Document 44JNmn1GbVzEVpvQ3J2kNOZgQ

% AR226-2873 Copies to E. I. du Pont de Nemours and Company , Haskell Laboratory for Toxicology and Industrial Medicine HASKELL LABORATORY REPORT NO. 718-78 Material Teste<^ Haskell No. 12,400 Other Codes Sample Ready for Testing 7-10-78 Submitted by CD&P Department, Jackson Lab., Chambers Works N-DOSE ORAL SUBACUTE TEST. Proced_ure; nT*h.etest m_a=t(e.orrxajla,i as aann aaqauueeoouuss ssoolxuutvioon,, was aadmwieneikstfejrJredtwboy wienetkrsa,gaasttraiereipnetautbeadtion days after the last dose. . sr^ isS ,*i test sets -- - _________ ______________,_____ -- Results ; Dose (mg/kg/day )_ 4,470 No. of Doses 10 Pathologic Changes: * * See Appendix Mortality 0/10 Clinical Signs First Week: Lacrimation, stained perineal area,__ stained aT ound eyes, nose and mouth and weight loss. e . ~ TM d week, Salivation, stained perineal area and mouth, alopecia and weight loss. Recovery Period: None Company Sanitized. Does not contain TSCA CBi 2 S f i ?riii3,-c5maie aterial on t h H p U S . " S i r ^ b ^ ^ r ^ a ^ t. 14-day recovery *,** thftSt"'" Report No. 718-78 Date Issued: December 1 , 1978 Report by , O . Louis Dashiell Toxicologist Approved by; Q. K} U ^ M jul. ~ A. Michael Kaplan ' Chief, Acute Investigations Section cnisin 1S C A C > Com; .G~r.m^-d. Does not Oral Subacute - ChR-CD Rats October 18. 1978 Results and Comments,; Gross and/or microscopic compound-related changes were observed in the liver, spleen, sternal bone marrow and thymus of male ChR-CD rats that received ten oral doses o f ^ g ^ ^ t W O mg/kg/dose. Rats killed on the last day of the dosing period had a mean weight loss of 81 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 64% 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 lymphoid cells suggesting that the hypocellularity may have Company Sanitized. Does not contain TS CA CBi 2 been due in part to the failure of the test animals to gain weight normally Ihe 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 spermatocytes 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. .pr^pang Sanitized, Does p.o contain T S C A C B i 3 In summary, administration f ^ p H V j Co In*le chR'CD rats for ten days at 4470 mg/kg/dose r e s e t s in weight loss, hypertrophy of the liver and hypocellulaxity of the spleen, bone marrow and thynus. The histological effects of the test compound on the spleen, sternal bone marrow and thymus 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 testicular changes is unclear. Liver, spleen, kidney, testis and thymus were weighed. NCC:WCK:mjb Report by: A Nancy C. Chroy, "Fh.D. Research Pathologist Approved by: William C. Krauss, D.V.M. rVn'pf Patholoev Section ISCA 0 nolcn W `n Sannilze*.0e' Cotnp30^ # TABLE 1 MICROSCOPIC OBSERVATIONS OF TISSUES F&PM CHR-CD . TH THAT RECEIVED TEN ORAL DOSES OB ' i ! Tlssue/Leslon Compound Doae Recovery Dsvb Animai No. 237- CONTROL 0 0 14 129 145 166 196 211 158 209 213 226 242 Spleen: Erythropoietic foci Erythropoietic foci decreased Sternal Bona Marrow: Hypocellular Epididymis: Increased degenerating spermatocytes Testis: Scattered degenerating spermatocytes Focal tubular atrophy Thymus: Hypocellular Lymph Nodes: Trachea: Dilated glands Lung: Interstitial pneumonitis Focal consolidation Perivascular cuffing Peribronchiolar Inflammatory cell infiltrate Pocal hemorrhage -1 -1 tl -t Liver: Perinuclear cytoplasmic clearing Lymphorettcular foci Focal necrosis Decreased glycogen Codei Cellular hypertrophy Scattered hepatocyte degeneration - Lesion absent, tissue within normal hietoiogical limits 3 - Marked change a - unilateral 0 Tissue mlaalng t - isolated lesion; very alight change W O ma/ka ^ :0 " 14 139 160 i8B 195 199 205 208 230 244 248 31 21 la ta 22 tt 22 1t 1 - Slight change . t-i 2 - Moderate change nCXcont,a;.nn -rSCACB* S * , * 1-0055 Co!nPan^ TABLE 1 (Continued) MICROSCOPIC OBSERVATIONS OF TISSUES FROHCIVR-CD RATS THAT RECEIVED TEtf ORAL POSES OFflM| fl Tlaaua/Laalon Comound Dose Recovery Dave dnliial Mo. 237- !. Kidneyi Focal tubular fibrosis Focal interstitial lnflaasnstory Infiltrat Hydronaphroala right Cyat CONTROL 0 0; - 1A 129 IAS 166 196 211 1S8 209 213 226 2A2 Codai - " LaIon abaant, tlaaua within normal histological limits * - laclatad las ion; very alight change 1 - Sligi.t change 2 Moderate change 3 Marked chcnge a - Ifnilateral 0 Tlaaua Biasing -** IM !>'~199 M 208 56 lU 248 Company Sanitjzed. Does net contain T S C A CB[