Animal & Veterinary
Questions and Answers Regarding 3-Nitro (Roxarsone)
What did FDA announce?
FDA announced that Alpharma, a subsidiary of Pfizer Inc, will voluntarily suspend sale of the animal drug 3-Nitro® (Roxarsone) in response to a new FDA study of 100 broiler chickens that detected inorganic arsenic, a known carcinogen, at higher levels in the livers of chickens treated with the drug 3-Nitro® (Roxarsone) than in untreated chickens. FDA officials stress that the levels of inorganic arsenic detected were very low and that continuing to eat chicken as 3-Nitro® is suspended from the market does not pose a health risk.
What does this new information mean to someone who regularly consumes chicken? Should I be concerned?
Continuing to eat chicken as 3-Nitro® is suspended form the market does not pose a health risk. The levels of inorganic arsenic found in chicken livers were very low.
Should consumers stop eating chicken in response to this announcement?
No. FDA does not believe there is a need to stop eating chicken or to conduct a recall of chicken already in commerce.
What is 3-Nitro®?
3-Nitro® (Roxarsone) is an arsenic-based animal drug, manufactured by Alpharma LLC, a subsidiary of Pfizer Inc. It is approved to help prevent coccidiosis when used in combination with certain animal drugs. Coccidiosis is a parasitic disease that infects the intestinal tracts in poultry and can lead to death in poultry. 3-Nitro® is also approved for weight gain, feed efficiency and improved pigmentation in chickens.
What is arsenic?
Arsenic is an element that is present in the environment as a naturally-occurring substance or as a result of contamination from human activity. It is found in water, air, and soil in organic and inorganic forms.
Is one type of arsenic more harmful than the other?
Yes. The inorganic form is more harmful than the organic form, and has been found to be a human carcinogen. Organic arsenic is not known to be carcinogenic. Organic arsenic is the form of arsenic that is the active ingredient in approved arsenic-based animal drugs, including 3-Nitro® (Roxarsone).
Are there animal drugs approved with arsenic in them?
Yes. 3-Nitro® (Roxarsone) was the first arsenic-based product approved for use in animal feed and is currently the most commonly used arsenic-based animal drug. Other arsenic-based drugs that are approved for use in food-producing animals (poultry and swine) include nitarsone, arsanilic acid, and carbarsone. Current data indicate that only the 3-Nitro® and nitarsone products are being marketed. These drugs all have forms of organic arsenic--the form of arsenic that is less toxic and not carcinogenic--as their active ingredient.
When were these animal drugs approved?
FDA approved the use of products containing arsenic many years ago. The first approval for 3-Nitro® (Roxarsone), NADA 005-414, was on March 21, 1944. There have been several subsequent approvals for 3-Nitro® (Roxarsone) for combination use, the most recent being 2009.
What are arsenic-based animal drugs used for?
Animal drugs containing arsenic are approved for use in animal feeds for chickens, turkeys, and pigs (most common use is in broiler chickens). In poultry, they are approved for growth promotion, feed efficiency and improved pigmentation; they are also approved in combination with other drugs to prevent coccidiosis.
How could FDA approve arsenic as safe for consumption in an animal intended for food?
The scientific understanding at the time of approval was that the organic arsenic in 3-Nitro® (Roxarsone) would be excreted as organic arsenic, which is not known to be a carcinogen. Until recently, scientific evidence indicated that animals exposed to organic arsenic rapidly excrete the compound in its original form--as organic arsenic. FDA approved the product at doses and withdrawal times that, based on this available information, allowed for the safe and effective use of the product when used according to the label directions.
What kinds of studies were done at the time of approval to determine the safety of 3-Nitro® (Roxarsone)?
FDA completed food safety assessments and established tolerances for the presence of total arsenic in animal-derived food; the tolerances assumed that arsenic present was organic arsenic. These studies included chronic toxicity, reproductive toxicity, and carcinogenicity studies of 3-Nitro® (Roxarsone) in laboratory animals. These studies showed that 3-Nitro® (Roxarsone) did not induce tumors in laboratory animals when those animals were fed 3-Nitro® (Roxarsone) daily over the lifetime of the laboratory rodents.
