Nicarbazin is a coccidiostat used on meat chickens. It is also used as a contraceptive for population control of Canada geese and feral pigeons.
It is also a wide-spectrum anti-parasitic drug approved for veterinary use, effective on Toxocara canis, Toxascaris leonina, Ancylostoma caninum, Uncinaria stenocephala, Trichuris vulpis, Dipylidium caninum, and Taenia sp. and Mesocestoides sp.. Known brand names for specific countries include: Carbigran (the United States) Ceva Nicarbazin (South Africa) Cycarb (New Zealand) Keymix (Australia) Koffogran (South Africa) Kofozin (Israel) Nicarb 25% (the United States) Nicarbazin (Israel) Nicarbazin Elanco (the United States) Nicarbmax 100% (New Zealand) Nicarmix (the United States) Ovistop (Italy and Costa Rica) OvoControl (the United States) PhiCarb (Australia) R-12 (Belgium)
From the chemical point of view, nicarbazin is an equimolar complex formed by 1,3 - bis (4- nitrophenyl) urea and 4-6 dimethyl-2- (1H) - pyrimidinone also called 4,4'-dinitrocarbanilide (DNC) and 2-hydroxy - 4,6 dimethylpyrimidine (HDP).
The DNC represents the biologically active part of the complex, but to be absorbed it must be bound to the HDP.Ott, WH, S. Kuna, CC Porter, and AC Cuckler. 1956. Biological studies on nicarbazin, a new anticoccidial agent. Poultry Science 35: 1355-1367. Because of its hydrophobic nature, the DNC alone is poorly absorbed and has a limited "biological availability" so, following oral administration, it would be eliminated without being absorbed. The DNC therefore requires HDP to be absorbed and to reach a plasma level that allows an effect in the target species.
Following oral administration, nicarbazin rapidly dissociates in vivo into its two HDP and DNC components, which follow different routes of excretion: 95% of HDP is rapidly eliminated with urine, while DNC remains longer and is eliminated predominantly with feces.
Metabolism and depletion of the two components have been studied extensively with the use of carbon-14-labeled nicarbazin.World Health Organization (WHO), FAO Food and Nutrition Paper number 41/11. Residues of Some Veterinary Drugs in Animals and Foods (1999). Following oral administration, nicarbazin rapidly dissociates in vivo into its two components HDP and DNC, which are absorbed through the intestine, then passing into the blood, and following different routes of excretion. The HDP is excreted more rapidly than the DNC, mainly through the kidneys via the urine, while the DNC is absorbed more rapidly than the HDP and is excreted more slowly than the latter through the liver, via the faeces.Porter CC, Gilfillan J. The absorption and excretion of orally administered nicarbazin in chickens Poultry Sci. 34, 995–1001, 1955 No significant residue of either component is noticeable in any fabric after 7 days. DNC accumulates in eggs and normally the concentration of DNC in eggs is less than 5 ppm.
The two components HDP and DNC do not undergo metabolism in vivo and in vitro, except for the formation of derivatives structurally similar to nitroaniline. However, this possibility appears extremely remote, achievable only in the laboratory, in particular chemical-physical conditions (high temperature in a strongly acid environment).Valfrè F, Macrì A, "Nicarbazina: use in feeding the broilers and evaluation of residues" Veterinary Objectives 1990, 10: 1116
Of the two components of the nicarbazin molecule, the DNC takes on a significance from a toxicological point of view as it remains longer in the body. The DNC molecule was therefore considered as a marker compound in residue studies.
Activities Nicarbazin, present long enough in the world market, is the product of first choice as coccidiostatic, due to its safe use, in the breeding of broiler. Known brand names for specific countries include: Carbigran (United States); Ceva Nicarbazin (South Africa); Cycarb (New Zealand); Keymix (Australia); Koffogran (South Africa); Kofozin (Israel); Nicarb 25% (United States); Nicarbazin (Israel); Nicarbazin Elanco (United States); Nicarbmax 100% (New Zealand); Nicarmix (United States); PhiCarb (Australia)
The use of nicarbazin as a coccidiostat has shown, even if in a completely reversible form, an inhibiting effect on the productive and reproductive functions of laying hens, with a consequent reduction in egg production and their weight as well as a decrease in hatching capacity. The depressive effects on ovulation found in poultry have formed the rational basis for the development of some preparation, containing nicarbazin, used for birth control in the population of stray pigeons. Known brand names for specific countries include: Ovistop (Italy); OvoControl (United States); R-12 (Belgium)
Nicarbazin is also a wide-spectrum anti-parasitic drug approved for veterinary use, effective on Toxocara canis, Toxascaris leonina, Ancylostoma caninum, Uncinaria stenocephala, Trichuris vulpis, Dipylidium caninum, and Taenia sp. and Mesocestoides sp..
Coccidiostatic activity Nicarbazin is active on some species of Emeria with different sensitivity. Unlike other coccidiostats, nicarbazin rarely presents resistance phenomena towards the most common coccidioses such as those supported by Emeria tenella.
The dose of nicarbazin generally used in the prevention of cecal and intestinal coccidiosis of chickens is 125 ppm in feed.
Nicarbazin is often used in combination with ionophoric antibiotics to increase the spectrum of activity and reduce the phenomenon of resistance.
