Document 7MD6y7pD0Xn90NrQ2b7BwM4nj

Project nmo' !< REPORT ounger Laboratories 128 CLIFF CAVE ROAD Saint Louis, Mo,, 63129 C/i PHONE) TlLDKN 6-2540 January 22nd, 1969 SUBJECT - Toxicological Investigation Of: Pydraul 312 (MCS-312) 0R-116021 Monsanto Sample Number 172 Monsanto Project Number Y-68-135 STUDY CONDUCTED FOR - Monsanto Company, St. Louis, Missouri EXPERIMENTAL PROCEDURE - A) Oral LD50 (Rats, Mixed Sex) The undiluted compound was fed by stomach tube to Sprague-Dawley strain albino male and female rat6. After the approximate Minimum Lethal Dose was determined, groups of male and female rats were fed in increasing doses at increments of 0.2 fractional log intervals at four levels designed to blanket the toxicity range thereby supplying data for calculation of the LD50 which was done according to a modification of the method of E. J. de Beer. Observations were made for toxic symptoms and the viscera of the animals that succumbed were examined macroecopically. The data are shown in Table I, B) Skin Absorption MLD (Rabbits, Mixed Sex) The undiluted compound was applied in increasing doses at increments of 0.2 fractional log intervals to the closely clipped, intact skin of New Zealand white male and female rabbits. The treated areas were covered with plastic strips and the animals held in wooden stocks for periods up to twenty-four hours, after which time they were assigned to individual cages. Observations were made for toxic symptoms and the viscera of the animals that succumbed were examined macroecopically. The data are shown in Table II. 007*997 TOXSTUDIES0760 To: Monsanto Company St. Louis, Missouri Younger Laboratories Certificate of Analysis - Page 2 (1/22/69) - -68-135 6'7 EXPERIMENTAL PROCEDURE - (Continued) . C) Skin Irritation (Rabbits, Mixed Sex) The undiluted compound was applied to the clipped, intact skin of albino male and female rabbits and removed after twenty-four hours. The application was covered with plastic strips to retard evaporation and avoid contamination. Observations were made over a period of several days for irritation. The data, scored according to the method of Draize, Woodard and Calvery (Journal of Pharm. and Exp. Therapeutics, Volume 82, December, 1944) are shown in Table III. D) Eye Irritation (Rabbits, Mixed Sex) ^ 0.1 Milliliter of undiluted sample was placed in the conjunctival sac of the right eye of each of three albino male and female rabbits and observations made over a period of several days for inflammation. The eyes were rinsed with warm isotonic saline solution after twenty-four hours. The data, scored according to the method of Draize, et al, are shown in Table IV. SUMMARY Pydraul__>12^(MCS:312)_0R-ll621 A) Oral LD50 (Rats, Mixed Sex) The Oral LD50 for male and female rats was placed at 553 milligrams per kilogram with lower and upper limits of 4430 to 6390 milligrams f>er kilogram. The compound was classed as practically non-toxic by oral ingestion in male and female rats. B) Skin Abcsorption MLD (Rabbits, Mixed Sex) The Minimum Lethal Dose by Skin Absorption in male and female rabbits was found to be greater than 3160 milligrams per kilogram and less than 5010 milligrams per kilogram. The compound was classed as slightly toxic by skin absorption in male and female rabbits. C) Skin Irritation (Rabbits, Mixed Sex) The compound was classed as a mild irritant when applied undiluted to intact skin of male and. female rabbits. The average maximum score was 2.6 out of a possible 8 in twenty-four hours. D) Eye Irritation (Rabbits, Mixed Sex) The compound was classed as a slight eye irritant in male and female rabbits. The average maximum score was 8,6 out of a possible 110 in one hour. YOUNGER LABORATORIES BY: MELVIN D. BIRCH 0074997.01 TOXSTUDIES0761 To: Monsanto Company St. Louis, Missouri Younger Laboratories Certificate of Analysis - Page 3 (1/22/69) - Y-68-135 TABLE I THE ORAL LD50 OF 'Pydraul 312 (HCS 312) 0R-116021' FOR RATS Sample Fed Undiluted Animal No. - Sex Weight Gb 1- Female 2- Male 3- Female 4- Male 5- Female 6- Male 7- Female 8- Male 9- Female 10- Male 11- Female 12- Male 13- Female 14- Male 15- Female 16- Male 17- Female 18- Male 19- Female 20- Male 230 240 225 255 190 230 205 245 225 235 210 240 210 255 230 230 225 235 220 255 Dose Mg. /Kg. 2,510 2,510 2,510 2,510 2,510 3,980 3,980 3,980 3,980 3,980 6,310 