EFFECTS ON THE WHOLE ANIMAL 627 



EFFECTS ON THE WHOLE ANIMAL 



The potential use of dehydroacetate as a food preservative led Spencer 

 et al. (1950 a,b) of the Dow Chemical Company, and Seevers et al. (1950) of 

 the University of Michigan, to investigate the effects on various animals and 

 man when administered by different routes for varying durations of time. 

 These studies were very thorough and our knowledge at this level of action 

 is better than for most inhibitors. We shall summarize only the more im- 

 portant aspects relative to the metabolic disturbances produced. 



Acute Toxicity 



The earliest evidence of toxicity in rats, dogs, and monkeys when de- 

 hydroacetate is given by any route is loss of appetite. As the dosage is in- 

 creased, various sjTnptoms related mainly to the central nervous system 

 appear: ataxia, salivation, emesis, incoordination, weakness, and stupor, 

 followed by muscle twitching and a gradual increase in muscle tone, passing 

 into clonic and tonic convulsions which persist until death, which is attri- 

 buted to respiratory i)aralysis. During the later phases, convulsions may be 

 initiated by excess sensory stimulation, indicating a general increase in the 

 reflex excitability. The effects are produced rather slowly and death occurs 

 usually after 24-72 hr. The acute oral toxicity in rats is given as: LD^.i = 

 0.52 g/kg, LDi6 = 0.80 g/kg, LD50 = 1.0 g/kg, LDg^ = 1.23 g/kg, and 

 LD99.9 = 1.92 g/kg. 



The initial effects of intravenous injection (0.3-0.4 g/kg) are probably 

 related to the temporary disturbance in blood pH if the solutions are not 

 neutralized. The alterations in nervous system function may not be specific 

 and due to the direct action of dehydroacetate on the nerve cells, but de- 

 pendent on the developing acidosis. An initial respiratory alkalosis in dogs 

 is soon followed by a shift toward metabolic acidosis, compensated at first 

 but later becoming uncompensated. As the plasma pH suddenly drops to 

 levels approaching 7, with simultaneous decreases in plasma bicarbonate 

 and Pqq , convulsions occur. We have noted that renal transport is more 

 sensitive to dehydroacetate than is nerve or muscle respiration, especially 

 in the presence of glucose. The plasma levels of dehydroacetate in acute 

 poisoning are probably between 1 and 3 mM in most cases, which, coupled 

 with the possible concentration in the kidney, could easily disturb renal 

 function seriously. The concentration in the central nervous system during 

 poisoning appears to be quite low (see page 631). All of this points to an 

 indirect action on the nervous system and perhaps a primary renal site for 

 the toxicity. 



Chronic Toxicity 



Rats fed diets containing 0.02-0.10% dehydroacetic acid for 2 years 

 showed no obvious adverse effects on growth, mortality, hematology, organ 



