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1436. Methanol: Neat or well diluted
828
PROCESSING AND PACKAGING CONTAMINANTS
It remains to be seen whether the ability of II to hydrolyse I in vivo contributes in any way to its acute toxicity. [Although the liver was no doubt chosen for its ease of workability, work on the brain would have been more appropriate.] 1434. Species difference in toxicity of 2;6-diehioro-4-nitroanillne Serrone, D. M., Pakdaman, P., Stein, A. A. & Coulston, F. (1967). Comparative toxicology of 2,6-dichloro-4-nitroaniline in rats and rhesus monkeys. Toxic. appl. Pharmac. 10, 404. 2,6-Dichloro-4-nitroaniline (Botran; I) is used as an agricultural fungicide. It has a very low acute oral toxicity in rats (LDso, 8 g/kg). The present study, reported briefly, shows it to be much more toxic to monkeys than to rats. Thus whereas rats tolerated daily oral doses of 400 mg/kg for 3 months and only a few animals died at 1000 mg/kg, monkeys fed 160 mg/kg/day all died within 3 months, females being more susceptible than males. The lack of coloration of monkey urine and orange coloration of rat urine indicated different routes of metabolism in the two species. Another species difference found was that in rats, but not in monkeys, I caused liver enlargement and enhanced activity of microsomal processing enzymes (demethylase and desulphurase) accompanied by increased oxygen utilization by liver mitochondria. I produced structural alterations in the liver and kidney in both rats and monkeys, including centrilobular fatty infiltration of monkey liver. Swelling of liver and kidney mitochondria and distortion of the cristae were also observed in monkeys. [As far as the rat is concerned we now know that 2,6-dichloro-4-nitroaniline is metabolized to chlorinated aminophenols and phenylenediamine derivatives (M~t6 et al. Fd Cosmet. Toxicol. 1967, 5, 657). Radiotracer techniques have also demonstrated rapid absorption and elimination from the body.] 1435. Acute toxicity of chlorinated pyridines Gehring, P. J., Torkelson, T. R. & Oyen, F. (1967). Acute toxicity of chlorinated pyridines. Toxic. appL Pharmac. 10, 403. Chlorinated pyridine derivatives, the subject of this preliminary report, find application as herbicides. The acute toxicity of these compounds has been determined in mice, rabbits and rats. Intraperitoneal LDso values in mice ranged from 0.82 meq/kg for the 2,3,6-trichloro derivative to 11.42 meq/kg for 2,5-dichloropyridine. The acute oral LDso of 2-chloropyridine (I) was found to be 0.97 meq/kg. In rabbits, I was equally toxic when given by the dermal and intraperitoneal routes (no values given). In a rat-inhalation study on I, 100~o mortality occurred at 1000 ppm for 1 hr, 500 ppm for 2 hr and 250 ppm for 7 hr; 0Yo mortality occurred under various conditions ranging from 1000 ppm for 6 min to 50 ppm for 4 hr. Histopathological change (mainly centrilobular necrosis, haemorrhage, fatty degeneration and perivascular cuffing of the liver) was discernible under various exposure conditions ranging from 500 ppm for 3 rain to 50 ppm for 30 rain.
PROCESSING AND PACKAGING CONTAMINANTS 1436. Methanol: Neat or well diluted Riegel, H. & Wolf, G. (1966). Schwere neurologische Ausf'~lle als Folge einer Methylalkoholvergiftung. Fortschr. Neurol. Psychiat. 34, 346. Eckes, P. (1966). Die Bildung und Toxizifiit yon Methylalkohol in Getr~inken. Obst- u. Gem~e-Verw. 51, 223. The toxic effects of methanol (I) are well known, but for various reasons fatal cases of poisoning are still comparatively common. Reporting primarily on the neurological effects,
PROCESSING AND PACKAGING CONTAMINANTS
829
Riegel & Wolf (cited above) describe the severe reactions encountered in one survivor from a party of eight who drank a spirit subsequently identified as I. Regaining consciousness after three days, the patient was very weak and unable to speak or swallow. Her eyesight was permanently and severely impaired and disturbances of movement associated with irreparable brain damage still make walking difficult 20 yr later. Many of the neurological symptoms are very reminiscent of Parkinson's syndrome and reflect in general a severe extrapyramidal disorder. While the drinking of I is clearly inadvisable, this alcohol is not entirely absent from our food and drink. Detectable traces of I in potable spirits have for some time been attributed to the enzymatic hydrolysis of pectin, a high molecular weight polymer of galacturonic acid, which is esterified to a varying extent with I. Pectin is present in many foods, apart from fruit and potable liquors and Eckes (cited above) has reviewed the possible fate of this inevitable daily intake of I. Several studies indicate that I freed in the alimentary tract is converted mainly to formic acid following absorption, very little being excreted unchanged in either faeces or urine. Levels of I in fruit juices range from 38 mg/1 in freshly pressed apple juice to 231 mg/l in blackcurrant juice. Such levels fall well short of providing an effective dose, since an intake of about 20 g I is required to evoke toxic signs even in sensitive persons. The higher levels of I found in brandies prepared from grape marc may, however, contribute to the liver damage attributable primarily to ethanol and resulting from a high daily consumption of this spirit. The snag about removing I from potable liquors is that the process (heating the juice to 65°C and spraying in vacuum) also removes many of the volatile aromatic constituents-and where would brandy be without its bouquet ? 