316 2. MALEATE 



after 37 min in 43 mM fumarate, whereas in the same concentration of 

 maleate there is slowing in 3 min, marked depression in 16 min, and paral- 

 ysis in 37 min. Maleate at 21.5 mM also paralyzed but it required 75 min. 

 Bull spermatozoa are even more sensitive, their motility being fairly rap- 

 idly and irreversibly abolished by 5-10 mM maleate (Lardy and Phillips, 

 1943 a, b). We have mentioned that this is not associated with a fall in the 

 ATP level and is accompanied by an acceleration of aerobic glycolysis. 

 It was postulated that maleate inactivates spermatozoa by preventing 

 the utihzation of ATP. 



The inflammatory and vesicant effects of various SH reagents point to 

 an important role of SH enzymes in the skin, so it is interesting to inquire 

 if maleate exerts an action on this tissue. Industrial exposure to maleic 

 acid and maleic anhydride fumes has led to severe conjunctivitis, vesicular 

 dermatitis, and upper respiratory tract irritation. Winter and TuUius 

 (1950) for this reason investigated the effects of these substances on the 

 eyes of rabbits. When the conjunctival sac is filled with a solution of maleic 

 acid at 86 mM (1%) for 2 min and then drained, corneal cloudiness, con- 

 junctival hyperemia, and edema of the nictitating membrane occur within 

 a few minutes, and this lasts for several hours, the eyes being normal after 

 1 day. A 430 mM (5%) solution causes a more intense irritation which in- 

 volves the iris as well as the cornea, and the effects do not disappear until 

 the sixth or seventh day. Maleic anhydride produces similar effects. The 

 ocular reflexes are unaffected and no systemic reactions occur. Since they 

 apparently did not neutralize the maleic acid, it is difficult to determine 

 how much of the action is due to maleate and how much to a nonspecific 

 acid injury. One might well expect acetic acid, or other organic acids, at 

 these concentrations to be quite irritant. 



EFFECTS ON WHOLE ANIMALS 



Minimal toxic and lethal doses for maleate have never been determined 

 accurately. Doses in the range 200-400 mg/kg* (1.7-4.3 millimoles/kg) 

 subcutaneously or intraperitoneally to rats produce marked changes in the 

 blood and urinary keto acids, glucose, amino acids, and pH (Krebs et al., 

 1938; Harrison and Harrison, 1954; El Hawary, 1955; Angielski et al., 

 1959). However, these doses do not usually produce significant toxic reac- 

 tions. The lethal dose in dogs is around 190-250 mg/kg (1.6-2.2 millimoles/ 

 kg) given intravenously (Orten and Smith, 1937; Hermann et al, 1938). 

 Fumarate is much less toxic, Fodera (1894) reporting that even 1940 

 mg/kg (17 millimoles/kg) intravenously to dogs produces only minor reac- 



* All doses are given in terms of maleic acid; in most cases the solutions were neu- 

 raljzed before injection. 



