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Administrative data

Description of key information

Dermal, 12 weeks (Rabbit, NZW, non-GLP, doses: 0 / 5 / 25  mg/kg, 5 h/day 7 times/week): NOEL < 5 mg/kg
[Schering AG, Report No: 2679, 1977-05-11]
Additionally, results of repeated dose toxicity studies with hydrocortisone-21-acetate are cited in RTECS database (Feb 2010):
Subcutaneous, 35 days (rat); TDLo: 175 mg/kg/35D-I
(Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 27, p. 2102, 1977 (ARZNAD))
Subcutaneous, 3 days(rat); TDLo: 22.5 mg/kg/3D-I
(Comparative Biochemistry and Physiology. (Elmsford, NY) V.1-37, 1960-70. v. 139, p. 11, 2004 (CBCPAI))
Oral, 8 days (rat); TDLo: 1000 mg/kg/8D-I
(Toksikologicheskii Vestnik. (18-20 Vadkovskii per. Moscow, 101479, Russia) v. (2), p. 42, 2002 (TOVEFN))
Oral, 7 days (rat); TDLo: 875 mg/kg/7D-I
(Toksikologicheskii Vestnik. (18-20 Vadkovskii per. Moscow, 101479, Russia) History Unknown v. (2), p. 42, 2002 (TOVEFN))
Oral, 14 days (rat); TDLo: 1750 mg/kg/14D-I
(Toksikologicheskii Vestnik. (18-20 Vadkovskii per. Moscow, 101479, Russia) History Unknown v. (2), p. 42, 2002 (TOVEFN))
Oral, 30 days (rat); TDLo: 3750 mg/kg/30D-I
(Toksikologicheskii Vestnik. (18-20 Vadkovskii per. Moscow, 101479, Russia) History Unknown v. (2), p. 42, 2002 (TOVEFN))
Dermal, 61 days (rat); TDLo: 2.25 mg/kg/61D-I
(Toksikologicheskii Vestnik. (18-20 Vadkovskii per. Moscow, 101479, Russia) History Unknown v. (2), p. 42, 2002 (TOVEFN))

Key value for chemical safety assessment

Mode of Action Analysis / Human Relevance Framework

Additional information

Dermal application of ZK 5192 (0, 5 and 25 mg/kg, 5 h/day 7 times/week) to rabbits (5/sex/group)over 12 weeks results in reduced body weight gain (females) and reduced thickness of skin fold (atrophy) including reduction of inflammation cells in corium infiltate. Hematology showed reduced hemoglobin, HK, erythrocytes, lymphocytes, eosinophiles. Erythrocyte sedimentation rate, neutrophiles, glucose, total protein, lipids, phosphatide, trigyceride, cholsterol, fibrinogen, GOT and GPT were increased. Organ weight was increased in liver and kidneys and decreased in adrenal glands, spleen and sceletal muscles (females). Histopathology showed lipid infiltration, swelling and focal necroses of liver cells, increase in kidney protein cylinders, enlargement of tubuli in Bowman capsule, lipid infiltration in medulla of kidney, haemosideroses in spleen, atrophy of zona fasciculata in adrenal gland and inflated cells in zona fasciculata and reticularis, thymus involution, atrophy of lymphatic tissue in lymph nodes. In pancreas ductus proliferation, degranulation, hypertrophy and hyperplasia of the B-cells were observed. Testes developed tubuli atrophy. Reduction in reaction of inflammation cells in liver. NOEL below 5 mg/kg [Schering AG, Report No: 2679, 1977-05-11]

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

Subcutaneous application of hydrocortisone-21-acetate to rats over 35 days results in weight loss or decreased weight gain and death; TDLo: 175 mg/kg/35D-I [Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 27, p. 2102, 1977 (ARZNAD)]

Subcutaneous application of hydrocortisone-21-acetate to rats over 3 days leads to adrenal cortex hypoplasia and changes in adrenal weight; TDLo: 22.5 mg/kg/3D-I [Comparative Biochemistry and Physiology. (Elmsford, NY) V.1-37, 1960-70. For publisher information, see CBPBB8. v. 139, p. 11, 2004 (CBCPAI)]

Daily oral administration to rats over 8 days results in death; TDLo: 1000 mg/kg/8D-I [Toksikologicheskii Vestnik. (18-20 Vadkovskii per. Moscow, 101479, Russia) History Unknown v. (2), p. 42, 2002 (TOVEFN)]

Rat were treated with hydrocortisone-21-acetate orally over 7 days. Animals developed somnolence (general depressed activity) and hemorrhages; TDLo: 875 mg/kg/7D-I [Toksikologicheskii Vestnik. (18-20 Vadkovskii per. Moscow, 101479, Russia) History Unknown v. (2), p. 42, 2002 (TOVEFN)]

Daily oral application to rats over 14 days leads to weight loss or decreased weight gain; TDLo: 1750 mg/kg/14D-I [Toksikologicheskii Vestnik. (18-20 Vadkovskii per. Moscow, 101479, Russia) History Unknown v. (2), p. 42, 2002 (TOVEFN)]

Rats were treated orally over 30 days, resulting in changes in heart, kidney, thymus and spleen weight, impairment in liver function tests and depressed renal function tests; TDLo: 3750 mg/kg/30D-I [Toksikologicheskii Vestnik. (18-20 Vadkovskii per. Moscow, 101479, Russia) History Unknown v. (2), p. 42, 2002 (TOVEFN)]

Dermal treatment to rats over 61 days results in alteration of classical conditioning and intermediar metabolism and in paternal effects on testes, epididymis and sperm duct; TDLo: 2.25 mg/kg/61D-I [Toksikologicheskii Vestnik. (18-20 Vadkovskii per. Moscow, 101479, Russia) History Unknown v. (2), p. 42, 2002 (TOVEFN)]

Justification for classification or non-classification

Following repeated exposure typical glucocorticoid effects (impaired wound healing, effects on calcium and phosphate metabolism, increased intra-ocular pressure after primarily local contamination, promotion of the spread of infection, degragation of lymphatic tissue, inhibition of the adrenal cortex, impairment of hematogenic tissue) are to be expected.

Classification with R 48/20/21/22 according to 67/548/EEC and STOT Cat 2 according to Regulation (EC) No. 1272/2008 (CLP) is required.