Document 2RrE0gyDBVQ24pNbLO3LZbnxg

Younger Laboratories Biodumidi.... Pliaimaaalixfiiti . .. Analfdi 123 CLirr CAVE ROAD Saint Louis, Mo, 6*139 PBONIi TiLDBH 6*3540 Ce/di]fioate &f Analfiii SUBJECT - Toxicological Investigation Cf; \ Monsanto Sample Number 244 Monsanto Project Number Y-65-213 395 January 10th, 1966 STUDY CONDUCTED FOR Monsanto Company, St. Louis, Missouri EXPERIMENTAL PROCEDURE - A) Oral LD50 (Rats, Mixed Se: The undiluted compound sale and female rate* ibe to Sprague-Jawley strain albino After the appro Ki^i^um LethaVtfase wa6 determined, groups of male and female rats eei ftd in ia^e^giftj^^see at increments of 0*1 fractional log intervals at ti levels il nipnarl i*r blanket the toxicity range thereby supplying dal Jor calculation cf the LD50 which was done according to a modification o\ ae aethodPif E J* de Beer* Observations wer^JsAs toxic symptoms and the viscera of the animals that succumbed were exafeueif'sacroscopically. The data are shown in Table I* E) Oral MLL (Rabbits, Mixed Sex) The undiluted compound was fed In increasing doses at increments of 0*2 fractional log intervals by stomach tube to New Zealand white male and female rabbits* Observations were mads for toxic symptoms and the viscsra of the animals that succumbed were examined nacrosccpically. ' The data are shown in Table II* 0619626 Thk ctnbfaiiliil wpwt ia not to bo and in ibt fora of idwbiiai without writton TOXSTUDIES0686 To: Monsanto Company fit* Louie, Hieeouri lounger Laboratories Certificate of Analysis - Page 2 (1/11/66) - y-65-213 EXPERIMENTAL PROCEDURE - (Continued) C) Skin Absorption KLD (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 oovered with plastic strips and the animals placed 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 macroscopically* The data are shown in Table III* D) Skin Irritation (Rabbits, Mixed Sex) The undiluted compound was applied to the clipped, intact skin of male and female albino 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 Drai&e, Woodard and Calvery (Journal of Pharm* and Exp* Therapeutics, Volume 82, December, 1944) are shown in Table IV. E) Eye Irritation (Rabbits, Mixed Sex) 0*1 Milliliter of undiluted sample was placed in the conjunctival sac of the right eye of three albino 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 V* F) Vapor Inhalation (Male Rats) Four mature male rats were placed in a metal chamber of 33 liters capacity and exposed for six hours to a concentrated atmosphere of vapors produced by passing a stream of air through 100 milliliters of the compound contained in a 300 milliliter Erlenmeyer flask* Vapors from the flask passed into a one liter bottle to remove droplets and then into the chamber* Air flow through the sample was five liters per minute as measured by a cali brated rotameter* This was sufficient to violently agitate the liquid* No supplementary air was introduced inasmuch as the above supply see ample`for the animals oxygen requirements* The animals were observed for behavior and, since there were no deaths, all were held for ten days observation* The data are shorn in Table VI* Ob19627 TOXSTUDIES0687 Tot Monsanto Company St. Louis, Missouri lounger Laboratories Certificate of Analysis - Page 3 (1/1V&6) - 7-65-213 SUMMARY MCS 395 A) Oral LD50 (Rats, Mixed Sex) The Oral LD50 for male and female rats was placed at 4615 milligrams per kilogram with lower and upper limits of 4O&0 to 526o milligrams per kilogram* The compound was classed as slightly toxic by oral ingestion in male and female rate. B) Oral MLD (Rabbits, Mixed Sex) The Minimum Lethal Oral Dose for male and