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Postscript on amaranth?
TOXICOLOGY:
BIBRA
ABSTRACTS
COLOURING
AND
COMMENTS
MATTERS
3194. Postscript on amaranth?
3195. Tobias acid eliminated
Khera, K. S., Roberts, G., Trivett, G., Terry, G. & Whalen, C. (1976). A teratogenicity study with amaranth in cats. Toxic. nppl. Phnrmnc. 38, 389.
Marchisio, M. A., Dubini, M., Serra, & Manara, L. (1976). Excretion of (2-naphthylamino, I-sulphonic acid) oral and intravenous administration. 33, 269.
A suggestion (Drake, Frl Cosrnet. Toxicol. 1977, 15, 153) that the last word might have been expressed on amaranth teratology has proved premature. No sooner had a series of studies in various mammalian species apparently established that amaranth was not embryotoxic in maternally tolerated doses than data from a study in the cat, a species not previously used in this context, renewed doubts about the colouring’s safety with respect to gonadal and foetal development (Report of the Comptroller General of the United States Food and Drug Administration, MWD-76-40, 20 October 1975). A further study was undertaken, therefore, in which groups of approximately 20 female cats were dosed daily for cl6 days before pregnancy and then throughout the gestation period, with one, two or three gelatin capsules each containing 305 mg amaranth. giving a total daily dose of approximately 92. 187 or 264 mg/kg at the onset of pregnancy. The 43 controls were given three placebos each day. If oestrus did not occur naturally within 15 days of the start of amaranth treatment. it was induced by injection of pregnant-mare serum gonadotrophin, and ovulation was stimulated in all the cats by injection of human chorionic gonadotrophin before mating. Caesarean sections were performed on day 61 or 62 of gestation and all live foetuses were incubated for 24 hr to determine the survival rate, after which some foetuses from each litter were prepared for visceral examination and the rest were processed for determination of skeletal defects. A red coloration of mucous membranes, skin, urine and faeces indicated that, in the cat, not all the amaranth administered was degraded to non-dye metabolites prior to distribution to the tissues. However, records of maternal body-weight gain, numbers of corpora lutea and incidences of pregnancy and abortion produced no evidence of any adverse effects related to the amaranth treatments. Data on total implantations, resorptions, dead foetuses, litter sizes, 24-hr postnatal viability, foetal weight, sex ratios of live foetuses and the incidence of foetal anomalies also showed no differences between control and treated animals indicative of any adverse effect by amaranth on the foetal development of the cat. It was concluded, therefore, that results in this species supported those previously obtained in the mouse (Larsson, Toxicology 1975, 4, 75), rat (Khera er al. Fd Comet Toxicol. 1974, 12, 507; Cited in F.C.~: 1975, 13, 473 & 1977, 15, 153). rabbit (ibid 1975, 13, 473) and dog (Mastalski et nl. Toxic. appl. Pharmnc. 1975, 33, 122).
G., Mennini, T. %-Tobias acid by the rat after Br. J. ind. Med.
Tobias acid (2-naphthylamine-I-sulphonic acid), an important dyestuffs intermediate, is not a known carcinogen in animals or man. However it differs from the powerful carcinogen /3-naphthylamine only in the presence of a sulphonic group ortho to the amino group, and an investigation of possible metabolic cleavage to free fl-naphthylamine was considered desirable. Six rats were given 35S-labelled Tobias acid (1 mg/kg) by the oral or iv roptes, and radioactivity in urine and faeces was determined for the next 3 days. After iv administration, most of the 35S excreted within 72 hr appeared in the urine in the first 24 hr; after 72 hr 71-86% had been eliminated by this route. Small amounts (O&2.6%) were detected in the faeces. After oral administration prompt elimination again occurred, and by 72 hr 29-55% had appeared in the urine and 2444% in the faeces, giving a total excretion of 69-85%. Chromatography of urine and faeces revealed a single peak of activity at the same R, as Tobias acid, and there was no loss of urinary activity after addition of barium chloride, confirming the absence of significant amounts of free 35S-labelled sulphate. As no attempt was made to wash the cages, it was assumed that the activity not recovered was trapped therein, although no analysis of body tissues was made. The results indicate that Tobias acid is rapidly eliminated unchanged, without significant cleavage, conjugation or biotransformation. This is consistent with the finding that no metabolism takes place if the amino group of an arylaminosulphonic acid is hindered by an adjacent group or ring (McMahon & O’Reilly, Fd Cosmet. Toxicol. 1969, 7, 497). Further investigation using ring-labelled Tobias acid of high specific activity would lower the limit of 2-naphthylamine detection and permit a more definite conclusion to be drawn. 3196. How the microflora
deals with dyes
Larsen, J. C., Meyer, T. & Scheline, R. R. (1976). Reduction of sulphonated water-soluble azo dyes by caecal microorganisms from the rat. Acta pharmac. tox. 38, 353.
487 F.C.T. I 515-H
unchanged
The reduction of azo dyes such as amaranth by the gut microflora is well established (Cited in F.C.?: 1977, 15, 77), and many nitro compounds may be reduced by the flora to more toxic metabolites (ibid 1977, 15, 262).