How are tolerance levels established?
A tolerance is the maximum amount of a veterinary drug and its related metabolites that can remain in food from animals treated with a new animal drug. FDA evaluates data about the safety of consuming residues of the drug over a lifetime. Based on these calculations, FDA determines the concentration of drug residue that may be safely consumed in the food; this is called the tolerance.
Withdrawal times are established by conducting studies to determine the concentrations of the residues in the edible tissues of treated animals at various times after treatment has ended. These studies provide information to set a withdrawal period for the drug that will result in residues in edible tissues below the tolerance. Products containing 3-Nitro® (Roxarsone) have a 5-day withdrawal period. This means that chickens may not be slaughtered for food until five days after the drug has been withdrawn from the feed.
Why did the FDA decide to conduct studies on what happens to 3-Nitro® (Roxarsone) fed to chickens?
FDA conducted the study in response to scientific reports that organic arsenic, a less toxic form of arsenic present in 3-Nitro® (Roxarsone), could transform into inorganic arsenic. Scientists from FDA’s Center for Veterinary Medicine (CVM) and Center for Food Safety and Applied Nutrition (CFSAN) followed up on those reports by developing a new analytical method capable of detecting very low levels of inorganic arsenic in edible tissue. Using that method, FDA scientists recently found that the levels of inorganic arsenic in the livers of chickens treated with 3-Nitro® (Roxarsone) were increased relative to levels in the livers of the untreated control chickens.
How does FDA regulate carcinogenic compounds used in food-producing animals?
Under the Delaney Clause for new animal drugs of the Federal Food, Drug, and Cosmetic Act, FDA cannot approve any compound for use in food-producing animals where the drug or its metabolites has been found to induce cancer. There is an exception, commonly referred to as the DES proviso. The DES proviso carves out an exception to the Delaney Clause allowing cancer-causing compounds (or compounds with cancer-causing metabolites) to be used in food-producing animals if 1) the drug does not harm the animal and 2) tests approved by FDA do not detect residues of the drug in any food from the animal. The Federal Food Drug and Cosmetic Act governs the withdrawal of approval of a new animal drug application, after due notice and an opportunity for hearing, where new evidence shows that the Delaney Clause applies.
What studies did FDA do?
CVM conducted a study in chickens to determine whether treating chickens with 3-Nitro® (Roxarsone) in feed according to the approved labeling results in increased levels of inorganic arsenic in edible tissues. The study involved 100 chickens fed either the medicated feed (containing 3-Nitro® (Roxarsone) at the approved dose or a control feed (without 3-Nitro® (Roxarsone) for a six week period. Tissue samples were collected at Day 0, Day 3, and Day 5 (the relevant time point for food consumption).
When were the studies conducted?
The study began in September 2009. Data collection, analysis, and peer evaluation of the analytical method were completed in December 2010. The final report for the study was completed in February 2011.
What is the withdrawal time for 3-Nitro® (Roxarsone) in chickens?
The withdrawal time for 3-Nitro® (Roxarsone) in chickens is 5 days, which means that chickens cannot be fed medicated feed containing 3-Nitro® (Roxarsone) within 5 days of being slaughtered for food.
What test method was used to measure the tissue samples?
FDA scientists at the Center for Veterinary Medicine and Center for Food Safety and Applied Nutrition developed a test method capable of measuring very low levels of inorganic arsenic in edible tissue. This test method uses state-of-the-art instrumentation (ion chromatography inductively coupled plasma mass spectrometry) to identify and measure very low levels (less than 10 ppb) of inorganic arsenic in the presence of much higher concentrations (nearly 2 ppm or 2000 ppb) of 3-Nitro® (Roxarsone). This method, specifically developed for the analysis of liver samples, was evaluated and validated by a second laboratory, FDA’s Office of Regulatory Affairs (ORA) Forensic Chemistry Center.
What was the outcome?