6,310 6,310 6,310 6,310 10,000 10,000 10,000 10,000 10,000 Fate Survived Survived Survived Survived Survived Died Survived Survived Survived Survived Survived Died Survived Died Died Died Died Died Died Died DISCUSSION - The Oral LD50 for male and female rats was placed at 5350 milligrams per kilogram with lower and upper limits of 4430 to 6390 milligrams per kilogram. The compound was classed as practically non-toxic by oral ingestion in male and female rats. Survival time was two to four days with most deaths occurring within two to three days. Toxic symptoms included slight tremors in two to six hours, loss of appetite, lethargy, and collapse. At autopsy there was inflammation of the gastrointestinal mucosa and renal, liver, and pulmonary hyperemia by macroscopic examination. 00 74996 TOXSTUDIES0762 To: Monsanto Company St. Louis, Missouri Younger Laboratories Certificate of Analysis - Page 4 (1/22/69) - Y-68-135 TABLE II THE MINIMUM LETHAL DOSE OF 'Pydraul 312 (MCS 312) OR-116021' BY SKIN ABSORPTION IN RABBITS Sample Applied Undiluted Animal No. - Sex 1 - Female 2 - Male 3 - Female 4 - Male 3 - Female 6 - Male Weight Kg . 2.3 2.4 1.9 2.4 2.1 2.2 Dose Mg. / Kg. 794 1260 2000 3160 5010 7940 Weight Change 5 Days Later Kg. + 0.1 + 0.2 + 0.1 + 0.1 - 0.1 - 0.2 Fate Survived Survived Survived Survived Died -- 8 Days Died -- 6 Days DISCUSSION The Minimum Lethal Dose by Skin Absorption in male and female rabbits was found to be greater than 3160 milligrams per kilogram and less than 3010 milligrams per kilogram. The compound was classed as slightly toxic by skin absorption in male and female rabbits. Survival time was six to eight days. Toxic symptoms included reduced activity and appetite followed by weakness and collapse. At autopsy there was liver discoloration and pulmonary congestion macroscopically. 0074996*01 TOXSTUDIES0763 To: Monsanto Company fit. Louie, Missouri Younger Laboratories Certificate of Analysis - Page 5 (1/22/69) - Y-6B-135 TABLE III SKIN IRRITATION IN RABBITS AFTER APPLICATION OF 'Pydraul 312 (MCS-312) OR-116021' Sample Applied Undiluted Animal No.-Sex 1 Hour Numerical Evaluation At The End Of 2k Hours k& Hours 72 Hours 120 Hours 166 Hours 1 - Male 0 2 2 1 0 0 2 - Female 0 3 3 2 0 0 3 - Male 0 3 3 1 0 0 Average 0.0 2.6 2.6 1.3 0.0 0.0 DISCUSSION - The compound was classed as a mild irritant when applied undiluted to intact skin of male and female rabbits. The average maximum score was 2.6 out of a possible 6 in twenty-four hours. No skin changes were noted in one hour. Moderate to marked erythema with no edema was recorded in twenty-four hours. Gradual improvement was noted in seventy-two hours and all animals received a score of zero in five days. 007*999 TOXSTUDIES0764 To: Monsanto Company St, Louie, Missouri Younger Laboratories Certificate of Analysis - Page 6 (1/22/69) - Y-68-135 &&/1 TABLE IV EYE IRRITATION IN RABBITS AFTER APPLICATION OF 'Pydraul 312 (MCS-312) 0R-116021' Sample (0,1 Milliliter) Applied Undiluted Numerical Evaluation At The End Of Animal No. - Sex 1 Hour 2^4 Hours i+8 Hours 72 Hours 120 Hours 1 - Female 8 2 2 0 2 - Male 10 b 2 0 3 - Female 8 2 2 0 0 0 0 Average 8.6 2.6 2.0 0.0 0.0 168 Hours 0 0 0 0.0 DISCUSSION The compound was classed as a slight eye irritant in male and female rabbits. The average maximum score was 8.6 out of a possible 110 in one hour. There was blinking and mild lacrimation immediately following application. In one hour there was marked redness of the lids and moderate lacrimation. Lacrimation had ceased and redness reduced to mild in twenty-four hours. There was no discernible corneal dullness. Redness had reduced to very slight in forty-eight hours on two animals and disappeared completely on the third. All animals received a score of zero within seventy-two hours. The material in this report ia to be u^ed in development of the product and may bo given to responsible comity, but it i rot To bo used by them in ndvertinirg copy. Ti> * source of this material is not to be clivulr;..*] ur.til it nom .r-v in formal puhJier.Liora. No ercupiipMu io the eslubliebod ij'> may be inr.dr without tho approval cf tlvv Medical l>p.n*; ment in St. Louis. Customers' inquiries regarding matters of toxicity are to be referred as before to the Medical Lepart- tnent in St Louis ior reply. rr Monsanto Company 0075000 TOXSTUDIES0765