 Commonwealth of Australia 2010


Kinetics and Metabolism in Animals



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31.Kinetics and Metabolism in Animals


Many of the studies assessed in this chapter and Chapter 32 have been primarily summarised from the ATSDR (2006) review, though occasionally studies have also been summarised from the NTP (1993) review. However, primary sources of data were consulted where necessary. In addition, a comprehensive literature search was carried out of studies conducted from 1996 to date, for additional material of relevance to the hazard assessment, which has not been included in the ATSDR or other sourced reports or provided by importers or end-users of sodium cyanide and sodium cyanide products. References in the report that have not been sighted are marked with an asterisk(*).

Toxicokinetic data on sodium cyanide have been supplemented with data from other cyanogenic compounds. The basis for this approach is that cyanide (as hydrogen cyanide) originates in vivo following dissociation of cyanogenic compounds (e.g. sodium and potassium cyanide) or arising from catabolism of cyanogenic glycosides.

Human data are not considered in this report.

31.1Absorption


Absorption of cyanide occurs rapidly through the gastrointestinal tract, lungs and skin. While data on in vivo absorption rates are not available, the extremely rapid onset of symptoms after exposure to cyanide (CN-) makes it clear that cyanide is readily absorbed (NTP, 1993).

31.1.1Inhalation


*Gettler and Baine (1938) reported that for dogs exposed to an unknown concentration of HCN, one dog reportedly absorbed 16.0 mg (1.55 mg/kg bw); the other dog absorbed 10.1 mg (1.11 mg/kg bw). These values correlated to fatal doses, with deaths occurring in 15 and 10 minutes, respectively. However, the accuracy of the reported values from such an old and briefly reported study is questionable.

31.1.2Oral


The rate of absorption of cyanide from the gastrointestinal tract depends on the form of the cyanide and the presence of food in the tract (ATSDR, 2006). Food in the stomach delays the absorption of cyanide: dogs and cattle can be protected from the lethal effects of cyanide by the presence of carbohydrates in the stomach (*Couch, 1934; *Liebowitz and Schwartz, 1948). Conversely, cyanide can be released in lethal concentrations from cyanogenic glycosides in plants and foods; however, the uptake of cyanide in such cases is usually relatively slow, and the onset of symptoms is often delayed (*Towill et al., 1978). Absorption of cyanide from the gut across the gastrointestinal mucosa depends on the pH of the gut and the acid-base ionisation constant (pKa) and lipid solubility of the particular cyanide compound. HCN is a weak acid (pKa of 9.2 at 25°C), and the acidic environment in the stomach favours the non-ionised form (HCN) and facilitates absorption (ATSDR, 2006).

Rats excreted 47% of a cyanide dose in the urine during 24 hours following gavage treatment with 2 mg CN-/kg as radiolabelled potassium cyanide (KCN), indicating that at least 47% of the cyanide was absorbed in 24 hours (Farooqui and Ahmed, 1982). NaCN has high acute oral toxicity in rats (LD50 = 2.7 - 8 mg CN/kg bw).

Three dogs were given lethal doses of cyanide. The amount absorbed was determined by the difference between the cyanide given and the cyanide left in the gastrointestinal tract (*Gettler and Baine, 1938). The dogs died 8, 21 and 155 minutes after treatment and absorbed 17%, 24% and 72% of the given dose respectively. Considering the methodology employed, the accuracy of these values from such an old and briefly reported study are questionable.

31.1.3Dermal


Shaved and unshaved dogs were placed in a chamber in which their bodies, with the exception of the head and neck, were exposed to HCN vapour (*Walton and Witherspoon, 1926). No signs of toxicity were reported after exposure to 4975 ppm HCN for 180 minutes. Deaths occurred after exposure to 13 400 ppm HCN for 47 minutes and suggest dermal absorption, as do dermal LD50 values of 14.6 mg NaCN/kg bw, 22.3 mg KCN/kg bw and 7.0 mg HCN/kg bw (6.7 mg CN/kg bw) in the rabbit (Ballantyne, 1983).

Some cyanide compounds, such as KCN, have a corrosive effect on the skin that can increase the rate of dermal absorption (*NIOSH, 1976).


31.2Distribution and macromolecular binding


Although the distribution of cyanide to the various tissues in the body is fairly uniform, the highest levels are typically found in the liver, lungs, blood and brain (NTP, 1993).

31.2.1Inhalation


Once cyanide is absorbed, it rapidly distributes in blood throughout the body. In two dogs exposed to unspecified fatal concentrations of HCN, the highest cyanide levels were found in the lungs, blood, and heart (*Gettler and Baine, 1938). After inhalation exposure, the highest concentrations of cyanide in rats were found in the lungs, followed by the blood and the liver (*Yamamoto et al., 1982). Rabbits exposed to HCN at 2714 ppm for 5 minutes had blood and plasma cyanide levels of 170 and 48 µg/decilitre (dL). Wet tissue levels were 62, 54, 50, 6, 6 µg/l00 g and less than the detection level in the heart, lung, brain, kidney, spleen and liver respectively (Ballantyne, 1983).

31.2.2Oral


Once cyanide is absorbed, it rapidly distributes in blood throughout the body. Combined data from rats that died 3.3 and 10.3 minutes after gavage doses of 7 or 21 mg CN/kg (as NaCN) showed average tissue concentrations of cyanide in µg/g (w/w) of 8.9, 5.8, 4.9, 2.1 and 1.5 in the liver, lung, blood, spleen and brain respectively (*Yamamoto et al., 1982). In rats treated with 4 mg CN/kg as KCN, cyanide levels 1 hour after exposure were 3380 µg/g in liver, 748 µg/g in brain, and 550 µg/g in kidney (*Ahmed and Farooqui, 1982). Similarly, rabbits administered 11.9 to 20.3 mg CN/kg as HCN by gavage had blood and plasma cyanide levels of 480 and 252 g/dL respectively, and tissue levels (µg/100 g wet tissue) of 512, 107, 105, 95, 83 and 72 in the liver, lung, heart, brain, kidney and spleen respectively at the time of death (Ballantyne, 1983). In a study using radioactively labelled KCN, the radioactivity detected in whole blood or plasma of rats decreased rapidly within 6 hours (*Farooqui and Ahmed, 1982).

Cyanide has the potential to form a variety of adducts in biological systems. A study of radiolabelled cyanide binding to regions of the brains of mice revealed that the hypothalamus accumulated more radiolabel than the cerebral cortex, hippocampus, or cerebellum (*Borowitz et al., 1994). Binding to certain tissue constituents may be important for decreasing the actions of cyanide and protecting cells from cyanide toxicity (*Devlin et al., 1989). However, cyanide has not been shown to accumulate in blood and tissues following chronic oral exposure to inorganic cyanides. Virtually no cyanide was found in plasma or kidneys of male and female rats that received HCN in the diet at approximately 10.4 mg CN/kg bw/day for 2 years, and only low levels were found in erythrocytes and liver: 1.97 and 0.97 g/100 g respectively (Howard and Hanzal, 1955). At this dose level, levels of thiocyanate, a primary metabolite of cyanide, increased 3.5-fold in plasma, 3.3-fold in erythrocytes, 2.5-fold in kidneys and 1.3-fold in liver.


31.2.3Dermal


Once absorbed, cyanide is distributed throughout the body, as shown in a study by Ballantyne (1983). Six rabbits administered 33.8 mg CN/kg as HCN had blood and plasma cyanide levels of 310 and 144 µg/dL, respectively. Wet tissue levels (µg/100 g) were 120, 110, 97, 66, 26 and 21 in the lung, heart, brain, kidney, liver and spleen respectively.


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