FDA analyzed liver tissue from the chickens in the study to determine whether residues of the inorganic form of arsenic could be detected. This analysis indicated that inorganic arsenic was present at higher levels in the livers of chickens treated with the drug 3-Nitro® (Roxarsone) than in untreated chickens. No measurable residues of inorganic arsenic were present in the livers from the untreated control chickens. Because of technical limitations of the method, the method was not used to measure inorganic arsenic levels in chicken muscle. However, levels of total arsenic (both organic and inorganic) measured in muscle using appropriate methods found substantially lower levels of total arsenic in muscle than in liver, reflective of the typical distribution of veterinary drug residues at higher levels in liver and kidney than in muscle.
Why didn’t FDA’s study test chicken muscle for the presence of inorganic arsenic?
Given the inherent differences between various tissues (e.g., liver, kidney, muscle), analytical methods often need to be developed or customized to function for a particular tissue or tissues. Due to technical difficulties in developing an analytical method for muscle tissue, FDA focused its attention on liver when it developed and validated its method for detecting inorganic arsenic in edible tissue.
What is FDA doing as a result of this study?
FDA advised Pfizer of the study findings and the agency concerns. The company decided to voluntarily initiate a plan to suspend sale of the product and to facilitate an orderly process for suspending use of 3-Nitro® (Roxarsone). This plan provides for maintained sales of the product for 30 days (from date of this announcement) before suspension. Maintaining sales for this period will not pose a risk to human health and will provide time for animal producers to identify and transition to other treatment strategies and will help assure that animal health and welfare needs are met. In conjunction with voluntary suspension of the product, the company is working with FDA to examine all relevant scientific data regarding the use of this product in animals.
What is the FDA recommending in light of the study results?
FDA officials stress that the levels of inorganic arsenic detected in the study were very low and that continuing to eat chicken as 3-Nitro is suspended from the market does not pose a health risk. USDA also conducted an analysis that confirms FDA’s findings that the risk is very low. Consumers do not need to take any action.
In conjunction with discontinuing sale of the product, the sponsor is working with FDA to examine all relevant scientific data regarding the use of 3-Nitro® (Roxarsone) in animals.
Where can I obtain a copy of the study?
The study report is available on CVM’s website.
Are 3-Nitro® (Roxarsone) or other arsenic-based drugs used in other food-producing species? What are the implications of the study for use in those species? What is FDA going to do?
Arsenic-based animal drugs are approved for use in chickens, turkeys, and pigs. The sponsor is working with FDA to examine all relevant scientific data regarding the use of arsenic-based drugs in animals.
If 3-Nitro® (Roxarsone) is not available, what will be the impact on the poultry industry?
3-Nitro® (Roxarsone) is primarily used to improve the effectiveness of the animal drugs, narasin or salinomycin, to control coccidiosis, a parasitic disease that infects the intestinal tracts of poultry and can lead to death in animals. 3-Nitro® (Roxarsone) is also approved for weight gain, feed efficiency and improved pigmentation. Suspending sale of Roxarsone may cause producers to rely more heavily on existing anticoccidial drugs or seek alternatives for controlling the disease through vaccines, better management practices, or other technologies. FDA is working closely with USDA and the manufacturer of 3-Nitro® (Roxarsone) in an effort to minimize impacts on the poultry industry to the extent possible.
What has Pfizer decided to do in response to FDA’s findings?
The company has decided to voluntarily initiate a plan to suspend sale of the product and to facilitate an orderly process for suspending use of 3-Nitro® (Roxarsone) in the U.S. This plan provides for maintained sales of the product for 30 days (from date of this announcement) before discontinuation. Maintaining sales for this period will provide time for animal producers to identify and transition to alternative therapy strategies and management practices, and will help assure that animal health and welfare needs are met.
While Pfizer has suspended sale of 3-Nitro® (Roxarsone) in the U.S., it continues to manufacture and export roxarsone overseas. How should our international partners view this?
FDA is taking steps to alert our international partners about our research findings. They will then make their own decisions regarding what actions to take, if any, with respect to this product within the context of their own communities and regulatory systems.