1437. Metabolic fate of Tergitol TP-9 Knaak, J. B., Eldridge, Jane M. & Sullivan, L. J. (1966). Excretion of certain polyethylene glycol ether adducts of nonylphenol by the rat. Toxic. appl. Pharmac. 9, 331. The polyethylene glycol ether adducts of nonylphenol (NP) are being used increasingly as detergents and wetting agents. Unpublished findings on one of these, Tergitol TP-9 (I), which contains on an average 9 moles of ethylene oxide (EO)/mole of NP, indicated that it has negligible long-term oral toxicity. Its metabolic fate has now been investigated in rats. In order to study the metabolism of both the NP and EO adduct moieties, I was labelled separately with carbon-14 (14C) in each moiety and a single dose of each label was administered to rats. Over a period of 7 days, 39 7o of the 14C from EO-labelled I was excreted in the urine in comparison with 20 70 for NP-labelled I. The smaller urinary excretion in the latter case was compensated for by a 25 7o increase in faecal 14C over the 52 70 found in the faeces of rats given EO-labelled I. Labelled NP per se behaved similarly to NP-labelled I. The results of other experiments, in which the 7-, 10-, 12- and 15-mole EO-labelled adducts of NP were administered, showed that intestinal absorption decreased as the molecular weight or adduct number increased. The 12- and 15-mole adducts were excreted to a greater extent in the faeces than in the urine and the reverse situation held for the 7- and 10-mole adducts. Ion-exchange chromatographic studies of the urinary metabolites of EO- and NP-labelled I showed that the principal metabolites of I are the mono- and dicarboxylic acids of polyethylene glycol and the glucuronic acid conjugates of NP. Only 1.2 70 of the total carbon of I (derived from the EO moiety) was oxidized to CO2. The almost quantitative recovery of ~4C in the excreta indicates that neither I nor its metabolites will accumulate in the body following ingestion of I.
1438. Triton for slimming? Pawar, S. S. & Tidwell, H. C. (1966). Effect of triton ingestion on fat retention, blood lipids and growth in rats. Proc. Soc. exp. Biol. Med. 122, 665.
PROCESSING AND PACKAGING CONTAMINANTS
It remains to be seen whether the ability of II to hydrolyse I in vivo contributes in any way to its acute toxicity. [Although the liver was no doubt chosen for its ease of workability, work on the brain would have been more appropriate.] 1434. Species difference in toxicity of 2;6-diehioro-4-nitroanillne Serrone, D. M., Pakdaman, P., Stein, A. A. & Coulston, F. (1967). Comparative toxicology of 2,6-dichloro-4-nitroaniline in rats and rhesus monkeys. Toxic. appl. Pharmac. 10, 404. 2,6-Dichloro-4-nitroaniline (Botran; I) is used as an agricultural fungicide. It has a very low acute oral toxicity in rats (LDso, 8 g/kg). The present study, reported briefly, shows it to be much more toxic to monkeys than to rats. Thus whereas rats tolerated daily oral doses of 400 mg/kg for 3 months and only a few animals died at 1000 mg/kg, monkeys fed 160 mg/kg/day all died within 3 months, females being more susceptible than males. The lack of coloration of monkey urine and orange coloration of rat urine indicated different routes of metabolism in the two species. Another species difference found was that in rats, but not in monkeys, I caused liver enlargement and enhanced activity of microsomal processing enzymes (demethylase and desulphurase) accompanied by increased oxygen utilization by liver mitochondria. I produced structural alterations in the liver and kidney in both rats and monkeys, including centrilobular fatty infiltration of monkey liver. Swelling of liver and kidney mitochondria and distortion of the cristae were also observed in monkeys. [As far as the rat is concerned we now know that 2,6-dichloro-4-nitroaniline is metabolized to chlorinated aminophenols and phenylenediamine derivatives (M~t6 et al. Fd Cosmet. Toxicol. 1967, 5, 657). Radiotracer techniques have also demonstrated rapid absorption and elimination from the body.] 1435. Acute toxicity of chlorinated pyridines Gehring, P. J., Torkelson, T. R. & Oyen, F. (1967). Acute toxicity of chlorinated pyridines. Toxic. appL Pharmac. 10, 403. Chlorinated pyridine derivatives, the subject of this preliminary report, find application as herbicides. The acute toxicity of these compounds has been determined in mice, rabbits and rats. Intraperitoneal LDso values in mice ranged from 0.82 meq/kg for the 2,3,6-trichloro derivative to 11.42 meq/kg for 2,5-dichloropyridine. The acute oral LDso of 2-chloropyridine (I) was found to be 0.97 meq/kg. In rabbits, I was equally toxic when given by the dermal and intraperitoneal routes (no values given). In a rat-inhalation study on I, 100~o mortality occurred at 1000 ppm for 1 hr, 500 ppm for 2 hr and 250 ppm for 7 hr; 0Yo mortality occurred under various conditions ranging from 1000 ppm for 6 min to 50 ppm for 4 hr. Histopathological change (mainly centrilobular necrosis, haemorrhage, fatty degeneration and perivascular cuffing of the liver) was discernible under various exposure conditions ranging from 500 ppm for 3 rain to 50 ppm for 30 rain.
