STUDIES OF THE TOXICITY AND OF THE ENZYME KINETICS OF ETHYL p-NITROPHENYL THIONOBENZENE PHOSPHONATE (EPN)

¹ Division of Pharmacology and Toxicology, University of Rochester School of Medicine and Dentistry, Rochester, N. Y.

1. EPN is moderately toxic in some species and highly toxic in others. In some species, marked sex differences in susceptibility were found.

2. In a two-year feeding study, groups of male and female albino rats (initially 50 of each sex per group) were maintained from weaning on diets containing the following amounts of EPN: Males-0 (controls), 50, 150, and 450 ppm; females 0 (controls), 25, 75, and 225 ppm. Amounts up to 150 ppm for male rats and 75 ppm for females had no effect on growth; the highest percentages retarded growth. There was no indication of a reduction in life span even at the highest level. No disturbances in the hematological values were noted. Normal urinary sugar and protein values were found near the end of the test. EPN is not stored in vital organs or in depot fat. Organ weights were within normal ranges. A thorough histological examination revealed no changes that were attributed to the administration of EPN.

3. During a one-year experimental period, two dogs (1 male, 1 female) were given each of the following doses of EPN: 0 (control dogs), 0.1, 0.5, and 2.0 mgm./kgm./day. The dogs maintained body weight. Periodic hematological examinations gave values in the normal ranges. Although initially red blood cell cholinesterase levels were decreased, they were normal at the end of the year. Urine analyses were negative. Organ weights were within normal ranges, although there was a trend toward larger kidney weights with increasing doses of EPN. Thorough histological studies gave no indication of any specific injury.

4. Like other organic phosphates with anticholinesterase activity, EPN exhibits a slowly increasing degree of inhibition with time, apparently as the result of the formation of an irreversible enzyme inhibitor complex. The inhibitory reaction is second order. EPN may be added to the list of those organic phosphates in which the highly purified material has no anticholinesterase activity in vitro.