Document dYqQgjbGYOpZ1Zz79ZBYMjBGB

REPORT AMENDMENT NO. 1 TWO YEAR ORAL (DIET) TOXICITYICARCINOGENICITY STUDY OF FLUOROCHEMICAL FM-3924 IN RATS Experiment No.0281CROO12 The attachedpages include revisions in the first paragraph on page 3 of the Summary and in the third paragraph of page 22 of the Discussion. The revisionswere made to clarifythat the incidenceof benign hepatic adenomas found in the high-dosefemales was not statistically significant,althoughit was outsidethe historicallimit. Study Director: Sitrin-skiB,.A. Date Senior Toxicologist Amendment Reviewed By: Jaid4sL. Allen, Ph.D. Diplomate, A.B.T. Research Toxicologist -A y4r Date Amendment Approved By: Sfe'vi-V.-Elrod, Ph.D. Date Diplomate, A.B.T. Manager, Pathology/Toxicologyand Laboratory Animal Medicine The overall incidence of hepatocellular adenomas and carcinomas was low in both control and FM-3924-treated groups with the high-dose female rats having a tumor incidencethat, while not statistically significant, was outside historical control limits. The majority of neoplasms were observed in endocrine or endocrine-sensitiveorgans which are typical neoplasticsites for older rats of this strain. The incidence of these neoplasms was similar_among control and test article-treated_grCLup_s,__anddid not demonstrate a unique tumor type. Based on tumor incidence, types of tumors, onset time of tumor appearance, malignancy patterns of tumors and the final mortality values at two years, FM-3924 was not considered to be carcinogenic in the rat under the design and conditions of this study. 3. parameters that were progressive over time. These findings were considered to be associated with the progressive degenerative changes of naturally occurring chronic renal disease commonly found in rats of thi-sstrain. The primary test article effect occurred in the liver as increased organ weight (both absolute and relative), as gross findings at necropsy, and as histopathologic alterations. These changes were observed at the one year necropsy, but showed remarkably little progression one year later at the two year necropsy. The high-dose males and females had essentially equal incidences of hepatic findings, while the mid- and low-dose males were more markedly affected than were the females from the corresponding dose groups. Hepatomegalocytosisand hepatocellular vacuolation are characteristic of increasedmetabolic activity in the rat. It is recognized that these lesions may progress to cystoid degeneration and, ultimately, hepatocellular necrosis. The incidence of hepatic necrosis in this study was slightly increasedonly in the high-dose males. Since the liver in the rat rarely repairs parenchymalcell loss with fibrosis or scar tissue, a more typical cellular reaction is hepatocellularhyperplasia. In this study, the incidence of hyperplastic nodules were increased only in the high-dose male and female animals (ie., 10% and 18%, respectively) compared to the control groups (ie. 0% and 2%, respectively). It is importantto note that no proliferativehepatic lesions (ie. hyperplasianor neoplasia) were seen in any of the high-dose rats after receiving FM-3924 for one year. Primary liver neoplasms observed in this study after two years consisted of hepatocellular adenomas and carcinomas. The overall incidence of these neoplasms was low, with carcinomas occurring in both the control and FM-3924 treated groups as follows: males 6%, 4%, 2% and 2%; and females 0%, 6% 0% and 0% for the control, high-, mid- and low-dose groups, respectively. Benign hepatic neoplasms (ie. adenomas) were not found in any group except the high-dose females where, although not statistically significant, an incidence of 8% was recorded. Considering the chronic liver stimulation noted in both the high-dose male and female gr@oupsduring their life span, the incidence of hepatic neoplasia appears to be within reasonable limits with the possible exception of the high-dose female group. Combined malignant and benign incidence values are within 22. reasonablehistoricalcontrol limits for the high-dosemales while the high-dose females appear to be slightly outside these limits only because there were no liver tumors seen in the control group. Based on these findings, FM-3924 was not consideredto be a hepatic carcinogenin the rat. Most of the neoplasmsobservedin this study originatedfrom endocrine or endocrine-sensitiveorgans including the adrenal glands, mammary gland, pituitary,thyroidand uterus. These are common sites for spontaneous or naturally occurring oncogenesis in this strainof rat as evidenced by the specifictumor incidencein the control group (see Table 19). Deviations from the control incidencefor these neoplasms were neither numerically meaningfulnor did they involve a unique tumor type not commonly seen in this strainof rat. The non-neoplastic findings reported from the histopathologic evaluationof all of the animals scheduledfor the two year necropsy were mostlygeriatriclesionstypicalfor this strain of rat. The organs in which these lesions were found included adrenal glands, heart, kidneys, lung, testes, ovaries,thyroid, urinary bladder and uterus. Specific deviationsfrom the control incidenceseen in FM-3924 treated groups were addressedin the resultssectionof this report. However, the following changes were considered equivocal test article related effects. The incidenceof nodular hyperplasiaof the adrenal cortex was significantly increased(22%) in the high-dosemales comparedto the same finding in the controls (4%), while the high-dose female rats showed a much lower incidence (2%). Lung changes were also sporadic in occurrencewith the incidencesof the accumulation of alveolarmacrophages increased in the high-dose males and females. The incidenceof ovarian (stromal)tubular hyperplasiawas increasedin a statisticallysignificantand dose dependentmanner. The interpretationof this findingis uncertain,but a possibleexplanationis that it was secondary to the hepatic changes which may evoke endocrine relatedeffects in older rats. Likewise,the increasein uterine cystic glands in the high-dosefemalescould be a manifestationof this biological phenomenon. 23.