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Target Organs and Levels of Evidence for TR-601

Toxicology and Carcinogenesis Studies of Di(2-ethylhexyl) Phthalate (CASRN 117-81-7) Administered in Feed to Sprague Dawley (Hsd:Sprague Dawley SD) Rats

Chemical CASRN (Study Title)	Peer Review Date	Route/Exposure Levels	Study Laboratory
Di(2-ethylhexyl) Phthalate 117-81-7	04/02/2021	Dosed-Feed R: 0, 300, 1000, 3000, or 10,000 ppm; 50/sex/group	Battelle Columbus Laboratory

Levels of Evidence

Male Rats: Clear Evidence

Type	Organ/Tissue (Lesion)
Neoplastic Lesions	Perinatal and Postweaning Study (Study 1) Liver: hepatocellular adenoma (0/50, 1/49, 0/50, 3/50, 8/49); hepatocellular carcinoma (1/50, 0/49, 0/50, 0/50, 3/49); hepatocellular adenoma or carcinoma (combined) (1/50, 1/49, 0/50, 3/50, 11/49) Pancreas Acinar Cell: acinar adenoma (10/50, 7/49, 8/50, 36/50, 22/49); acinar carcinoma (0/50, 0/49, 0/50, 3/50, 1/49); acinar adenoma or carcinoma (combined) (10/50, 7/49, 8/50, 38/50, 22/49) Postweaning-Only Study (Study 2) Liver: hepatocellular adenoma (0/50, 2/50, 0/50, 1/50, 6/50); hepatocellular carcinoma (0/50, 0/50, 0/50, 0/50, 6/50); hepatocellular adenoma or carcinoma (combined) (0/50, 2/50, 0/50, 1/50, 12/50) Pancreas Acinar Cell: acinar adenoma (1/49, 4/50, 5/50, 23/50, 30/50); acinar carcinoma (0/49, 1/50, 0/50, 1/50, 5/50); acinar adenoma or carcinoma (combined) (1/49, 5/50, 5/50, 23/50, 33/50)
May Have Been Related	Postweaning-Only Study (Study 2) Testis: interstitial cell, adenoma (7/50, 3/50, 3/50, 6/50, 15/50)
Non-Neoplastic Lesions	Perinatal and Postweaning Study (Study 1) Liver: hepatocyte, cytoplasmic alteration; hepatocyte, hypertrophy; pigment; necrosis; eosinophilic focus; basophilic focus Testis: germinal epithelium, degeneration (includes bilateral); interstitial cell, hyperplasia, focal (includes bilateral); seminiferous tubule, dysgenesis (includes bilateral) Epididymis: hypospermia (includes bilateral) Kidney: papilla, edema; papilla, hemorrhage; epithelium, papilla, hyperplasia; infarct Heart: valve, fibrosis; valve, thrombus Bone marrow: hypercellularity Pituitary gland: pars distalis, hypertrophy Postweaning-Only Study (Study 2) Liver: hepatocyte, cytoplasmic alteration; hepatocyte, hypertrophy; pigment; necrosis; eosinophilic focus; clear cell focus Pancreas: acinus, hyperplasia Testis: germinal epithelium, degeneration (includes bilateral); edema (includes bilateral); interstitial cell, hyperplasia, focal (includes bilateral) Epididymis: hypospermia (includes bilateral); duct, exfoliated germ cell (includes bilateral) Heart: valve, fibrosis; valve, thrombus Bone marrow: hypercellularity Pituitary gland: pars distalis, hypertrophy
Other Considerations	Perinatal and Postweaning Study (Study 1) Testis: small (2/49, 2/49, 4/50, 2/50, 45/49); enlarged (or swelling) (0/49, 0/49, 0/50, 0/50, 1/49); fluid or blood filled (0/49, 1/49, 1/50, 1/50, 1/49); right or left, abdominal, undescended (1/49, 0/49, 0/50, 0/50, 19/49); right or left, inguinal, undescended (0/49, 1/49, 1/50, 0/50, 4/49); right or left, abdominal or inguinal, undescended (1/49, 1/49, 1/50, 0/50, 23/49); right, not present (0/49, 0/49, 0/49, 0/50, 1/49); cranial suspensory ligament (0/49, 0/49, 0/50, 0/50, 5/49) Epididymis: small (0/49, 0/49, 2/50, 0/50, 14/49); right, cauda, agenesis (0/49, 0/49, 0/49, 0/50, 2/49); right or left, caput, agenesis (0/49, 0/49, 0/50, 0/50, 4/49); right or left, cauda, agenesis (0/49, 0/49, 0/50, 0/50, 2/49); right or left, corpus, agenesis (0/49, 0/49, 0/50, 0/50, 3/49 Levator ani/bulbocavernosus muscle: small (0/50, 0/49, 0/50, 0/50, 2/48) Cowper’s glands: left, small (0/50, 0/49, 0/50, 0/50, 1/47); right, small (0/50, 0/49, 0/50, 0/50, 1/47) Prostate glands: small (0/50, 0/49, 0/50, 0/50, 1/47) Seminal vesicles/ coagulating glands: small (1/50, 0/49, 1/50, 1/50, 8/47) Phallus: small (0/50, 0/49, 0/49, 0/50, 3/49); cleft (0/50, 0/49, 0/49, 0/50, 3/49) Prepuce: cleft (0/50, 0/49, 0/50, 0/50, 1/49); incomplete preputial separation (0/50, 0/49, 0/50, 0/50, 7/49) Gubernaculum: right or left, not present (0/47, 0/49, 0/49, 0/50, 18/41); ↑ right length

