K e t t e m a n a n d Mrs. M. Blyth for their careful technical
assistance.
FREE F O R M A L D E H Y D E FROM PLASTICS DISHES Sir,--A query was raised concerning the possibility of free formaldehyde being extracted from dishes made from urea or melamine resins if hot liquids were poured into them. Since information on this subject was not readily available, two plastics dishes were obtained for testing from a local retail outlet. One was a small brown bowl, the other was a flatter, white dish; both were made of thermosetting plastics. Boiling water was used in the first test. Approximately i00 ml boiling water was poured into each dish; after 30 rain the water had returned to room temperature and triplicate 2-ml samples were taken for the determination of formaldehyde by the method of Nash (Biochem. J. 1953, 55, 416). Both distilled water and tap water were used. All samples gave a very small positive response, less than 0.1 ppm formaldehyde. (Here and throughout, ppm are based on the 100 ml solution used.) Three additional extractants (3 Yo sodium chloride, 3 ~o acetic acid and 3 ~o sodium bicarbonate) were used in a second test, following the lines suggested in "Information Required for the Consideration of Packaging Materials" (Internal Memorandum of Food and Drug Directorate, Ottawa, Canada, 1961). As before, I00 ml boiling solution was poured into each bowl, and tested for formaldehyde after it had cooled. Again, trace amounts were found in each case (less than 0.2 ppm). Since plastics dishes become scratched in use, an extreme test was devised. Boiling solvent (100 ml of each of those used before) was poured into beakers containing 8 g of pieces of the broken dishes, each piece being approximately 3 c m × 1.5 cm. The eight beakers (four solvents on two plastics) were covered with watch-glasses and placed in an oven maintained at 57°C. Samples were taken for analysis at I, 2, 4, 6, 24 and 28 hr. In general, all solvents gave similar results. Less than 2 ppm formaldehyde was extracted in the first hour, with the amount gradually rising to an average of 2.3 ppm at 2 hr, 3-5 ppm at 4 hr, 4.8 ppm at 6 hr and 19 ppm at 28 hr. Exceptions were (1) the water extract from the white pieces which was consistently low, reaching only 10 ppm at 28 hr, and (2) the acetic acid extract from the brown pieces which was consistently high, reaching 33 ppm at 28 hr. The results at 24 hr are not quoted, as the sample sizes used were such as to make the results only very approximate. They did, however, indicate the ranges subsequently found at 28 hr.