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Key value for chemical safety assessment

Effects on fertility

Description of key information
No data available.
Additional information

There is no fertility study with hydrocortisone-21-acetate (ZK 5192) available. However results of fertility studies are cited in RTECS database (Feb 2010):

Subcutaneous application to rats on day 1 to 7 of pregnancy leads to post-implantation mortality (e.g., dead and/or resorbed implants per total number of implants) and fetotoxicity (except fetal death); TDLo: 350 mg/kg (1-7D preg) [Anatomical Record. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1906/08- v. 129, p. 133, 1957 (ANREAK)]

Intraperitoneal application to rats on day 2 to 5 of pregnancy leads to pre-implantation mortality (e.g., reduction in number of implants per female; total number of implants per corpora lutea); TDLo: 2 mg/kg (2-5D preg) [Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 81, p. 1091, 1967 (ENDOAO)]

Pigs were treated intramuscularly 12 days premating resulting in effects on fertility not further specified; TDLo: 100 mg/kg (12D pre) [Journal of Reproduction and Fertility. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1960- v. 64, p. 85, 1982 (JRPFA4)]

Intramuscular application to mice on day 11 of pregnancy results in post-implantation mortality (e.g., dead and/or resorbed implants per total number of implants); TDLo: 64 mg/kg (11D preg) [Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 4, p. 31, 1971 (TJADAB)]


Short description of key information:
There is no fertility study with hydrocortisone-21-acetate (ZK 5192) available. However results of fertility studies are scited in RTECS database (Feb 2010):

Subcutaneous, day 1 to 7 of preg (rat): TDLo: 350 mg/kg (1-7D preg)
(Anatomical Record. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1906/08- v. 129, p. 133, 1957 (ANREAK))

Intraperitoneal, day 2 to 5 of preg (rat): TDLo: 2 mg/kg (2-5D preg)
(Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 81, p. 1091, 1967 (ENDOAO))

Intramuscular, 12 days premating (pig): TDLo: 100 mg/kg (12D pre)
(Journal of Reproduction and Fertility. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1960- v. 64, p. 85, 1982 (JRPFA4))

Intramuscular, day 11 of preg (mouse): TDLo: 64 mg/kg (11D preg)
(Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 4, p. 31, 1971 (TJADAB))

Effects on developmental toxicity

Description of key information
Subcutaneous, day 6 to 15 of preg (rat, Sprague-Dawley, non-GLP, doses: 0/ 0.2/ 2 mg/kg): NOAEL: 0.2 mg/kg
(Schering AG, Report No: 2304; 1976-07-20)
Subcutaneous, day 6 to 18 of preg (rabbit, NZW, non-GLP, doses: 0/ 0.5/ 1.5 mg/kg): LOAEL: 0.5 mg/kg
(Schering AG, Report No: 2325; 1976-08-20)
Subcutaneous, day 6 to 18 of preg (rabbit, NZW, non-GLP, doses: 0/ 0.2/ 2 mg/kg): LOAEL:0.2 mg/kg
(Schering AG, Report No: 2318; 1976-08-18)
Subcutaneous, day 6 to 15 of preg (rat, Sprague-Dawley, non-GLP, doses: 0/ 0.2/ 2 mg/kg): NOAEL:0.2 mg/kg
(Schering AG, Report No: 2515; 1976-12-28)
Subcutaneous, day 11 to 14 of preg (mouse, NMRI, non-GLP, doses: 0/ 10/ 20 / 45 / 65 / 100 mg/kg): LOAEL:10 mg/kg
(Schering AG, Report No: 2677; 1977-04-29)
Subcutaneous, day 6 to 15 of preg (rat, Sprague-Dawley, non-GLP, doses: 0/ 20 mg/kg): LOAEL:20 mg/kg
(Schering AG, Report No: 2791; 1977-08-25)
Subcutaneous, day 6 to 18 of preg (rabbit, NZW, non-GLP, doses: 0/ 0.2/ 1 / 2 mg/kg): NOAEL: 0.2 mg/kg
(Schering AG, Report No: 3161; 1978-03-16)
Additionally, results of teratogenicity studies conducted on rats, mice and rabbits with hydrocortisone-21-acetate as well as observations made on human newborn exposed via placenta to hydrocortisone-21-acetate are cited in RTECS database (Feb 2010). The results are further described in chapter DISCUSSION.
Additional information

Daily subcutaneous application of ZK 5192 to female rats on pregnancy day 6 to 15 in doses of 0, 0.2 and 2.0 mg /kg results in reduces body weight gain in dams and suspicion of embryolethality in high dose group. NOAEL 0.2 mg/kg [Schering AG, Report No: 2304; 1976-07-20]

