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20. The toxicology of carbon black
106
FLAVOURING MATTERS, SOLVENTS AND SWEETENERS
in part for the differences in toxicity between members of this group of compounds. Webb, J. M. & Brouwer, E. (1962). Excretion patterns of fltiorescein and halogenated fluorescein dyes in rats. Fed. Proc. 21, 449. 18. F E E D I N G A N D INJECTION STUDIES IN RATS O N EOSINIC ACID Eosinic acid or tetrabromofluorescein (1) is of considerable importance in the cosmetics industry in which it is employed to colour lipsticks. While Willhelm et al. (Deutsche Forschungsgemeinschaft Farbstoff-Kommission Mitteilung 6, Steiner Verlag GMBH, Wiesbaden, 1957) reported that no tumours were produced by oral administration in rats and mice, Umeda (Gann 1955, 46, 367) detected 2 sarcomas in a group of 20 rats given weekly subcutaneous injections of I over a period of 1.5-2 yr. The latter result suggested that further study of the toxicology of I would be valuable. In the present feeding study, twenty 45-day-old rats received daily over their entire life-spans 0.5 g I in the free acid form, and a further 20 animals were given subcutaneously twice weekly 1 ml of a 4.5 ~o solution of I. The mean life-span of 624 days of the animals receiving I by mouth did not differ appreciably from the controls. Post-mortems on rats which died showed no effects which were attributable to I, regardless of the route employed. In particular no turnouts of the type observed by Umeda were found. The results demonstrate the suitability for inclusion in lipstick on safety grounds of the free acid form of I. Hiller, F. K. (1962). P ~ f u n g des Tetrabromfiuoresceins (Eosinsiiure) auf Vetr~glichkeit und Cancerogenitiit. Arzneimittel-Forsch. 12, 587. 19. POLYCYCLIC HYDROCARBONS I N R U B B E R A N D CARBON BLACKS No detectable amounts of polycyclic hydrocarbons can be eluted with hot benzene from channel carbon blacks, but furnace blacks have yielded extracts containing such hydrocarbons (Nan et al. Arch. induatr. Hlth. 1958, 17, 511). Extracts of the latter materials may induce turnouts when applied to the skin, or injected subcutaneously in animals (Steiner, Cancer Res. 1954, 14, 103). It was suggested that the elution of polycyclichydrocarbons from carbon black, used as a component of rubber tubing, conveyor belts, gaskets, or sealingmaterialsby oils,food juicecomponents or gastrointestinal juices may present a health hazard. To investigate this possibility, the present authors examined extracts obtained from channel and furnace carbon blacks and commercial rubber materials containing these materials, using as ¢xtractants human plasma, artificial gastric and intestinal juices, cottonseed oil, citric and acetic acids, sodium bicarbonate and sodium chloride solutions, and milk. No significant amounts of polycyclic hydrocarbons were eluted from the channel or furnace carbon blacks by human plasma, or artificial gastric or intestinal juices, and none of the extractants listed above eluted polycyciic hydrocarbons
from commercial rubber samples containing 10--20 ~o of carbon black. Attempts to elute with artificial gastric juice 3,4-benzpyrene which had been added deliberately to a channel carbon black sample failed; so firmly was it adsorbed. Neal, J., Thornton, M. & Nau, C. A. (1962). Polycyclic hydrocarbon elution from carbon black or rubber products. Arch. environ. Hlth. 4, 598. 20. T H E TOXICOLOGY OF CARBON BLACK In earlier studies the authors reported upon the effects of carbon black in animals to whom it was administered orally, subcutaneously or by application to the skin. Ingestion by mice for 12-18 month periods, of food containing 10~o of whole carbon black or whole carbon black which had been extracted with benzene, did not produce any gross or microscopic abnormalities(Nau et al. Arch. industr. Hlth. 1958, 17, 21). The authors now report that mice and monkeys that had inhaled high concentrations of channel or furnace carbon black for prolonged periods, showed no abnormalities when examined by post mortem, except the accumulation of carbon dust in the lungs. Minimal or no fibrous changes were observed at the sitesof accumulation. Nau, C. A., Neal, J., Stembridge, V. A. & Cooley, R. N. (1962). Physiologicaleffectsof carbon black. iv. Inhalation.Arch. environ. HIth. 4, 415.
