Hydrocortisone

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Additional information

There is no internal fertility study with hydrocortisone available. However results of fertility studies are cited in RTECS database (Feb 2010):

 

The oral application of hydrocortisone to female rats over 14 days results in effects on uterus, cervix and vagina. TDLo: 210 mg/kg (14D pre) [Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 24, p. 284, 1973 (FESTAS)]

 

The parenteral application to female rats over 7 days results in effects on uterus, cervix and vagina. TDLo: 35 mg/kg (7D pre)

[Journal of Experimental Medicine. (Rockefeller Univ. Press, 1230 York Ave., New York, NY 10021) V.1- 1896- v. 102, p. 347, 1955 (JEMEAV)]

Short description of key information:
There is no fertility study with hydrocortisone (ZK 5191) available. However results of fertility studies are cited in RTECS database (Feb 2010):

Oral, 14 days (rat, female): TDLo: 210 mg/kg (14D pre)
(Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 24, p. 284, 1973 (FESTAS))

Parenteral, 7 days (rat, female): TDLo: 35 mg/kg (7D pre)
(Journal of Experimental Medicine. (Rockefeller Univ. Press, 1230 York Ave., New York, NY 10021) V.1- 1896- v. 102, p. 347, 1955 (JEMEAV))

Effects on developmental toxicity

Additional information

There is no teratogenicity study with hydrocortisone available. However, results of different teratogenicity studies are scited in RTECS database (Feb 2010):

 

Intraplacentar application of hydrocortisone to pregnant mice on day 11 of pregnancy results in fetal death and developmental abnormalities not further specified. TDLo: 4 mg/kg (11D preg) ["Evaluation of Embryotoxicity, Mutagenicity and Carcinogenicity Risks In New Drugs, Proceedings of the Symposium on Toxicological Testing for Safety of New Drugs, 3rd, Prague, 1976," Benesova, O., et al., eds., Prague, Czechoslovakia, Univerzita Karlova, 1979 -,207,1979 (40YJAX)]

 

Subcutaneous application to pregnant rats on day 1 to 22 of pregnancy results in endocrine system effects on newborn (growth statistics e.g., reduced weight gain). TDLo: 330 mg/kg (1-22D preg) [Annales Medicinae Experimentalis et Biologiae Fenniae. (Helsinki, Finland) V.25-51, 1947-73. For publisher information, see MDBYAS. v. 40, p. 297, 1962 (AMEBA7)]

 

Subcutaneous application to guinea pigs on day 16 to 17 of pregnancy leads to specific developmental abnormality of the eye, ear and homeostasis. TDLo: 12 mg/kg (16-17D preg) [Anatomical Record. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1906/08- v. 144, p. 155, 1962 (ANREAK)]

 

Intraperitoneal application of hydrocortisone to pregnant rats on day 14 to 15 of pregnancy results in biochemical and metabolic effects on newborn. TDLo: 80 mg/kg (14-15D preg) [Biochemical and Biophysical Research Communications. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 75, p. 125, 1977 (BBRCA9)]

 

Pregnant mice were treated subcutaneously with hydrocortisone on day 12 of pregnancy. Offsprings developed specific craniofacial developmental abnormalities (including nose and tongue) TDLo: 200 mg/kg (12D preg) [Congenital Anomalies. (Nippon Senten Ijo Gakkai, 377-2 Ono-higashi, Osakasayama, Osaka-Fu 589 Japan) V.27- 1987- v. 32, p. 373, 1992 (CGANE7)]

 

After subcutaneous application to pregnant rats on day 14 to 15 of pregnancy fetotoxic effects were reproted (except fetal death). TDLo: 200 mg/kg (14-15D preg) [Congenital Anomalies. (Nippon Senten Ijo Gakkai, 377-2 Ono-higashi, Osakasayama, Osaka-Fu 589 Japan) V.27- 1987- v. 35, p. 133, 1995 (CGANE7)]

 

Intramuscular appliaction of hydrocortisone to mice on day 12 of pregancy results in fetotoxicity including fetal death. TDLo: 200 mg/kg (12D preg) [Journal of Craniofacial Genetics and Developmental Biology. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 7, p. 341, 1987 (JCGBDF)]

 

Subcutaneous application to female rats on pregnancy day 9 to 19 leads to fetotoxicity (except fetal death) and specific developmental abnormalities of the endocrine system and biochemical and metabolic effects on newborn. TDLo: 220 mg/kg (9-19D preg) [Journal of Developmental Physiology. (Oxford University Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1979- v. 11, p. 346, 1989 (JDPHDH)]

 

Intraperitoneal administration of hydrocortisone to female mice on pregnancy day 11 to 14 results in post-implantation mortality (e.g., dead and/or resorbed implants per total number of implants) and specific craniofacial abnormalities (including nose and tongue). TDLo: 400 mg/kg (11-14D preg) [Journal of Dental Research. (International Assoc. for Dental Research, 734 15th St., NW, Suite 809, Washington, DC 20005) V.1- 1919- v. 50, p. 609, 1971 (JDREAF)]