Effects on reproductive function in chickens Administration of nicarbazin in laying hens was associated with a reduction in egg production and weight. The minimum dose that proved to be able to produce these effects was 50 ppm on egg weight and 70 ppm on egg production.Sherwood DH, Milby TT, Witz HL. "Further studies on the effect of nicarbazin on the reproduction of chickens" Poultry Sci. 35, 1171, 1956 The intensity of these effects was correlated with the dose and duration of the treatment period. Treatment with nicarbazin for a week, at a concentration of 125 ppm, reduced egg production by 50%,McLoughlin DK, Wher EE, Rubin R, "Egg Shell Color and Egg Production in New Hampshire Laying Hens as Affected by Nicarbazin Medication" Poult. Sci. 36: 880–884 while, at a dose of 400 ppm, egg production was totally suppressed.Hurwitz S, Bornstein S, Lev Y, "Some responses of laying hens to induced arrest of egg production", Poult. Sci. 1975, 54: 415-422
The mechanism by which egg production is reduced appears to be the result of reduced hypothalamic sensitivity to exogenous progesterone, while the ability of the pituitary to respond to the lutein excretion factor (LHRF) remains intact.Luck MR "The adverse effects of nicarbazin on reproductive activity in the hen" Br. Poul. Sci., 1979, 20: 605-607
It was hypothesized that nicarbazin could not only prevent the deposition of the constituents of the yolk in the ovary, but that it was also able to counteract the stimulating function of the hypothalamus, probably due to an inadequate hormonal arrangement. Injection of LHRF in nicarbazin-treated animals results in an immediate and elevated plasma LH concentration due to the previously accumulated LH pituitary gland due to the lack of hypothalamic stimulus.
Recent studies have shown that the mechanism of action of nicarbazin is related to the inhibition of sperm receptor sites ZP3.Barbato, G., A. MacDonald. 2006. Pekin Duck Model for Action of Nicarbazin on Fertility. Pennsylvania State University. Pending publication
These effects on egg production and weight have proven to be reversible. Normal production resumes from one to three weeks after the end of nicarbazin treatment.Weiss HS, Fisher H, Griminger P., "Chemical Control of Onset of Egg Production" Poult. Sci. (1960) 39: 1221–1223Cuckler AC, WH Ott, and DE Fogg. Factor in the evaluation of coccidiostats in poultry. Cornell Vet. 47, 400–412, 1957 The eggs return to normal size within about ten days.Polin D, Ott WH, Siegmund OH "The incidence and degree of yolk mottling in eggs from hens fed diet with and without nicarbazin" Poultry Sci. 1957, 36: 524–528
Reduction of egg hatching Nicarbazin administered to hens has no effect on fertility or the survival of chicks. The main effect is the increase in embryo mortality in the first seven days.
The mechanism of action of nicarbazin requires that the bird ingest the bait in sufficient quantity to reach a blood concentration such as DNC that can subsequently allow its deposition in the yolk of the eggs being formed. It takes 5–7 days to reach the blood level which allows absorption into the yolk. In the laying hen, as in almost all birds, the egg takes about 14 days to develop before being deposited. During the development of the egg the last 5–7 days are of particular importance, a period in which the yolk reaches its maximum development, the albumen and the shell are completed and the egg is deposited.Jones, JE, J. Solis, BL Hughes, DJ Castadldo, and JE Toler. 1990. Reproduction responses of broiler-breeders to anticoccidial agents. Poultry Science. 69: 27-36 Interference with egg hatching is achieved only if the target animal consumes an effective dose of bait during this period of egg development.
The minimum dose level that affects hatching is 10 to 20 ppm.Polin, D, WH Ott, and OH Siegmund. The incidence and degree of yolk mottling in eggs from hens fed diets with and without nicarbazin. Poultry Sci. 36, 524–528, 1957 Increasing the dosage increases the effects on hatching. At 20 ppm the hatching capacity is reduced by about 20%, from 50 to 125 ppm by about 50%. The eggs of hens treated with 700 ppm of nicarbazin do not hatch.
The hatching returns to normal from 7 to 21 days after the withdrawal of nicarbazin.
Effects on the reproductive function of the pigeon The uncontrolled numerical development of pigeon colonies in urban areas entails health problems for humans and other animals and puts the integrity of the building and monumental heritage of cities at risk.
The limiting effects on reproductive capacity, which occurred in laying hens following treatment with nicarbazin, suggested the use of this compound for pigeon birth control.
In a study conducted in 1993, 40 pairs of pigeons were used, subdivided into 4 groups and treated with nicarbazin medicated feed at doses of 0, 50, 230 and 400 ppm for a period of 120 days
100% of fertile eggs with birth of as many chicks in the control group (0 ppm), they corresponded fertility rates of 33.3% to 50 ppm, of 43.3% to 230 ppm, while fertility was zero at the dosage higher (400 ppm).
The results obtained appear to be linked to the morphofunctional modifications shown in the reproductive apparatus of the sacrificed animals even if their size does not seem proportional to the dosages. The treatment does not seem to have changed the overall health status of the animals. The biochemical and anatomopathological investigations have excluded anatomical damage to the doses used, while the reversibility of the functional modifications of the reproductive apparatus has been confirmed.
A study, conducted by ChelazziChelazzi G, Lebbroni M, Scoccianti G. (2000), Monitoring of the columba population of Columba livia forma domestica in the municipality of Florence (February 1999-February 2000), Ecology Laboratory, Department of Animal Biology and Genetics, Faculty of Mathematical, Physical and Natural Sciences, University of Florence in the district of Florence, with the aim of evaluating the effects of nicarbazin on the number of pigeons in different areas, involved treatment of the animals with maize grains added with nicarbazin (800 ppm) during the period between the end of February and the beginning of October, with a daily dose of 10 g/head for 5 days a week.