BIBRA
ABSTRACTS
COLOURING
AND
COMMENTS
MATTERS
3194. Postscript on amaranth?
3195. Tobias acid eliminated
Khera, K. S., Roberts, G., Trivett, G., Terry, G. & Whalen, C. (1976). A teratogenicity study with amaranth in cats. Toxic. nppl. Phnrmnc. 38, 389.
Marchisio, M. A., Dubini, M., Serra, & Manara, L. (1976). Excretion of (2-naphthylamino, I-sulphonic acid) oral and intravenous administration. 33, 269.
A suggestion (Drake, Frl Cosrnet. Toxicol. 1977, 15, 153) that the last word might have been expressed on amaranth teratology has proved premature. No sooner had a series of studies in various mammalian species apparently established that amaranth was not embryotoxic in maternally tolerated doses than data from a study in the cat, a species not previously used in this context, renewed doubts about the colouring’s safety with respect to gonadal and foetal development (Report of the Comptroller General of the United States Food and Drug Administration, MWD-76-40, 20 October 1975). A further study was undertaken, therefore, in which groups of approximately 20 female cats were dosed daily for cl6 days before pregnancy and then throughout the gestation period, with one, two or three gelatin capsules each containing 305 mg amaranth. giving a total daily dose of approximately 92. 187 or 264 mg/kg at the onset of pregnancy. The 43 controls were given three placebos each day. If oestrus did not occur naturally within 15 days of the start of amaranth treatment. it was induced by injection of pregnant-mare serum gonadotrophin, and ovulation was stimulated in all the cats by injection of human chorionic gonadotrophin before mating. Caesarean sections were performed on day 61 or 62 of gestation and all live foetuses were incubated for 24 hr to determine the survival rate, after which some foetuses from each litter were prepared for visceral examination and the rest were processed for determination of skeletal defects. A red coloration of mucous membranes, skin, urine and faeces indicated that, in the cat, not all the amaranth administered was degraded to non-dye metabolites prior to distribution to the tissues. However, records of maternal body-weight gain, numbers of corpora lutea and incidences of pregnancy and abortion produced no evidence of any adverse effects related to the amaranth treatments. Data on total implantations, resorptions, dead foetuses, litter sizes, 24-hr postnatal viability, foetal weight, sex ratios of live foetuses and the incidence of foetal anomalies also showed no differences between control and treated animals indicative of any adverse effect by amaranth on the foetal development of the cat. It was concluded, therefore, that results in this species supported those previously obtained in the mouse (Larsson, Toxicology 1975, 4, 75), rat (Khera er al. Fd Comet Toxicol. 1974, 12, 507; Cited in F.C.~: 1975, 13, 473 & 1977, 15, 153). rabbit (ibid 1975, 13, 473) and dog (Mastalski et nl. Toxic. appl. Pharmnc. 1975, 33, 122).
G., Mennini, T. %-Tobias acid by the rat after Br. J. ind. Med.
Tobias acid (2-naphthylamine-I-sulphonic acid), an important dyestuffs intermediate, is not a known carcinogen in animals or man. However it differs from the powerful carcinogen /3-naphthylamine only in the presence of a sulphonic group ortho to the amino group, and an investigation of possible metabolic cleavage to free fl-naphthylamine was considered desirable. Six rats were given 35S-labelled Tobias acid (1 mg/kg) by the oral or iv roptes, and radioactivity in urine and faeces was determined for the next 3 days. After iv administration, most of the 35S excreted within 72 hr appeared in the urine in the first 24 hr; after 72 hr 71-86% had been eliminated by this route. Small amounts (O&2.6%) were detected in the faeces. After oral administration prompt elimination again occurred, and by 72 hr 29-55% had appeared in the urine and 2444% in the faeces, giving a total excretion of 69-85%. Chromatography of urine and faeces revealed a single peak of activity at the same R, as Tobias acid, and there was no loss of urinary activity after addition of barium chloride, confirming the absence of significant amounts of free 35S-labelled sulphate. As no attempt was made to wash the cages, it was assumed that the activity not recovered was trapped therein, although no analysis of body tissues was made. The results indicate that Tobias acid is rapidly eliminated unchanged, without significant cleavage, conjugation or biotransformation. This is consistent with the finding that no metabolism takes place if the amino group of an arylaminosulphonic acid is hindered by an adjacent group or ring (McMahon & O’Reilly, Fd Cosmet. Toxicol. 1969, 7, 497). Further investigation using ring-labelled Tobias acid of high specific activity would lower the limit of 2-naphthylamine detection and permit a more definite conclusion to be drawn. 3196. How the microflora
deals with dyes
Larsen, J. C., Meyer, T. & Scheline, R. R. (1976). Reduction of sulphonated water-soluble azo dyes by caecal microorganisms from the rat. Acta pharmac. tox. 38, 353.
487 F.C.T. I 515-H
unchanged
The reduction of azo dyes such as amaranth by the gut microflora is well established (Cited in F.C.?: 1977, 15, 77), and many nitro compounds may be reduced by the flora to more toxic metabolites (ibid 1977, 15, 262).