COLISTINI SULFAS

Overview

Chemical Names
COLISTIN A: N-[3-AMINO-1-[[1-[[3-AMINO-1-[[6,9,18-TRIS(2-AMINOETHYL)-3-(1-HYDROXYETHYL)-12,15-BIS(2-METHYLPROPYL)-2,5,8,11,14,17,20-HEPTAOXO-1,4,7,10,13,16,19-HEPTAZACYCLOTRICOS-21-YL]CARBAMOYL]PROPYL]CARBAMOYL]-2-HYDROXYPROPYL]CARBAMOYL]PROPYL]-6-METHYL-OCTANAMIDE COLISTIN B: N-[3-AMINO-1-[[1-[[3-AMINO-1-[[6,9,18-TRIS(2-AMINOETHYL)-3-(1-HYDROXYETHYL)-12,15-BIS(2-METHYLPROPYL)-2,5,8,11,14,17,20-HEPTAOXO-1,4,7,10,13,16,19-HEPTAZACYCLOTRICOS-21-YL]CARBAMOYL]PROPYL]CARBAMOYL]-2-HYDROXYPROPYL]CARBAMOYL]PROPYL]-5-METHYL-HEPTANAMIDE
Synonyms
POLYMYXIN E1 (COLISTIN A); POLYMYXIN E2 (COLISTIN B); POLYMYXIN E SULFATE (COLISTIN SULPHATE); COLISTINI SULFAS; MULTIMYCINE; COLYMYCIN; FIRST GUARD; STERILE POWDER; POLYMYXIN E1; POLYMYXIN E2; POLYMYXIN E SULFATE; COLISTIN A; COLISTIN B; COLISTIN SULPHATE
Functional Class
Veterinary Drug
ANTIMICROBIAL_AGENT

Evaluations

Evaluation year: 2006

ADI:
0-7 µg/kg bw/d

Comments:
Colistin has no significant genotoxic activity or structural alerts for carcinogenicity, is poorly absorbed from the gastrointestinal tract, and no neoplastic or preneoplastic lesions were observed in 26-week studies in rats given repeated oral or parenteral doses. As such, the Committee concluded that colistin compounds are unlikely to be carcinogenic. The relevant endpoint for risk assessment was determined to be disruption of the colonization barrier in the colon via toxicity to gut flora, the most sensitive organism of which was E. coli, with a minimum inhibitory concentration for 50% of strains (MIC50) of 1 µg colistin base/ml in an in vitro study. The Committee established an ADI of 0–7 µg/kg bw/d (420 µg/p/d for 60-kg adult) on the basis of the MIC50 for E. coli converted to an upper bound ADI value using the following formula: ADI (µg/kg bw/d) = (MIC50 (1 µg/ml) x mass of colonic contents (220 g))/(bioavailable fraction of dose (0.5) x safety factor (1) x bodyweight (60 kg)). The Committee recommended MRLs, measured as colistin A+B, in cattle, sheep, goats, pigs, chickens, turkeys and rabbits of 150 µg/kg liver, muscle and fat (including skin+fat, where applicable), 200 µg/kg in kidney, 300 µg/kg in hens’ eggs, and 50 µg/kg in cows’ and sheep’s milk. The MRLs recommended would result in a TMDI of 229 µg (55% ADI). The calculated EDI values represent 4% (for chickens) to 9% (for cattle) of the upper bound of the ADI. The EDI of 56.9 µg (14% ADI) is calculated using the highest median values from among the tissues and food-producing species.
MRL Comment:
MRLs: FAT, LIVER AND MUSCLE (CATTLE, SHEEP, GOAT, PIGS, CHICKEN, TURKEY AND RABBITS): 150 µg/kg; KIDNEY (CATTLE, SHEEP, GOAT, PIGS, CHICKEN, TURKEY AND RABBITS): 200 µg/kg; MILK (CATTLE AND SHEEP): 50 µg/kg, EGGS (CHICKEN): 300 µg/kg The MRL for fat includes skin + fat where appropriate.
Intake:
TMDI of 229 µg/p/d. EDI of 56.9 µg/p/d, using the highest median values from among the tissues and food-producing species.
Meeting:
66
Report: 
TRS 939-JECFA 66/18
Tox Monograph: 
FAS 57-JECFA66/3
Residues: 
FAO JECFA MONOGRAPHS 2-JECFA 66/8

Toxicological study

Pivotal Study:
In vitro microbiological study, author & study methodology unstated.
Animal Specie:
E. coli
Effect:
Inhibitory concentration
Point of departure:
MIC50 = 1 µg colistin base/ml