Daily subcutaneous application of 0, 0.5, 1.0 and 1.5 mg/kg ZK 5192 to female rabbits on day 6 to 18 of pregnancy results in reduction in fetal body weight, embryo resorption and reduced maternal body weight. LOAEL:0.5 mg/kg [Schering AG, Report No: 2325; 1976-08-20]

Female rabbits were treated on pregnancy day 6 to 18 with daily subcutaneous applications of 0, 0.2 and 2 mg/kg ZK 5192. At 2 mg/kg body weight loss in dams and embryolethality was noted. NOAEL: 0.2 mg/kg [Schering AG, Report No: 2318; 1976-08-18]

Subcutaneous administration of hydrocortisone to female rats at 0, 0.2 and 2 mg/kg bw on day 6 to 15 of pregnancy results in reduced body weigth gain of dams. NOAEL:0.2 mg/kg [Schering AG, Report No: 2515; 1976-12-28]

Subcutaneous administration of 0, 10, 20, 45, 65 and 100 mg/kg hydrocortisone-21-acetate to female mice on pregnancy day 11 to 14 results in cleft palates (from 10 mg/kg) and reduced body weight (from 45 mg/kg) in the fetuses and reduced body weight gain in dams from lowest dose on. LOAEL:10 mg/kg [Schering AG, Report No: 2677; 1977 -04 -29]

Female rats were treated daily subcutaneously on pregnancy day 6 to 15 with 0 and 20 mg/kg ZK 5192 resulting in reduced body weight gain of the dams. LOAEL:20 mg/kg [Schering AG, Report No: 2791; 1977-08-25]

Daily subcutaneous application of ZK 5192 to female rabbits on pregnancy day 6 to 18 in doses of 0, 0.2, 1.0 and 2.0 mg/kg results in reduced body weight of dams and fetuses, retarded ossification and increased resorptions. NOAEL:0.2 mg/kg [Schering AG, Report No: 3161; 1978-03-16]

Additionally, results of teratogenicity studies with hydrocortisone-21-acetate are cited in RTECS database (Feb 2010):

Subcutaneous application of hydrocortisone-21-acetate to rats on day 1 to 14 of pregnancy leads to extra embryonic structures (e.g., placenta, umbilical cord) and specific develomental abnormalities on endocrine system; TDLo: 200 mg/kg (7-14D preg) [Anatomical Record. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1906/08- v. 129, p. 133, 1957 (ANREAK)]

Rats were treated orally on day 6 to 15 of pregnancy, leading to fetotoxicity (except fetal death) and fetal death; TDLo: 1 gm/kg (6-15D preg) [Bollettino Chimico Farmaceutico. (Societa Editoriale Farmaceutica, Via Ausonio 12, 20123 Milan, Italy) V.33- 1894- v. 119, p. 391, 1980 (BCFAAI)]

Oral administration to rats on day 6 to 15 of pregnancy results in specific developmental abnormalities of the central nervous system and craniofacial (including nose and tongue); TDLo: 1500 mg/kg (6-15D preg) [Bollettino Chimico Farmaceutico. (Societa Editoriale Farmaceutica, Via Ausonio 12, 20123 Milan, Italy) V.33- 1894- v. 119, p. 391, 1980 (BCFAAI)]

Oral application to mice on day 6 to 15 of pregnancy results in fetotoxicity (except fetal death), fetal death and specifc developmental abnormalities: Craniofacial (including nose and tongue); TDLo: 125 mg/kg (6-15D preg) [Bollettino Chimico Farmaceutico. (Societa Editoriale Farmaceutica, Via Ausonio 12, 20123 Milan, Italy) V.33- 1894- v. 119, p. 391, 1980 (BCFAAI)]

Rabbits were treated orally on day 6 to 18 of pregnancy leading to fetotoxicity (except fetal death) and specific developmental abnormalities of central nervous system and musculoskeletal system; TDLo: 13 mg/kg (6-18D preg) [Bollettino Chimico Farmaceutico. (Societa Editoriale Farmaceutica, Via Ausonio 12, 20123 Milan, Italy) V.33- 1894- v. 119, p. 391, 1980 (BCFAAI)]

Subcutaneous application of hydrocortisone-21-acetate to rats on day 15 to 21 of pregnancy results in specific developmental abnormalitie of central nervous system and the endocrine system as well as biochemical and metabolic effects on newborn; TDLo: 350 mg/kg (15-21D preg) [Comparative Biochemistry and Physiology. (Elmsford, NY) V.1-37, 1960-70. For publisher information, see CBPBB8. v. 138, p. 169, 2004 (CBCPAI)]

Subcutaneous administration to rats on day 16 to 18 of pregnancy results in specific developmental abnormalities of the central nervous system and the endocrine system as well as biochemical and metabolic effects on newborn; TDLo: 100 mg/kg (16-18D preg) [Comparative Biochemistry and Physiology. (Elmsford, NY) V.1-37, 1960-70. For publisher information, see CBPBB8. v. 138, p. 169, 2004 (CBCPAI)]

