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4 male sheep (average weight: 53.5 kgs) were fed a semisynthetic diet containing acetamide as sole source of nitrogen. At the beginning of the trial twin-labelled 15N-14C-acetamide was administered by way of a ruminal fistula. The curve pattern of 14C activity in the TCE-soluble fraction of the ruminal fluid showed a synchronous behaviour in all animals beginning at 3 hours after the beginning of the trial. A half-life of 2 1/2 hours for the rate of absorption of 14C acetamide and deaminated 14C acetate was established from the decline in 14C activity observed in the TCE-soluble fraction of the ruminal fluid. The peak level of 14C labelling in ruminal proteins was reached after 6 hrs. The specific 14CO2 activity in respiratory air reached its maximum level after 4 hrs, and was then found to decline continuously. 56% of the administered amount of 14C was excreted over a period of up to 50 hrs after beginning of the trial. The very fact that the peak level of 14C activity was observed to appear in the TCE-soluble fraction of the blood plasma as early as after 1 hr seems to indicate that acetamide is also absorbed through the ruminal wall. The half-life of decline in the 14C activity of this fraction was 5.7 hrs. Analysis by thin layer chromatography showed that 75% of this amount of activity is present in 14C acetamide. The rate of 14C incorporation into blood plasma proteins reached a plateau region after 21 hrs, which was also maintained on the 2nd day of the experiment. 6.5% of the administered amount of 14C activity was excreted in the urine until the 7th day of experiment. 76.6% of the amount of urinary 14C activity excreted within a period of 48 hrs were voided as 14C acetamide. 3.8% of the administered amount of 14C activity was excreted with the faeces within the first 6 days of experiment.
4 male sheep (average weight: 53.5 kgs) were fed a semisynthetic diet containing acetamide as sole source of nitrogen. At the beginning of the trial twin-labelled 15N-14C-acetamide was administered by way of a ruminal fistula. The curve pattern of 14C activity in the TCE-soluble fraction of the ruminal fluid showed a synchronous behaviour in all animals beginning at 3 hours after the beginning of the trial. A half-life of 2 1/2 hours for the rate of absorption of 14C acetamide and deaminated 14C acetate was established from the decline in 14C activity observed in the TCE-soluble fraction of the ruminal fluid. The peak level of 14C labelling in ruminal proteins was reached after 6 hrs. The specific 14CO2 activity in respiratory air reached its maximum level after 4 hrs, and was then found to decline continuously. 56% of the administered amount of 14C was excreted over a period of up to 50 hrs after beginning of the trial. The very fact that the peak level of 14C activity was observed to appear in the TCE-soluble fraction of the blood plasma as early as after 1 hr seems to indicate that acetamide is also absorbed through the ruminal wall. The half-life of decline in the 14C activity of this fraction was 5.7 hrs. Analysis by thin layer chromatography showed that 75% of this amount of activity is present in 14C acetamide. The rate of 14C incorporation into blood plasma proteins reached a plateau region after 21 hrs, which was also maintained on the 2nd day of the experiment. 6.5% of the administered amount of 14C activity was excreted in the urine until the 7th day of experiment. 76.6% of the amount of urinary 14C activity excreted within a period of 48 hrs were voided as 14C acetamide. 3.8% of the administered amount of 14C activity was excreted with the faeces within the first 6 days of experiment.
Three fistula sheep with average weights of 52.2 kgs were given 37.9 g of 15N and 14C labelled acetamide (= 1.09 mg 15N' and 0,95 mCi14C) which were administered directly through the fistula. The half-life period of 15N retention in the ruminal fluid (TCE soluble portion) was found to be 4 hrs. 18 hrs after 15N administration increasing amounts of 15N were carried back to the rumen by way of the rumino-hepatic circulation. The 15N concentration in the blood (TCE soluble portion) rapidly increased up to a peak value and, from 3 hrs after isotope administration, the 15N concentration was found to decline continuously, with a slight discontinuation at about the 10th hr of experiment. The rate of 15N incorporation into the protein fraction (TEC soluble portion) of the blood was delayed by 4 hrs, relative to the rate of 15N incorporation into ruminal proteins. An average of 43.1% of the administered amount of 15N was excreted in the urine within 7 days. Up to the 4th day of experiment the half-life period of urinary 15N excretion was 19 hrs. An average of 15% of the administered total amount of 15N was excreted in the faeces. In this process, the peak values in both TCE fractions were observed to occur on the 2nd day of experiment. The proportion of isotope in the TCE soluble fraction was found to increase continuously compared with the total amount of the isotope excreted in the faeces. Isotope concentrations between 0.03 and 0.13 atom% of surplus 15N were found in organ and muscle tissues of a sheep that had been slaughtered 7 days after administration of the isotope. The results obtained are discussed on the basis of comparisons made with the analogous behaviour of 14C activity.
The industrial use of certain acetamides and formamides (particularly DMAC and DMF) for their solvent properties has resulted in rather extensive examination of their biological properties. Both DMAC and DMF are rapidly absorbed through biological membranes and are metabolized by demethylation first to monomethyl derivatives and then to the parent acetamide or formamide. Relatively high single doses to various species following oral, dermal, i.p., i.v., or inhalation exposures generally are required to produce mortality. The liver is the primary target following acute high level exposure, but massive doses can also produce damage to other organs and tissues. Repeated sublethal treatment by various routes also shows the liver to be the target organ with the degree of damage being proportional to the amount absorbed. With MMF, the potential usefulness as a cancer chemotherapeutic agent needs to be measured against the hepatotoxic effects produced in man. Acetamides and formamides are generally inactive in mutagenicity tests. Mammalian test systems do not appear to be genetically sensitive and DMF has been recommended for use as the vehicle in microbial assays designed to test for genetic activity of hard-to-dissolve chemicals. Embryotoxicity can be demonstrated at high doses; doses which generally show toxicity to the maternal animals. Structural abnormalities in sensitive species such as the rabbit are produced following exposure at near-lethal levels. The spectrum of abnormalities seen is broad and fails to show any time or site specificity in terms of developing organs/organ systems. Inhalation exposures to DMAC and DMF at levels producing some maternal toxicity in rats have produced no teratogenic response and only slight evidence of embryotoxicity. Long-term feeding of relatively high levels of acetamide produces liver cancer in rats. DMAC and DMF appear to be noncarcinogenic. The environmental toxicity of these chemicals is low. Liver damage can be produced by overexposure to these chemicals in man. Airborne concentrations need to be controlled and care should be taken to avoid excessive liquid contact as the chemicals are absorbed through the skin. A relationship exists between the amount of DMAC or DMF absorbed and the amount of MMAC or MMF excreted in the urine so that biomonitoring of the urinary metabolites can indicate situations in which total exposures, both dermal and inhalation, are excessive. An interaction between DMF and ethanol occurs such that signs, including severe facial flushing, appear when DMF-exposed individuals consume alcoholic beverages.
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