P-1496

Overview

Chemical Names
6-(6,10-DIHYDROXYUNDECYL)-beta-RESORCYLIC ACID-alpha-LACTONE
Synonyms
alpha-ZEARALANOL; p-1496
CAS number
55331-29-8
Functional Class
Veterinary Drug
GROWTH_PROMOTER

Evaluations

Evaluation year: 1988

ADI:
0 - 0.5 µg/kg bw

Comments:
Zeranol was shown to be a weak estrogen in long-term studies in mice, rats, dogs, and monkeys. A no-hormonal-effect level could not be established in male cynomolgus monkeys since no estrogenic effects were observed even at the highest dose administered (5 mg/kg bw/d). In intact female cynomolgus and rhesus macaque monkeys, 5 mg/kg bw/d was the no-hormonal-effect level. In ovariectomized female cynomolgus monkeys the no-hormonal-effect level was 0.05 mg/kg bw/d. The Committee concluded that this study was relevant to the human population and, since the ovariectomized female cynomolgus monkey is highly sensitive to estrogenic substances, set an ADI of 0 - 0.5 µg/kg bw using the NOEL in ovariectomized cynomolgus monkeys and a 100-fold safety factor.
MRL Comment:
Acceptable residue level: 0.01 mg/kg bovine liver, based on a level consistent with good animal husbandry practice; 0.002 mg/kg bovine muscle
MRL Code:
MRL
Intake:
TMDI 70 µg/d for 70-kg person
Meeting:
32
Report: 
TRS 763-JECFA 32/26
Tox Monograph: 
FAS 23-JECFA 32/123
Residues: 
FNP 41-JECFA 32/38

Toxicological study

Pivotal Study:
13-week monkey study (Singh et al., 1984a; CIC, 1985): Bilaterally-ovariectomized cynomolgus monkeys (6/group) were dosed orally with zeranol in 0.2% carboxymethylcellulose in a flavoured beverage at levels equivalent to 0.05, 0.5, or 5 mg/kg bw/d for 13 weeks. A control group was not used. Routine clinical chemistry, haematology, and urinalysis determinations were made one month prior to dosing, and at 1 and 3 months during the test period. Serum insulin and TSH were determined once prior to dosing, and at 1 and 3 months during the dosing period. FSH was determined on a weekly basis during the study through 4 weeks post-dosing. Baseline measurements and measurements of maturation index of vaginal epithelial cells during the course of the study indicated an estrogenic effect in animals receiving 0.5 and 5 mg/kg bw/d. The effect was not apparent at 0.05 mg/kg bw/d.
Animal Specie:
Cynomolgus monkeys
Effect:
Estrogenic effects on maturation of vaginal epithelial cells
NOEL:
0.05 mg/kg bw/d
Point of departure:
0.05 mg/kg bw/d
Previous Years:
1983, TRS 696-JECFA 27/33, NOT PREPARED, NOT PREPARED. MAXIMUM TOLERABLE DAILY INTAKE (MTDI) LIMITED BY GOOD HUSBANDRY PRACTICE (PROVISIONAL ACCEPTANCE) 1982, TRS 683-JECFA 26/33, NOT PREPARED, NOT PREPARED. NO ADI ALLOCATED. NO. O
1983, TRS 696-JECFA 27/33, NOT PREPARED, NOT PREPARED. MAXIMUM TOLERABLE DAILY INTAKE (MTDI) LIMITED BY GOOD HUSBANDRY PRACTICE (PROVISIONAL ACCEPTANCE) 1982, TRS 683-JECFA 26/33, NOT PREPARED, NOT PREPARED. NO ADI ALLOCATED. NO. O