History of the Phase 2 assessment of nicarbazin
Nicarbazin is a coccidiostat, which is mixed with feed for broiler chickens for the prevention and control of coccidiosis caused by Eimeria spp. Coccidiosis is a common disease of poultry and can result in a high death rate.
Nicarbazin is a 1:1 molar mixture of 4,4'-dinitrocarbanilide (DNC) and 4,6-dimethyl-2-hydroxypyrimidine (HDP). On a weight/weight basis, DNC makes up 70.9% of nicarbazin. After oral ingestion, the complex dissociates to DNC and HDP and both components undergo metabolism via different routes and at different rates.
In 2006, nicarbazin was nominated for review by a State Department following the death of broiler chickens from accidental overdosing of the coccidiostat in two separate incidents. The State Department also raised concerns that the residue definition for nicarbazin, which was ‘nicarbazin’ at the time, may have been incorrect, thus limiting the validity of residue analyses conducted by the state and monitoring for compliance with the MRL Standard. This definition was inconsistent with the chemistry of nicarbazin. The State Department identified inadequacies in the registration data for nicarbazin in the area of toxicology, noting the compound’s very low acute toxicity and apparently low chronic toxicity. There were also concerns about the dietary risk for humans who eat treated chickens.
In 2007, as a preliminary step ahead of the APVMA beginning a formal review and calling in any new data, the Office of Chemical Safety and Environmental Health (OCSEH) identified the toxicological aspects of nicarbazin that could be reviewed. OCSEH supported the chemical’s nomination for a review on the basis of concerns about its teratogenic potential arising from dietary exposure to residues of nicarbazin. OCSEH’s concern was a new one, not previously identified by them.
In 2008, OCSEH completed an investigation of the toxicological concerns with nicarbazin and presented their preliminary findings and conclusions. OCSEH recommended a downward revision to the acceptable daily intake (ADI) from 2 mg/kg bw/day to 0.4 mg/kg bw/day (same as the JECFA-recommended ADI) and recommended an acute reference dose (ARfD) of 0.4 mg/kg bw, a new standard. Both health standards were based upon a developmental toxicity NOEL of 200 mg/kg bw/d with a safety factor of 500. The added safety factor of 5 was due to uncertainty arising from the quality of the existing toxicology database.
At the time of OCSEH’s assessment, there were no First Aid Instructions, Warning Statements and Safety Directions for nicarbazin. OCSEH determined that occupational exposure to nicarbazin through the dermal, ocular and inhalation routes is likely to occur during feed milling operations and during on-farm feed mixing when product containers are opened and the product is poured into chicken feed. Estimates of acute and repeated exposure suggested that margins of exposure are acceptable and that personal protective equipment is adequate to manage the exposure risks.
In the absence of any new exposure data, OCSEH recommended new safety directions for nicarbazin-only products. The safety directions are: May irritate the eyes and nose and throat May irritate the eyes and nose and throat. Avoid contact with eyes. Do not inhale dust. When opening the container and mixing wear a disposable dust mask covering mouth and nose if dust is present. Wash hands after use. OCSEH considered the existing safety directions for nicarbazin + ionophore combination products in the FAISD Handbook to be adequate since the hazards and consequential risks associated with narasin and maduramicin are more severe than those for nicarbazin. The first aid instruction, ‘If poisoning occurs, contact a doctor or Poisons Information Centre. Phone Australia 131126; New Zealand 0800 764 766,’ applies to all nicarbazin products.
Initially, OCSEH had recommended that labels should contain a statement warning pregnant women of exposures to nicarbazin. This recommendation was later rescinded, as the ADI was deemed to be adequately protective of any possible human health effects. In addition, OCSEH advised that there was no evidence of foetal toxicity in the absence of maternotoxicity.
Because of the five fold downward revision to the ADI and the establishment of an ARfD of the same value as the ADI, the APVMA investigated whether nicarbazin needed to be reviewed.
The APVMA conducted a survey to find out how nicarbazin was used and the possible risks that the use of the chemical may pose. This survey highlighted the important role of nicarbazin in controlling coccidiosis and confirmed that exposure to nicarbazin on farms and in feed mills was limited because of mechanisation of the feed milling, delivery and feeding operations. Two registrants, the Australian Chicken Meat Federation and the Australasian Veterinary Poultry Association responded to the survey.
Simultaneous to the survey, the APVMA conducted a residue assessment to consider whether or not the proposed changes to the ADI required a revision to the existing MRLs, withholding periods and dietary exposure estimates for nicarbazin. The APVMA also revisited the residue definition of nicarbazin. This consideration led to the recommendation that the Australian definition/marker residue for nicarbazin should be changed from "nicarbazin" to "4,4'-dinitrocarbanilide (DNC)". The new residue definition is consistent with JECFA’s definition.
With DNC being the residue marker for nicarbazin, the APVMA re-evaluated residues data from studies where nicarbazin alone was fed to chickens at the maximum approved rate of 125 ppm in feed, and a 4-day meat withholding period was observed. The APVMA's assessment initially recommended MRLs of 1 mg/kg for DNC in chicken kidney and chicken skin/fat, and 0.5 mg/kg for chicken muscle for nicarbazin, which were substantially lowered than the 20 mg/kg for edible offal and 5 mg/kg for poultry meat set in 1982. The 4-day withholding period was retained.
These MRLs would have increased the previous meat withholding periods for the registered nicarbazin + narasin combination product from zero to two days and the nicarbazin + maduramicin ammonium combination product from one to two days. The existing restriction from administering nicarbazin to chickens that will lay eggs for human consumption was retained, as residues data for nicarbazin in eggs were not available for assessment.
Instead of advancing nicarbazin through the chemical review process, the APVMA decided to invite registrants to voluntarily amend their labels with the safety directions and withholding periods recommended in the toxicology and residue reports, through the registration process. Some registrants and the Australian Chicken Meat Federation expressed concerns about the impact the recommended increase in the meat withholding period would have on the chicken meat industry. Subsequently, the APVMA considered the feasibility of increasing the initial recommended MRLs for nicarbazin so as to determine whether the previous meat withholding periods for the registered nicarbazin + narasin combination product of zero days, at equal inclusions of 50 ppm in feed, could be retained.
An upward revision to the initial MRLs led to recommended reductions in the meat withholding period for nicarbazin only products from four days to 1 day at an inclusion of 125 ppm in feed and for the nicarbazin + maduramicin ammonium product from one day to zero days at an inclusion of 40 ppm nicarbazin + 3.75 ppm maduramicin ammonium in feed. The revised MRLs for nicarbazin are 35 mg/kg for chicken liver, 20 mg/kg for chicken kidney, 5 mg/kg for chicken muscle and 10 mg/kg for chicken skin/fat.
From a dietary exposure perspective using the JECFA daily diet, the revised MRLs were acceptable since the daily exposure estimate for nicarbazin represented 70% of the recommended ADI of 0.4 mg/kg bw/day. From a dietary exposure perspective using Australian consumption figures, chronic exposure to nicarbazin was equivalent to 4% of the revised ADI, while acute exposure was less than 100% of the recommended acute reference dose.
Since these recommendations only required relatively minor changes to the product labels, the APVMA decided to give effect to the recommendations through the registration process rather than proceeding to a formal review. Each registrant accepted APVMA's second invitation to amend their labels with the safety directions and withholding periods recommended in the toxicology and revised residue reports, respectively. All nicarbazin product labels have been updated and registrants requested the APVMA to cancel all previous label approvals for these products. The MRL Standard was amended with the new MRLs, with action to make corresponding amendments to the Food Standards Code.
Nicarbazin Phase 2 assessment reports