female rabbits was found to be greater than 1580 milligrams per kilogram and less than 2510 milligrams per kilogram. The compound was classed as slightly toxic by oral Ingestion in male and female rabbits. C) Skin Absorption MLD (Rabbits, Mixed Sex) The Minimum Lethal Dose by skin absorption in male and female rabbits was found to be greater than 2510 milligrams per kilogram and less than 3980 milligrams per kilogram* The compound was classed as slightly toxic by skin absorption in male and female rabbits. D) Skin Irritation (Rabbits, Mixed Sex) The compound was classed as non-irritating when applied undiluted to the intact Bkin of male and female rabbits. E) Eye Irritation (Rabbits, Mixed Sex) The compound was classed as a slight eye irritant in male and female rabbits. The average maximum score was 6*3 out of a possible 110 in one hour. F) Vapor Inhalation (Male Rats) All animals survived the six hour exposure as well as the following ten day observation period. It was concluded that the vapors were practically non-toxic under conditions of the test. Y0UN3ER LABORATORIES Of.l'ibZ* TOXSTUDIES0688 Tot Monsanto Company St Louis, Missouri lounger Laboratories Certificate of Analysis - Page 4 (1/10/66) - Y-65-215 TABLE I THE ORAL LD50 OF 'M C S 595* FOR RATS Sample Fed Undiluted Animal^o*_~_Sex 1- Female 2- Male V Female 4- Hal. Female 6- Kale 7- Female 6- Kale 9- Female 10- Male 11- Female 12- Hal. 1J- Female 14- Male 15- Female l6- Male 17- Female 18- Male 19- Female 20- Hale W.lght -SJ.1- Til 240 220 255 255 260 2J0 270 255 255 250 255 225 265 255 280 22^ 245 240 265 Dose 5160 5160 5160 5160 5160 59#o 5980 5980 5980 5960 boio 5010 5010 5010 5010 6510 6510 6510 6510 6510 Fate Survived Survived Survived survived Survived Survived Died Survived Survived Survived Died Survived Died Survived Died Died Died Died Died Di.d DISCUSSION The Oral LD50 for male and female nits was placed at 4615 milligrams per kilogram with lower and upper limits of 4o6o to $26o milligrams per kilogram. The compound was classed as slightly toxic by oral ingestion in male and female rata. survival time was several hours to three days with most deaths occurring overnight. Toxic symptoms included severe diarrhea, increasing weakness, tremors, and collapse* At autopsy there was inflammation of the gastric mucosa and renal hyperemia macroscoplcally . obi'**'2'* TOXSTUDIES0689 Toi Monsanto Company St* Louie, Missouri younger Laboratories cortificafca of Analysis - Pago 5 (1/10/66) - y-65-213 TABLE II THL MINIMUM LETHAL ORAL DOSE OF 'HCS 395' FOR RABBITS Sample Fed Undiluted Animal No* - Sex 1 - Female 2 - mi 3 - Female 4 - Male 5 - r*ml. 6 - M*lo Weight JULu 2.6 5-0 2.7 J.l 2.7 2.9 Dose SfcwdKfc 651 1000 1560 2510 5980 6?lo weight Change 5 Days Later Kg* 0*0 + 0*1 - 0.1 - 0*4 - 0.3 -- Fate Survived Survived Survived Died -- 0 Days Died -- 5 Days Died -- 2 Days DISCUSSION " The Minimum Lethal Oral Dose for sale and female rabbits was found to be greater than 1580 milligrams per kilogram and leaa than 2510 milligrams per kilogram. The compound was classed am slightly toxic by oral ingestion in male and female rabbits* Survival time was two to sight days* Toxic symptoms in animals #4 nd #5 included poor appetite In two to three days, weight loss, increasing seaknass, tremors, and eollapae* At autopsy there was evidence of liver dysfunction and renal hyperemia* 'rtof .< of ,-.u- Monsanto CJicmic-aj Ccajjja 0619630 TOXSTUDIES0690 Tot Monsanto Company St.Louis, Missouri Younger laboratories Certificate of Analysis - Page 6 (1/10/66) - Y-6^-215 TABLE III THE MINIMUM LETHAL DOSE OF 'MCS 395' BT SKIN ABSORPTION IN RABBITS Sample Applied Undiluted 1 * Male 2 - Female 5 - Male . 