 

After female mice were treated subcutaneously on day 11 to 14 of pregnancy, post-implantation mortality (e.g., dead and/or resorbed implants per total number of implants) and craniofacial developmental abnormalities occured (including nose and tongue). TDLo: 400 mg/kg (11-14D preg) [Journal of Dental Research. (International Assoc. for Dental Research, 734 15th St., NW, Suite 809, Washington, DC 20005) V.1- 1919- v. 50, p. 609, 1971 (JDREAF)]

 

After intramuscular application of hydrocortisone to female mice on day 11 to 14 of pregnancy effects on fertility (post-implantation mortality e.g., dead and/or resorbed implants per total number of implants) and specific developmental abnormalities (craniofacial including nose and tongue) occured. TDLo: 400 mg/kg (11-14D preg) [Journal of Dental Research. (International Assoc. for Dental Research, 734 15th St., NW, Suite 809, Washington, DC 20005) V.1- 1919- v. 50, p. 609, 1971 (JDREAF)]

 

Parenteral administration to female rats on day 16 to 18 of pregnancy results in effects on embryo or fetus not further specified. TDLo: 50 mg/kg (16-18D preg) [Pediatric Research. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1967- v. 11, p. 282, 1977 (PEREBL)]

 

Subcutaneous application to female rabbits on day 24 to 26 of pregnancy results in effects on newborns growth statistics (e.g., reduced weight gain) and further effects not specified. TDLo: 6 mg/kg (24-26D preg) [Pediatric Research. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1967- v. 12, p. 38, 1978 (PEREBL)]

 

After subcutaneous application to rats on pregnancy day 18 biochemical and metabolic effects on newborns occured. TDLo: 50 mg/kg (18D preg) [Soviet Journal Developmental Biology (English Translation). Translation of Ontogenez. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.1- 1970- v. 10, p. 425, 1979 (SJDBA9)]

 

Subcutaneous application of hydrocortisone to female mice on day 11 to 14 of pregnancy results in specific developmental craniofacial abnormalities (including nose and tongue). TDLo: 156 mg/kg (11-14D preg) [Teratogenesis, Carcinogenesis, and Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 1, p. 15, 1980 (TCMUD8)]

 

Intramuscular application to female rats on day 13 of pregnancy results in fetotoxicity (except fetal death) and specific developmental craniofacial abnormalities (including nose and tongue). TDLo: 500 mg/kg (13D preg) [Teratogenesis, Carcinogenesis, and Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 3, p. 313, 1983 (TCMUD8)]

 

Subcutaneous administration of hydrocortisone to female mice on day 10 to 13 of pregnancy results in fetotoxicity (except fetal death) and specific developmental craniofacial abnormalities (including nose and tongue). TDLo: 100 mg/kg (10-13D preg) [Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 33, p. 29, 1986 (TJADAB)]

 

After intramuscular administration of hydrocortisone to hamsters on day 11 of pregnancy followinf effects were seen: on embryo or fetus: Cytological changes (including somatic cell genetic material); specific developmental abnormalities: Craniofacial (including nose and tongue). TDLo: 400 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. 40, p. 173, 1989 (TJADAB)]

 

Intramuscular application to female hamsters on day 12 of pregnancy results in fetotoxicity (except fetal death) and specific developmental abnormalities: craniofacial (including nose and tongue). TDLo: 150 mg/kg (12D preg) [Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 7, p. 191, 1973 (TJADAB)]

 

Ocular application to female rabbits on pregnancy day 6 to 18 results in fetal death. TDLo: 2945 ug/kg (6-18D preg) [Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 16, p. 773, 1970 (TXAPA9)]

 

Oral application to female mice on day 11 to 14 of pregnancy results in specific developmental craniofacial abnormalities (including nose and tongue). TDLo: 10 mg/kg (11-14D preg) [Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 45, p. 344, 1978 (TXAPA9)]

 

Intramuscular application of hydrocortisone to femlae mice on day 10 of pregnancy results in post-implantation mortality (e.g., dead and/or resorbed implants per total number of implants). TDLo: 333 mg/kg (10D preg) [Journal of Embryology and Experimental Morphology. (Essex, UK) V.1-98, 1953-86. For Publisher information, see DEVPED v. 35, p. 213, 1976 (JEEMAF)]

Justification for classification or non-classification

There is no internal company reproductive toxicity study with hydrocortisone available. However, results of different studies are scited in RTECS database (Feb 2010) showing hydrocortisone derived effects on the fertility in rats and extensive 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 an 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).

According to the Regulation (EC) 1272/2008 (CLP), hydrocortisone is classified as Category 1A for reproduction toxicity.