PROCESSING AND PACKAGING CONTAMINANTS 1436. Methanol: Neat or well diluted Riegel, H. & Wolf, G. (1966). Schwere neurologische Ausf'~lle als Folge einer Methylalkoholvergiftung. Fortschr. Neurol. Psychiat. 34, 346. Eckes, P. (1966). Die Bildung und Toxizifiit yon Methylalkohol in Getr~inken. Obst- u. Gem~e-Verw. 51, 223. The toxic effects of methanol (I) are well known, but for various reasons fatal cases of poisoning are still comparatively common. Reporting primarily on the neurological effects,
PROCESSING AND PACKAGING CONTAMINANTS
829
Riegel & Wolf (cited above) describe the severe reactions encountered in one survivor from a party of eight who drank a spirit subsequently identified as I. Regaining consciousness after three days, the patient was very weak and unable to speak or swallow. Her eyesight was permanently and severely impaired and disturbances of movement associated with irreparable brain damage still make walking difficult 20 yr later. Many of the neurological symptoms are very reminiscent of Parkinson's syndrome and reflect in general a severe extrapyramidal disorder. While the drinking of I is clearly inadvisable, this alcohol is not entirely absent from our food and drink. Detectable traces of I in potable spirits have for some time been attributed to the enzymatic hydrolysis of pectin, a high molecular weight polymer of galacturonic acid, which is esterified to a varying extent with I. Pectin is present in many foods, apart from fruit and potable liquors and Eckes (cited above) has reviewed the possible fate of this inevitable daily intake of I. Several studies indicate that I freed in the alimentary tract is converted mainly to formic acid following absorption, very little being excreted unchanged in either faeces or urine. Levels of I in fruit juices range from 38 mg/1 in freshly pressed apple juice to 231 mg/l in blackcurrant juice. Such levels fall well short of providing an effective dose, since an intake of about 20 g I is required to evoke toxic signs even in sensitive persons. The higher levels of I found in brandies prepared from grape marc may, however, contribute to the liver damage attributable primarily to ethanol and resulting from a high daily consumption of this spirit. The snag about removing I from potable liquors is that the process (heating the juice to 65°C and spraying in vacuum) also removes many of the volatile aromatic constituents-and where would brandy be without its bouquet ? 1437. Metabolic fate of Tergitol TP-9 Knaak, J. B., Eldridge, Jane M. & Sullivan, L. J. (1966). Excretion of certain polyethylene glycol ether adducts of nonylphenol by the rat. Toxic. appl. Pharmac. 9, 331. The polyethylene glycol ether adducts of nonylphenol (NP) are being used increasingly as detergents and wetting agents. Unpublished findings on one of these, Tergitol TP-9 (I), which contains on an average 9 moles of ethylene oxide (EO)/mole of NP, indicated that it has negligible long-term oral toxicity. Its metabolic fate has now been investigated in rats. In order to study the metabolism of both the NP and EO adduct moieties, I was labelled separately with carbon-14 (14C) in each moiety and a single dose of each label was administered to rats. Over a period of 7 days, 39 7o of the 14C from EO-labelled I was excreted in the urine in comparison with 20 70 for NP-labelled I. The smaller urinary excretion in the latter case was compensated for by a 25 7o increase in faecal 14C over the 52 70 found in the faeces of rats given EO-labelled I. Labelled NP per se behaved similarly to NP-labelled I. The results of other experiments, in which the 7-, 10-, 12- and 15-mole EO-labelled adducts of NP were administered, showed that intestinal absorption decreased as the molecular weight or adduct number increased. The 12- and 15-mole adducts were excreted to a greater extent in the faeces than in the urine and the reverse situation held for the 7- and 10-mole adducts. Ion-exchange chromatographic studies of the urinary metabolites of EO- and NP-labelled I showed that the principal metabolites of I are the mono- and dicarboxylic acids of polyethylene glycol and the glucuronic acid conjugates of NP. Only 1.2 70 of the total carbon of I (derived from the EO moiety) was oxidized to CO2. The almost quantitative recovery of ~4C in the excreta indicates that neither I nor its metabolites will accumulate in the body following ingestion of I.
1438. Triton for slimming? Pawar, S. S. & Tidwell, H. C. (1966). Effect of triton ingestion on fat retention, blood lipids and growth in rats. Proc. Soc. exp. Biol. Med. 122, 665.