4 - Female 5 - Male 6 - Female Weight JSAi. J.O 2.5 2.8 2.4 2.5 J.l Dose 651 1000 1580 2510 5960 6510 Weight Change 3 Days L&ter ,, Hi 0*2 + 0.1 + 0*1 - 0*1 - 0.5 - 0.2 _____ ^^.Fate______ Survived Survived Survived Survived Died - 7 Days Died - 9 Daye DISCUSSION The Minima Lethal Dose by Skin Absorption in male and female rabbits wae found to be greater than 2^10 milligrams per kilogram and lese than 3980 milligram* per kilogram* The compound mas classed ae slightly toxic by akin absorption in male and famale rabbits* Survival tine was seven to nine days* Toxic symptoms in animals #5 and $6 included.reduced appetite and activity in threa to four days with increasing weakness, dyspnea, and paralysis* At autopsy the lungs vert hemorrhagic and there was liver discoloration macroacepically 0619631 TOXSTUDIES0691 Toi Monsanto Conp*oy St. Louifli Missouri Younger Laboratories Certificate of Analysis - page 7 (l/iO/66) - Y-65-213 TABLE IV SKIN IRRITATION IN RABBITS AFTER APPLICATION OF 'MCS 395* Sample Applied Dndllutsd Numerical Evaluation At Tbs End Of l.Hpur 24_Hours 40 Hours J2_HourB 120, Hours 1 - Female 0 0 0 0 2 - Male 00 0 0 3 " Female 0 0 0 0 0 0 0 DISCUSSION Ths compound was classed as non-irritating to intact rabbit akin when applied undiluted. No edema or erythema developed on any of the animals as a result of a twenty-four hour exposure to the undiluted compound. All animals reoelved a score of aero throughout the observation period. 061963? TOXSTUDIES0692 Tot Monsanto Conpony St. Louis, Missouri Younger Laboratories Certificate of Analysis - Page 8 (1/10/86) - y-6^21} TABLE V EYE IRRITATION IN RABBITS AFTER APPLICATION OF fMCS 595' Sample (0.1 Milliliter) Applied Undiluted Anioal_No._^_Sex 1iHour Humrioal Evaluation At The End Of 24_bourfi 4B_Hours Hours 120_Hours 1 - Female 7 4 2 0 2 - Kale 74 4 0 5 - Female ll 6 4 2 0 0 0 Average 8.5 4.6 5.5 0.6 o.o DISCUSSION The compound was classed as a slight eye Irritant in male and female rabbits* The average maximum score was 8.5 out of a possible 110 in one hour. Little discomfort mas shown Immediately following application. After one hour there was slight discharge and redness, practically no edema, and very alight corneal dullness. Iris and cornea were clear in twenty-four hours and within three days only a trace of redness of the palpebral conjunotivae remained on one animal. 0619*33 TOXSTUDIES0693 Tos Monsanto Company St* Louis, Missouri Younger laboratories Certificate of Analysis * Page $ (1/10/66) - y-63-213 TABLE VI INHALATION Of 'MCS 3951 VAPORS BY RATS Average Temperature Inside Chamber.......... .......................... Average Relative Humidity Inside Chamber *..................................... Amount of Sample -- To Start ..................................... 100*0 cc Recovered ................................... 99*7 cc Vaporised or left in equipment .......... o3 cc (C*3%) 76* F 45 % Ani5J2i JT-522 1 - Male 2 - Male 3 - Male 4 - Male _____Fate^ Survived Survived Survived Survived Mo immediate reaction ... Normal breathing rate ... No disootffort or nasal discharge ... No weakness .. Moderate lethargy after two hours. WSCUSSIOW All animals survived the six hour exposure as well as the following ten day observation period. It was concluded that the vapors were practically non*toxic under conditions of the teat. The animals appeared to be unaffected by the exposure. Nasal and ocular mucosae were normal when the animals were removed from the chamber. The ten day observation period was uneventful* Obl`b3`' TOXSTUDIES0694