Halquinol

Product Name: Halquinol

Physical & Chemical Properties:

Description:
Halquinols (halquinol) is an antimicrobial for treatment of skin infections available as topical skin pharmaceutical. Tarquinor skin cream, a dermatological preparation of halquinol 0.2% and 1% coal tar has been approved for use in New Zealand in 1962 and is in use in Australia at present. Halquinols has a broad antimicrobial activity in vitro against a wide variety of bacteria, fungi and protozoa including Candida albicans, Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus pyogenes. It has a significant antimycoplasmal (MICs of 3 to 4 ug/ml) and anticryptosporidial activity at 1 or 20 uM against Cryptosporidium parvum. As some antimicrobials halquinol has been used as a growth promotor in poultry. Study of fresh water fish Catla catla treated with halquinol suggested enhanced anabolic metabolism resulting in weight gain. However, the mechanisms by which the drug improves performance are not fully understood. Halquinol was the only antimicrobial drug tested in chicken that did not affect microbial membership compared to the control group.

Residues in food and their evaluation.

Conditions of use Halquinol:
(Trade name Quixalud®) is an antimicrobial used as a feed additive for poultry and as a growth promotant in pigs. Halquinol also is used in swine for the control, treatment and prevention of scours caused or complicated by E. coli and Salmonella spp. Halquinol for swine is approved in multiple Asian and Latin American countries and feed concentrates range from 12-60 % halquinol, with varying dose regimens.

Dosage:

Halquinol is composed of a mixture of chlorinated products of quinolin-8-ol. Chlorinating quinolin-8-ol yields a mixture, generically called halquinol, which contains 5, 7- dichloroquinolin-8-ol (5, 7-DCL; 57-74 % w/w), 5-chloroquinolin-8-ol (5-CL; 23-40 % w/w) and 7-chlorquinolin-8-ol (7-CL; 0-4 % w/w). The product, available under the trade name Quixalud, is composed of chlorohydroxyquinoline (halquinol; 60 % w/v), silicon dioxide (1.2 % w/v) and chalk (calcium carbonate; to 100 % w/v). Halquinol is administered to swine orally in the feed at a dose inclusion rate varying from 60 to 600 mg halquinol/kg feed (ppm), for up to 10 consecutive days. Based on a typical daily feed intake of approximately 4 % body weight/day for pigs, this results in a dose of approximately 2.4 to 24 mg halquinol/kg bw.

Uses:
Halquinol (5, 7-dichloro-quinolin-8-ol) is an antimicrobial used as a feed additive for poultry and as a pig growth promotant. It is also used for the control and treatment of non- specified diarrhoea, particularly in pigs.

Handling and Storage:
Handling: Minimize dust generation and accumulation. Avoid contact with eyes, skin, and clothing. Keep container tightly closed. Use with adequate ventilation. Wash clothing before reuse. Avoid breathing dust

Storage: Store in a well closed container

Data on pharmacokinetics and metabolism:

To demonstrate linearity of pharmacokinetics over a dose range comparable to the approved doses, the sponsor performed a GLP-compliant pharmacokinetic study in swine (86). Four male and four female pigs in the fed state (weight range 25.2–36.0 kg) were garaged with oral capsules containing 12 or 40 mg commercial halquinol (Halquinol BP 80) per kg body weight. Table 8 Summary of toxicity studies – halquinol Species/study type (route of administration) Doses (mg/kg bw per day) Critical end-point NOAEL (mg/kg bw per day) LOAEL (mg/kg bw per day) Mouse Developmental study (gavage) 0, 30, 100, 300 Maternal toxicity: clinical signs 30** 100 Embryo and fatal toxicity: delayed bone ossification 30 100 Rat 13-week toxicity (gavage) 0, 50, 150, 450 Histopathological lesions in the kidneys 50 150 1-year toxicity and carcinogenicity study (diet) 0, 15, 50, 150 Histopathological lesions in the kidneys 15* 50 Two-generation reproduction study (gavage) 0, 50, 150, 450 Parental toxicity: increase in kidney and spleen weights 50 150 Offspring toxicity: kidney lesions in pups 150 450 Reproductive toxicity: none 450a – Developmental study (gavage) 0, 100, 300, 1000 Maternal toxicity: clinical signs 300 1000 Embryo and fatal toxicity: lower mean fatal body weights correlating with delayed bone ossification – 100b Dog 13-week toxicity study (gelatin capsule) 0, 3, 10, 60, 150 Body weight loss 30c 60d 39-week toxicity study (gelatin capsule) 0, 30, 60, 90 Body weight loss ADI: acceptable daily intake; ARfD: acute reference dose; bw: body weight; LOAEL: lowest-observed-adverse-effect level; NOAEL: no- observed-adverse-effect level. * Pivotal study value used for the establishment of the ADI. **Pivotal study value used for the establishment of the ARfD. A Highest dose tested. B Lowest dose tested. C Overall NOAEL. D Overall LOAEL. An addendum to the monograph was prepared. 55 Comments on residues of specific veterinary drugs Blood samples were collected at intervals from 0 to 72 hours post dose. The concentrations of parent halquinol

components (5-CL and 5, 7-DCL) and their glucuronide metabolites (i.e. components of proposed halquinol MR) were determined in plasma using a validated LC-MS/MS method (lower LOQ of 2 ng/mL) (88). Non-compartmental analysis was used to derive the pharmacokinetic parameters for each of the individual halquinol components (5-CL and 5, 7- DCL, and their respective glucuronide metabolites). Pharmacokinetic parameters were not derived for unconjugated 5-CL because this component was detectable in only a few plasma samples. Absorption was rapid, with mean Tmax for all halquinol components being less than or equal to 3 hours. The mean elimination half-life for all halquinol components ranged from 2 to 5 hours. The linearity of halquinol pharmacokinetics was assessed via comparison of pharmacokinetic parameters after dose normalization. The parameters for detectable halquinol components (5, 7-DCL, 5-CLG and 5, 7-DCLG) were all considered to be dose- proportional (i.e. linear pharmacokinetics) because there were no statistically significant differences in dose-normalized Cmax or AUC0-t between the 12 and 40 mg/kg dose.