MELENGESTROL ACETATE
Overview
Chemical Names
17alpha-ACETOXY-6-METHY-16-METHYLENEPREGNA-4,6-DIENE-3,20-DIONE ACETATE
Functional Class
Veterinary Drug
PRODUCTION_AID
PRODUCTION_AID
Evaluations
Evaluation year: 2008
ADI:0-0.03 µg/kg bw
ADI:
0-0.03 µg/kg bw
Comments:
The Committee concluded that the most appropriate end-point for evaluating the safety of residues of melengestrol acetate is the progestational effect in non-human primates. An ADI of 0-0.03 µg/kg bw was established by applying a safety factor of 200 to the minimally effective dose of 5 µg/kg bw/d (rounded to one significant figure) of melengestrol acetate for affecting the menstrual cycle in female cynomolgus monkeys in a study over three menstrual cycles. This safety factor was used because the ADI is not based on a clear NOEL.
MRL Comment:
MRLs (EXPRESSED AS MELENGESTROL ACETATE): FAT (CATTLE): 18 µg/kg; LIVER (CATTLE): 10 µg/kg; MUSCLE (CATTLE): 1 µg/kg; KIDNEY (CATTLE): 2 µg/kg.
Intake:
EDI at median residue levels: 0.25 µg/p/d (14% of ADI)
Meeting:
70
Report:
Tox Monograph:
Residues:
Toxicological study
Pivotal Study:
GLP-compliant monkey study to estimate hormonal NOEL (Chenault et al., 1993): Female cynomolgus monkeys (8 normally cycling animals/dose; 5-11 years old) were orally-treated with melengestrol acetate over 3 consecutive menstrual cycles (up to 105 days) at doses of 0 (ethanol only), 5, 10, or 25 µg/kg bw/d. Significantly decreased serum LH and estradiol were noted at 10 & 25 µg/kg and decreased progesterone at the high dose. Significantly fewer high dose animals menstruated and ovulated, and significantly increased incidences of changed cycles were seen at 10 & 25 µg/kg. Although the authors concluded that melengestrol acetate at a dose of 5 µg/kg bw had no effects of biological significance, the effects at this dose, even though not statistically significant, were consistent with the hormonal response seen at higher doses. Therefore, the lowest dose of 5 µg/kg bw/d was the minimally effective dose and was close to the NOEL for hormonal effects.
Animal Specie:
Monkey
Effect:
Altered serum hormones & menstrual cyclicity
LOEL:
5 µg/kg bw/d
Point of departure:
5 µg/kg bw/d
Previous Years:
2004, TRS 925-JECFA 62/22, FNP 41/16-JECFA 62/45, FAS 45-JECFA 54/143 (2000). 0-0.03 µg/kg bw (2000). MRLs (EXPRESSED AS MELENGESTROL ACETATE): LIVER (CATTLE): 5 µg/kg; FAT (CATTLE): 8 µg/kg.
2002, TRS 911-JECFA 58/48, FNP 41/14-JECFA 58/55, FAS 45-JECFA
2004, TRS 925-JECFA 62/22, FNP 41/16-JECFA 62/45, FAS 45-JECFA 54/143 (2000). 0-0.03 µg/kg bw (2000). MRLs (EXPRESSED AS MELENGESTROL ACETATE): LIVER (CATTLE): 5 µg/kg; FAT (CATTLE): 8 µg/kg.
2002, TRS 911-JECFA 58/48, FNP 41/14-JECFA 58/55, FAS 45-JECFA