Subcutaneous application to rats on pregnancy day 17 to 19 leads to specific developmental abnormalities of the endocrine system and delayed effects on newborn; TDLo: 22.5 mg/kg (17-19D preg) [Comparative Biochemistry and Physiology. (Elmsford, NY) V.1-37, 1960-70. For publisher information, see CBPBB8. v. 139, p. 11, 2004 (CBCPAI)]

Rats treated once parenterally on day 11 of pregnancy develop pups with craniofacial abnormalities (including nose and tongue); TDLo: 200 mg/kg (11D preg) [Cleft Palate Journal. (American Cleft Palate Assoc., Univ. of Pittsburgh, 331 Salk Hall, Pittsburgh, PA 15261) V.1- 1964- v. 9, p. 210, 1972 (CLPJAX)]

Subcutaneous application to mice on day 10 to 12 of pregnancy result in specific craniofecial developmental abnormalities (including nose and tongue), developmental abnormalities of the musculoskeletal system and further not specified abnormalities; TDLo: 75 mg/kg (10-12D preg) [Journal of Embryology and Experimental Morphology. (Essex, UK) V.1-98, 1953-86. For Publisher information, see DEVPED v. 20, p. 355, 1968 (JEEMAF)]

Subcutaneous administration to mice on pregnancy day 10 to 12 leads to fetal death; TDLo: 84 mg/kg (10-12D preg) [Journal of Embryology and Experimental Morphology. (Essex, UK) V.1-98, 1953-86. For Publisher information, see DEVPED v. 20, p. 355, 1968 (JEEMAF)]

Intramuscular application to mice on day 10 to 21 of pregnancy leads to specific craniofacial abnormalities in pups (including nose and tongue) and effects on live birth index (similar to fetuses per litter, except measured after birth); TDLo: 1200 mg/kg (10-21D preg) [Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 169, p. 665, 1952 (NATUAS)]

Mice were treated subcutaneously on day 14 of pregnancy resulting in developmental abnormalities of eye and ear; TDLo: 50 mg/kg (14D preg) [Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 30(1), p. 11A, 1984 (TJADAB)]

Intramuscular application to mice on day 11 of pregnancy lead to developmental craniofacial abnormalities (including nose and tongue); TDLo: 320 mg/kg (11D preg) [Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 4, p. 31, 1971 (TJADAB)]

Subcutaneous administration to mice on pregnancy day 12 results in specific developmental abnormalities of the urogenital system;

TDLo: 250 mg/kg (12D preg) [Teratology, The International Journal of Abnormal Develoment. (Alan R. Liss, Inc., 41 E. 11th St.,

New York, NY 10003) V.1- 1968- v. 43, p. 571, 1991 (TJADAB)]

Dermal, application to male rats 16 days premating result in extra embryonic structures (e.g., placenta, umbilical cord), fetotoxicity (except fetal death) and fetal death; TDLo: 30.5 mg/kg (61D male) [Toksikologicheskii Vestnik. (18-20 Vadkovskii per. Moscow, 101479, Russia) History Unknown v. (2), p. 42, 2002 (TOVEFN)]

Toxicity to reproduction: other studies

Additional information

No data available.

Justification for classification or non-classification

There is no internal company fertility study with hydrocortisone-21-acetate (ZK 5192), but some teratogenicity studies available. However, results of different studies are also cited in RTECS database (Feb 2010) showing effects of hydrocortisone-21-acetate

on the fertility and teratogenic effects in studies conducted with different animal species.

In animal experiments glucocorticoids have embryolethal and teratogenic effects. However, since there are no clear signs of such effects following therapeutic use in humans, pregnancy is not regarded as a contraindication to the use of glucocorticoids. Higher levels during pregnancy could, however, lead to a risk of an embryotoxic effect. Following long-term systemic therapy with glucocorticoids such as prednisone and beclomethasone proprionate for asthmatic and other chronic diseases reduced birth weight (=<2500 g) and placental weight were reported, which are supposed to be an indication for a reversible fetotoxic effect. Similar effects are expected at high levels of hydrocortisone. Long-term exposure to glucocorticoids can impair fertility (due to a negative influence on the hypophyseal-gonadal axis).

Classified according to German legislation (TRGS-905) as Repr. (F) Cat. 3 and Repr. (E) Cat. 1 (EEC criteria).

According to the Directive 67/548/EEC, hydrocortisone is classified:

Category 3; R62 - May impair fertility.

Category 1; R61 - Possible risk of harm to the unborn child.

Classified as Category 1A according to Regulatiom (EC) 1272/2008 (CLP).