Document 6bJv7azB3Ndn8XmpEgjoe8qOo

AR226-2873 Procedure: The test material, as an aqueous solution, was administered by intra to a group of ten young adult ChR-CD male rats, five times a week f'-ios two weeks dosage level of 4,470 nig/kg/day; an additional group of ten rats seirved as cont intubated with distilled water. Five controls and five test rats w^re sacrifice four hours after the last dose. The remaining five control and five test rats days after the last dose. Results: Dose tmg/kq/day) 4,470 No. of Doses 10 Pathologic Changes;** See Appendix Mortality 0/10 Clin ical Siqns First Weeks Lacrimatipn, stained stained around eyes, n|ose and mou Second Weeks Salivation, stained mouth, alopecia and weight loss. Recovery Period; None Company Sanitized. Does not co Summary; iJIHHIBPJ^as administered orally to young adult ChR-CD male rats at a r level of 4,470 mg/Kg/day for ten days over a two-week period. Compound-related noted in the liver, spleen, bone marrow and thymus. The histologic^l effects of material on the spleen, sternal bone marrow and thymus are considered reversible not observed after the 14-day recovery period, however, liver hypentrophy was s * Composition: Report by; 0. Louis Toxico Approved by: Q.^^U^ A. Micha Chief, Acute Inve Report No. 718-78 -- Date Issued: December 1, 1978 Compaq , S^5- .D-----^..tc^ aemicala. Dyes and Pigments Department Oral Subacute - ChR-CP Rats October 18, 1978 Results and Comments,: Gross and/or microscopic compound-related changes were observed in the liver, spleen, sternal bone marrow and thysus of asale ChS-CD rats that t^^^^t received ten oral doses ^^^^^^^BI^ 4470 ng/kg/dose. B^^^^f* . Rats killed on the last day of the dosing period had a mean weight loss of 8% compared to a mean weight gain of 32% for the control group. Mean abso lute weights of spleen, thymus, kidney and testis were all lower than controls; however, only spleen and thymus were lower than controls if calculated as a percentage of total body weight. Despite the overall decreased size of the test animals the mean absolute liver weight of the test group was increased 14%, corresponding to a 647. increase over controls when calculated as a per centage of total body weight. On microscopic examination, the spleen, thymus and sternal bone marrow were slightly to markedly hypocellular (Table 1). Hypocellularity in the spleen was due primarily to the absence of the extramedullary hemopoiesis that is normally seen in young male rats. The more primitive members of the erythroid and granulocytic series were reduced in the sternal bone marrow with a cor responding increased fat content. The cortex of the thymus appeared to be more affected than the medullary regions. There was no apparent necrosis of hemopoietic or lynphoid cells suggesting that the hypocellularity may have company Sanitized. Does not contain TSCA CBI - 2 - been due in part to the failure of the test animals to gain weight normally. Fhe parenchymal cells of the liver were slightly enlarged and the cytoplasm lacked the cleared areas seen in controls which are associated with glycogen stores. Most of the gross and microscopic changes described above were not ob served in test animals killed after a 14-day recovery period. All of the animals had gained weight; the mean body weight of the test group was only 16% lower than control. The mean absolute and relative liver weight, however; remained increased over control (18% and 40% respectively). Microscopic changes reflected the improved condition of the recovery test animals. Thymus and sternal bone marrow were histologically indistin guishable from controls, while the spleen differed in that the test animals exhibited more erythropoietic activity. Three of five livers, however, still showed evidence of decreased glycogen content. In three of five livers, there were also scattered degenerating hepatocytes. One rat in this group exhibited an increased number of degenerating spennatocytes in the epididymis as well as degenerating germ cells sparsely scattered throughout the testis. The changes were unilateral. There was a small area of tubular atrophy in one testicle in a second rat in this group. These changes are possibly but not clearly compound related. Other histologic changes noted in the trachea, lungs, liver, kidney, and thyroid are believed to be incidental or the result of intercurrent disease and are not effects of exposure to Zonyl FSN. Representative sections from brain (9/10), adrenals, heart, eyes, upper and lower gastrointestinal tracts, pancreas (7/10), lymph nodes (8/10), and parathyroid (5/10) were unremarkable. .'SpjTipsn^Sanitized!, 'Jms rw "on^n TSCA CEI - 3 - In summary, administration ^JH^^^^BP0 male ChR-CD rats for ten days at A470 mg/kg/dose results in weight loss, hypertrophy of the liver and hypocellularity of the spleen, bone marrow and thymus. The histologlcal effects of the test compound on the spleen, sternal bone aarrsa aad thysas are considered reversible since they were not observed after a 14-day recovery period. Liver hypertrophy, however, was still apparent. The significance of the low incidence of testlcular changes is unclear. Liver, spleen, kidney, testis and thymus were weighed. CC:WCK:mjb Report by:_____Na^^L C. CM^^f-^ Nancy' C. Chroiaey, "Ph.D. Research Pathologist Approved by: '"' / - a ^1 / / ~ [A/^/AA/^/^C I^'WL^^ ^ William C. Krauss, D.V.M. Chief, Pathology Sectioa ^.-.---'- MICROSCOPIC OBSERVATIONS OP TISSUES RECEIVED TEN ORAL DOSES CHR-CD RATS THAT Tlilue/Leilon Spleen: Erychropoletic fuel Compound Dole Recovery Dave Animal No. 237- 129 145 1 1 Epidldymtsi Increased degenerating spermacocytea Teatta: Scattered degenerating apennatocytes Thyaxit! Focal tubular afiophy Hypocellular Lymph Hade*: Trachea! Dilated glands - Lung: Interstitial pneuisonltis t !; Focal coniolldatlon Perivcular cuffing Peribronchtolar Inflnnoatory cell Infiltrate Focal hemorrhage Liverf Perlnuclear cytop&aamlc Lyohoreticular foci Focal nei:roila Decreased glycogen clearing 1 1 - t - t Codei Cellular hypertrophy Scattered hepatocyte degeneration - - Lealon abient, tiaiuo within normal htatological linlti 3 - Harked change a unilateral 0 Tiaaue mtaaing CONTROL 0 0 14 166 196 211 158 209 213 226 242 t t 1 - - t t - ....... - - ::: ::0 :: 111.-.1. l - t t 1 t - - 1 t t - l I l t t t l ------------ : 0 : 139 160 i8819 23331231 . 0210 - - 1 t . t - 2-1t2t 2-l1-1t11 . . . . t liolated lei ion; very alight change - .... 2t 2t 2t 2 1 . Slight chang ^d-Ooe^con'^msc ColW^58"' fMKt II ,400 TABLE 1 (Continued) "H------------1 MICROSCOPIC OBSERVATIONS OF TISSUES PROH CHR-CP RATS THAT RECEIVED TEH ORAL DOSES IHMttZl CooDOund POIC Recovery Py" Aniul No. 237. COMTROL 0 0 ; 129 145 ^6() t9b " 14 158 209 213 m TO Kidntyi roc*l cubular fIbcaniB 1 1 Focal infrititlal ImfliWMtory infllcracn 1 - - - - . . . Hydroniphroa ii iright Cyt - 1 1 - - - - - - - 1 i Cod*) - - Leilun brot, ttrue within nornrl hiltologleal llmlf * Iiclifd Id Ion; very light change 1 Sllgl.t change 2 " Moderate change 3 - (larked chenge a Iftillateral 0 Tiaaue nifBing " 139" f60 W - . - 1 ' - 1 - r* . S.ni^.Do------"" Compaq .^^H?;'U"