Estradiol

Endpoint summary

Additional information

Test system	Substance	Application	End point/Effect	Literature
Pig	^14C-estradiol	Infusion into selected portions of the gastro- intestinal tract of gilts.	Blood samples were collected from the jugular and portal veins. The concentration of free estrogens in the jugular vein was low (< 1%) The concentration of conjugated estrogens in the jugular vein peaked rapidly after instillation. 60-90% of the radiolabel in blood was present as glucuronide conjugates; smaller amounts of sulfated compounds were detected and approximately 1% as diconjugates. The principal steroid identified after cleavage by ß-glucuronidase and sulfatase was estrone. Conjugation occurs as estradiol crosses the mucosa of the gastrointestinal tract, and free estradiol in the ortal plasma is conjugated during the first pass through the liver.	Moore et al., 1982. J. Anim. Sci., 55, 124-134 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
Pig	17ß-Estradiol- D-glucuronide	Instillation into sections of intestineof gilts.	Blood samples were collected from the jugular and portal veins. The limiting factor in absorption of conjugates was hydrolysis to free estrogen.	Pohland et al., 1982 J. Anim. Sci., 55, 145-152as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
Pig	Gestadiol-17ß- D-glucuronide	Gavage	A possible dose-limiting rate of absorption was observed at the highest dose (4 mmol 3H- estradiol glucuronide)	Coppoc et al., 1982,J. Anim. Sci., 55, 135-144 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
Pig	Crystalline estradiol (10 mg in cocoa butter)	Gavage	The concentrations of estradiol, estrone, estradiol glucuronide, and estrone sulfate in the hepatic portal vein rose within 5 min and remained elevated for several hours. Estrogens administered orally are conjugated by the gut wall and pass to the liver, where they enter either the bile pool for enterohepatic circulation or the bloodstream.	Ruoff & Dziuk, 1994. Domest. Anim. Endocrinol., 11, 197-208 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
Wister Rat, female	17ß-Estradiol	Intravenous administration of 0.1 mg/kg bw   Gavage of 10 mg/kg bw	Concentrations of estradiol in liver was 20 times higher after intragastric than after intravenous administration. Absolute bio- availability was 8.3% after an intragastric dose of 10 mg/kg bw. The total clearance was 154 ml/min per kg bw. The half-life of estradiol in liver was 2.6 h	Schleicher et al., 1998. Pharmacol. Toxicol., 82, 34-39 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000
Rat, female	Levonorgestrel and 17ß-Estradiol	Dermal patch for a period of 7 days	Only slight changes in serum-level over the time of application. Systemic drug exposure was 0.048 µg h/mL/d or 500 µg/d for Estradiol-	Final Report No. KIST10000001, Schering AG, Concentration of Levonogestrel and Estradiol in rat serum following application of estradiol/Levonogestrel transdermal combination patches over a period of 7 days, dated 09 Sept. 1999.
			Circulating estradiol is bound to sex hormone-binding globulin (SHBG) and, to a lesser extent, serum albumin. Only 1-2% of circulating estradiol is unbound; 40% is bound to SHBG and the remainder to albumin.	Carr, 1998. In: Wilson et al., eds, Williams Textbook of Endocrinology, 9th Ed.,, W.B. Saunders Co., pp. 751-817 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000
			Estrogens are eliminated in faeces and urine. The principal metabolites found in urine are polyhydroxylated forms conjugated at C3 to glucuronic acid or sulfate. Elimination in bile is subject to enterohepatic circulation, and 20% of estrogens may be lost through faecal elimination.	Lewis et al., 1998 Eur. J. Gastroenterol. Hepatol., 10, 33-39 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000
			Two main competing, irreversible pathways for estradiol hydroxylation are 2-or 4-hydroxylation and 16 alpha- hydroxylation.	Michnovicz et al., 1989. Metabolism, 38, 537-541. 817 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000
Hamster, in vitro, liver microsomes			Does dependency of metabolism. 16alpha-hydroxylation predominates at low (< 25 µmol/L) concentrations, whereas 16 alpha-and C2-hydroxylation contributed equally to estradiol metabolism at higher concentrations.	Butterworth et al., 1996Drug. Metab. Disposition, 24, 588-594 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
Syrian hamster			Metabolism in Kidney: 2-hydroxy formation after catalysis by CYP1A1/2 and CYP3A	Hammond et al., 1997.Toxicol. Appl. Pharmacol., 145, 54-60 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
Mouse CYP1B1 expressed in E. coli			Significant differences in steroid metabolism are seen between rodents and humans. Human but not mouse CYP1B1, was identified as an estrogen 4- hydroxylase,.	Savas et al., 1997. Arch. Biochem. Biophys., 347, 181-192 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
Syrian hamster, in vitro, liver and kidneys lysosomes, male			Deconjugation of estradiol and estrone glucuronides with rates of 56% and 34%, respectively.   Demethylation of catechol estrogens with fivefold higher rates in liver than in kidney.	Zhu et al., 1996. Toxicol. Appl. Pharmacol., 136, 186-193as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty- second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
			Redox cycling of catechol (hydroxyquinone) to quinone through semiquinone intermediates is catalysed by oxidation of catechol estrogens by peroxidases or CYP1A1 lipid hydroperoxide cofactors. Oxygen radicals formed in this redox process may increase the carbonyl content of proteins, formation of DNA adducts, and lipid peroxidation. It was concluded that redox cycling is a critical step in estrogen-mediated carcinogenesis.	Yager & Liehr, 1996. Annu. Rev. Pharmacol. Toxicol., 36, 203-232 as cited by Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.
			In general, estradiol is inactive when given orally because it is inactivated in the gastrointestinal tract and liver, although fine-particle formulations of estradiol are effective when given orally and are used therapeutically. The bioavailability of a single 4-mg dose of fine-particle estradiol administered orally to 14 young women was 5% of that of a dose administered intravenously. At least 60% of the absorbed dose appeared in the serum as estrone and estrone sulfate and was available as part of the endogenous pool. Estradiol shows little toxicity when given as a single oral dose. Few conventional short-and long-term studies of the systemic toxicity of estradiol in animals treated orally were available, but there is sufficient information to demonstrate that the reverse effects of estradiol seen in animals are associated with estrogenic activity. Because of the specificity and affinity with which estradiol binds to its receptors, the hormonal effects occur at much lower doses than other toxicological responses and hence are the most appropriate for use in evaluating the safety of the compound.	Toxicological Evaluation of certain Veterinary Drug Residues in Food. WHO Food Additives Series: 43, prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2000.