Flavouring M a t t e r s , S o l v e n t s and Sweeteners 21. LIME OIL PROMOTES T U M O U R G R O W T H I N M O U S E STOMACH Skin turnouts may be initiated by, among other methods, a two-stage mechanism which involves administration of a sub-carcinogenic level of a carcinogenic compound (the 'initiator') followed by repeated applications of another substance, termed a 'promoter'. Such substances, of which an example is croton oil, have essentially no carcinogenic activity per se but assist in inducing tumour formation by a level of a carcinogen which alone would not do so. Roe & Peirce (J. nat. Cancer Inst. 1960, 2, 1389) showed that four different citrus oils promote tumour growth on mouse skin after pretreatment with a sub-carcinogenic dose of 9,10-dimethyl-1, 2-benTanthracene (DMBA). In the present paper the effect of treatment with these compounds on the gastro-intestinal tract is described. The author gave groups of 20 mice 100pg D M B A and 1, 2, 5, 50, or 200 Bg 3,4-benzpyrene (BP) by stomach tube followed after 21 days by weekly doses of 0.05 rnl lime oil. Autopsies on mice dying between 50 and 280 days, and on half the survivors at 280 days, showed that more tumours of the forestornach were found in the groups which received lime oil with D M B A or BP than in those which had D M B A or BP alone. In addition, a small number of tumours developed in mice given lime oil alone whereas none
FLAVOURING MATTERS, SOLVENTS AND SWEETENERS
in part for the differences in toxicity between members of this group of compounds. Webb, J. M. & Brouwer, E. (1962). Excretion patterns of fltiorescein and halogenated fluorescein dyes in rats. Fed. Proc. 21, 449. 18. F E E D I N G A N D INJECTION STUDIES IN RATS O N EOSINIC ACID Eosinic acid or tetrabromofluorescein (1) is of considerable importance in the cosmetics industry in which it is employed to colour lipsticks. While Willhelm et al. (Deutsche Forschungsgemeinschaft Farbstoff-Kommission Mitteilung 6, Steiner Verlag GMBH, Wiesbaden, 1957) reported that no tumours were produced by oral administration in rats and mice, Umeda (Gann 1955, 46, 367) detected 2 sarcomas in a group of 20 rats given weekly subcutaneous injections of I over a period of 1.5-2 yr. The latter result suggested that further study of the toxicology of I would be valuable. In the present feeding study, twenty 45-day-old rats received daily over their entire life-spans 0.5 g I in the free acid form, and a further 20 animals were given subcutaneously twice weekly 1 ml of a 4.5 ~o solution of I. The mean life-span of 624 days of the animals receiving I by mouth did not differ appreciably from the controls. Post-mortems on rats which died showed no effects which were attributable to I, regardless of the route employed. In particular no turnouts of the type observed by Umeda were found. The results demonstrate the suitability for inclusion in lipstick on safety grounds of the free acid form of I. Hiller, F. K. (1962). P ~ f u n g des Tetrabromfiuoresceins (Eosinsiiure) auf Vetr~glichkeit und Cancerogenitiit. Arzneimittel-Forsch. 12, 587. 19. POLYCYCLIC HYDROCARBONS I N R U B B E R A N D CARBON BLACKS No detectable amounts of polycyclic hydrocarbons can be eluted with hot benzene from channel carbon blacks, but furnace blacks have yielded extracts containing such hydrocarbons (Nan et al. Arch. induatr. Hlth. 1958, 17, 511). Extracts of the latter materials may induce turnouts when applied to the skin, or injected subcutaneously in animals (Steiner, Cancer Res. 1954, 14, 103). It was suggested that the elution of polycyclichydrocarbons from carbon black, used as a component of rubber tubing, conveyor belts, gaskets, or sealingmaterialsby oils,food juicecomponents or gastrointestinal juices may present a health hazard. To investigate this possibility, the present authors examined extracts obtained from channel and furnace carbon blacks and commercial rubber materials containing these materials, using as ¢xtractants human plasma, artificial gastric and intestinal juices, cottonseed oil, citric and acetic acids, sodium bicarbonate and sodium chloride solutions, and milk. No significant amounts of polycyclic hydrocarbons were eluted from the channel or furnace carbon blacks by human plasma, or artificial gastric or intestinal juices, and none of the extractants listed above eluted polycyciic hydrocarbons
from commercial rubber samples containing 10--20 ~o of carbon black. Attempts to elute with artificial gastric juice 3,4-benzpyrene which had been added deliberately to a channel carbon black sample failed; so firmly was it adsorbed. Neal, J., Thornton, M. & Nau, C. A. (1962). Polycyclic hydrocarbon elution from carbon black or rubber products. Arch. environ. Hlth. 4, 598. 20. T H E TOXICOLOGY OF CARBON BLACK In earlier studies the authors reported upon the effects of carbon black in animals to whom it was administered orally, subcutaneously or by application to the skin. Ingestion by mice for 12-18 month periods, of food containing 10~o of whole carbon black or whole carbon black which had been extracted with benzene, did not produce any gross or microscopic abnormalities(Nau et al. Arch. industr. Hlth. 1958, 17, 21). The authors now report that mice and monkeys that had inhaled high concentrations of channel or furnace carbon black for prolonged periods, showed no abnormalities when examined by post mortem, except the accumulation of carbon dust in the lungs. Minimal or no fibrous changes were observed at the sitesof accumulation. Nau, C. A., Neal, J., Stembridge, V. A. & Cooley, R. N. (1962). Physiologicaleffectsof carbon black. iv. Inhalation.Arch. environ. HIth. 4, 415.
Flavouring M a t t e r s , S o l v e n t s and Sweeteners 21. LIME OIL PROMOTES T U M O U R G R O W T H I N M O U S E STOMACH Skin turnouts may be initiated by, among other methods, a two-stage mechanism which involves administration of a sub-carcinogenic level of a carcinogenic compound (the 'initiator') followed by repeated applications of another substance, termed a 'promoter'. Such substances, of which an example is croton oil, have essentially no carcinogenic activity per se but assist in inducing tumour formation by a level of a carcinogen which alone would not do so. Roe & Peirce (J. nat. Cancer Inst. 1960, 2, 1389) showed that four different citrus oils promote tumour growth on mouse skin after pretreatment with a sub-carcinogenic dose of 9,10-dimethyl-1, 2-benTanthracene (DMBA). In the present paper the effect of treatment with these compounds on the gastro-intestinal tract is described. The author gave groups of 20 mice 100pg D M B A and 1, 2, 5, 50, or 200 Bg 3,4-benzpyrene (BP) by stomach tube followed after 21 days by weekly doses of 0.05 rnl lime oil. Autopsies on mice dying between 50 and 280 days, and on half the survivors at 280 days, showed that more tumours of the forestornach were found in the groups which received lime oil with D M B A or BP than in those which had D M B A or BP alone. In addition, a small number of tumours developed in mice given lime oil alone whereas none