Document mqDZR8G3nkQ5v13O3vYa32kVO

April 23, 1956 Dr. Hymin Shapiro Ethyl Corporation 1600 West Eight Mile Road Ferndale 20 Detroit, Michigan Dear Doctor Shapiros The information which we have concerning the toxicity of APR-128 is as follows: Signs of Illness When absorbed in sufficient concentrations into the tissues of rabbits and rats, APR-128 induced signs of illness which were characterized by initial mild excitement and hyperactivity, tremors, severe tonic spasms, weakness, slow and labored respiration, oc casional feeble clonic convulsions and terminal coma. Animals that were given sublethal amounts of the compound showed these signs to less extent and in addition generally showed mild transient losses in body weight. Female rats were somevhat more susceptible than were male rats to the toxic effects of the compound. Intravenous Toxicity When given Intravenously to rabbits as 5 per cent solutions In peanut oil, the lethal dose of APR-128 was 5.0 mg. per kg. body weight irrespective of the sex of the animals (Table 1). One male that was given this dose died after 18 days and in this instance death may have resulted from some secondary Infection. Two other rabbits died within a few hours after they were given equivalent amounts of the compound. Oral Toxicity The compound was given orally to male and female rats as 2 per cent solutions in peanut oil. The results are summarized in Table 2. Approximately 180 mg. of APR-128 per kg. body weight was lethal to the males. Amounts of the compound that were lethal to females ranged from 16 to 120 mg. per kg., with 55 mg. per kg. probably representing the average lethal dose. 2-- Percutaneous Toxicity When APR-128 was allowed to remain in contact with the intact abdominal skin of rats for 6 consecutive hours, 940 mg. per kg. was lethal to male rats (Table 3). The lethal dose for the females ranged from 420 to 940 mg. per kg. body weight. The compound seemed to be mildly irritating to the skin but the effects were transient; when the compound wa3 washed from the skin of the animals, no gross evidence of local injury was found. The Toxicity of Vapors of APR-128 Table 4 contains a summary of the data pertaining to the toxicity of the vapors of APR-128. Pour experiments were per formed in which rats were supplied with air saturated at temper atures of 24, 28, 33 and 37 degrees, respectively, with vapors of the compound. Female rats were confined individually in a glass chamber (5.8 liters in capacity), through which the satu rated air was circulated. The chamber was maintained at the same temperature as that at which the air was saturated. The first column of Table 4 indicates the consecutive minutes of an exposure period. The second column shows the theoretical percentage ratio of the atmospheric concentration of the compound in the inhalation chamber to that in the air supplied. The other columns show the probable atmospheric con centrations of the compound in the inhalation chamber through out the course of each of the 4 experiments. Air saturated with the compound in its gaseous phase was estimated to contain 1.48 mg. per liter at 24 C., 1.71 mg. per liter at 28 C., 2.73 mg. per liter at 33 C., and 3.33 mg. per liter at 37 C. These concentrations were lethal to female rats; the length of the period of exposure required to cause death being 6 hours at 1.48 mg. per liter. As the concentration was increased, the length of the period of survival decreased. Comments In Table 5 the toxicity of APR-128 is compared with that of APR-122. The signs of illness induced in experimental ani mals by the two compounds are similar. Both compounds elicit differential responses in the two sexes. The intravenous and vapor toxicity both indicate that APR-122 may be 2 to 3 times as toxic as APR-128. However, when the compounds were absorbed from the intestinal tract or through the intact skin, the difference was not so obvious. KE 0019289 3- Prom the aspects of safety in making and working with these compounds, both must be considered potentially dangerous and the customary safeguards rigorously observed. Particular care should be taken to prevent any inhalation of the vapors of either material. If you can inform us as to the molecular weights of APR-122 and APR-128, we shall re-evaluate the data pertaining to the toxicity of the vapors of these compounds and get some estimate of the vapor pressures involved. Shall we hereafter refer to these and other compounds by their new code numbex*s? SYi/bf Sincerely yours, /S/ Sylvan Witherup Sr. Research Associate cc: Dr. R. A. Kehoe Dr. F. F. Heyroth Dr. L. VI. Sanders Dr. K. V. 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