Female Rats: Clear Evidence

Type	Organ/Tissue (Lesion)
Neoplastic Lesions	Perinatal and Postweaning Study (Study 1) Liver: hepatocellular adenoma (1/49, 0/50, 5/50, 9/50, 5/48); hepatocellular carcinoma (0/49, 0/50, 0/50, 0/50, 8/48); hepatocellular adenoma or carcinoma (combined) (1/49, 0/50, 5/50, 9/50, 13/48) Pancreas Acinar Cell: acinar adenoma or carcinoma (combined) (0/49, 0/50, 0/50, 2/50, 1/48) Postweaning-Only Study (Study 2) Liver: hepatocellular adenoma (0/50, 0/50, 1/50, 1/50, 13/49); hepatocellular carcinoma (0/50, 0/50, 0/50, 0/50, 2/49); hepatocellular adenoma or carcinoma (combined) (0/50, 0/50, 1/50, 1/50, 14/49) Pancreas Acinar Cell: acinar adenoma or carcinoma (combined) (0/50, 0/50, 0/50, 1/50, 2/47) Uterus: adenoma, adenocarcinoma, squamous cell carcinoma, or squamous cell papilloma (combined) (2/50, 4/50, 1/50, 6/50, 13/50)
May Have Been Related	Perinatal and Postweaning Study (Study 1) Uterus: adenoma, adenocarcinoma, squamous cell carcinoma, or squamous cell papilloma (combined) (3/50, 1/50, 1/50, 3/50, 7/50)
Non-Neoplastic Lesions	Perinatal and Postweaning Study (Study 1) Liver: hepatocyte, cytoplasmic alteration; hepatocyte, hypertrophy; pigment; necrosis; eosinophilic focus; basophilic focus; bile duct hyperplasia Pancreas: acinus, hyperplasia Kidney: papilla, edema; epithelium, papilla, hyperplasia; infarct; renal tubule, cyst; renal tubule, dilation Postweaning-Only Study (Study 2) Liver: hepatocyte, cytoplasmic alteration; hepatocyte, hypertrophy; pigment Pancreas: acinus, hyperplasia Uterus: inflammation, chronic
Other Considerations	Perinatal and Postweaning Study (Study 1) Vagina: not patent (0/50, 0/50, 0/50, 0/50, 5/48) Phallus: cleft (0/50, 0/50, 0/50, 2/50, 1/48)