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Description of key information

2,4- dinitrophenol (2,4-DNP) can readily enter in the body through inhalation, through the stomach if swallowed and probably can be absorbed through the skin. It is well metabolized and the parent compounds and metabolites are excreted in the urine. 2,4-DNP is an uncoupling of oxidative phosphorylation has the potential to affect all tissues and organs. 

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Additional information

The available data from human case reports and experimental animal studies indicate that 2,4 -dinitrophenol (2,4-DNP) is readily absorbed by the oral and inhalation routes. There is some evidence suggesting significant absorption through the skin as well.

The half-time for absorption of 2,4-DNP following gavage administration was 0.5 hours. Maximum values for the plasma concentration of 2,4-DNP were seen at 0.5 and 1.0 hours after dosing, giving additional evidence of rapid absorption (Robert et al., 1983).

The time course of plasma concentrations of 2,4-DNP following oral administration to dogs in Kaiser (1964) study confirmed substantial absorption of about 0.5 hours; furthermore no evidence of a trend towards higher plasma levels with continued daily dosing was reported.

2,4-DNP is rapidly metabolized via reduction of the nitro groups, in fact nitroreductase reduces 2,4-DNP to the aminonitrophenols. The maximum metabolism activity was found in the cytosol, which is the site of other nitroreductases, although nitroreductases can also be located in microsomes (Eiseman et al, 1952).

In the blood, 2,4-DNP is transported both free and bound to serum proteins. The unbound fraction of the 2,4-DNP in the blood enters organs and tissues such as the liver, the kidneys, and especially in the eyes.

Pharmacokinetic analysis indicated that a two-compartment open model best characterized the disposition of 2,4-DNP in the serum, liver, and kidney of mice given a gavage dose; concentrations found of 2,4-DNP were much lower in liver and kidney than in serum (Robert et al., 1983). The similar half-times for absorption and biphasic elimination in all three tissues (except terminal elimination phase in kidney) indicated that rapid exchange of 2,4-DNP occurred among these sites: the authors suggested that the apparent persistence of 2,4-DNP in the kidney could be related to tissue binding of the compound (Robert et al., 1983).

The parent compound and metabolites are excreted in the urine.

Half-times for the slow terminal elimination phases were 7.7 hours for serum, 8.7 hours for liver, and 76.2 hours for kidney (Robert et al., 1983).

2-amino-4-nitrophenol and 4-amino-2-nitrophenol were identified as metabolic products, with the 4-amino-2-nitrophenol present in greater abundance; an additional ether-insoluble metabolite was tentatively identified as 2,4-diaminophenol (Parker, 1952).

Eiseman (1952) identified under optimal pH and cofactor levels that the 81% of the 2,4-DNP was metabolized. 2-Amino-4-nitrophenol accounted for 75%, 4-amino-2-nitrophenol for 23%, and 2,4-diaminophenol for ≈1% of the total amine metabolites produced. Also in this case 2-amino-4nitrophenol was determined as the predominant metabolite. A proposed metabolic pathway for 2,4-DNP is reported in the attachment below (Eiseman et al., 1952).

Further studies investigated the relationship between the susceptibility of cataractogenesis and the concentrations of 2,4-DNP in the compartments of the eye. The uncoupling of mitochondrial electron transport from oxidative phosphorylation with resultant decreased production of ATP by 2,4-DNP is related to the cataractogenesis of 2,4-DNP (Kuck, 1970).

The concentration of 2,4-DNP in the ocular compartments appears to be more important than the elimination rates in determining susceptibility of developing cataracts, showing a correlation between local concentration of 2,4-DNP and cataract formation (Gehring et al., 1969b).

The uncoupling of oxidative phosphorylation has the potential to affect all tissues and organs.

Limited toxicokinetic and mechanism data for the other DNP isomers indicate that these isomers also uncouple oxidative phosphorylation but that, with the exception of 2,6-DNP, they are eliminated much more rapidly than is 2,4-DNP (Harvey, 1959).

Only two studies were identified that described the effects of human exposure (reported in 7.10.5 IUCLID section). Both report cases of illness and death associated with occupational exposure to 2,4-DNP. The first study (Perkins 1919) reports findings in workers exposed via inhalation to vapour and airborne dust of 2,4- DNP and by direct contact of the skin with the solid chemical. Exposure may have occurred by the dermal and possibly oral routes, as well as by inhalation. In addition, examination of the blood, unspecified organs, and urine of workmen in this industry who died from exposure to 2,4-DNP revealed the presence of 2,4-DNP and its metabolites; quantitative data were not provided (Perkins 1919).

The second study reported a fatal occupational 2,4-DNP poisoning from exposure to mists and airborne dust of 2,4-DNP and the relative urine analysis (Gisclard and Woodward 1946). No conclusions regarding fraction absorbed can be drawn from this study, but it does provide additional evidence of absorption from the inhalation route.