Questions and Answers on Arsenic-based Animal Drugs
What is the current status of arsenic-based animal drugs?
What is arsenic and why would it be used in animals?
What was the purpose for these drugs?
When were these animal drugs approved?
How does FDA regulate carcinogenic compounds used in food-producing animals?
Why did the FDA decide to conduct studies on what happens to 3-Nitro (roxarsone) fed to chickens?
What studies did FDA do?
What test method was used to measure the tissue samples?
What was the outcome?
Why didn’t FDA’s study test chicken muscle for the presence of inorganic arsenic?
Where can I obtain a copy of FDA’s studies?
What is the current status of arsenic-based animal drugs?
On April 1, 2015, FDA announced that it had received a letter of commitment from Zoetis Animal Health that the company will suspend sale of the drug Histostat (nitarsone) in the fall of 2015 and will request that FDA withdraw the approval for the drug by the end of 2015. With the withdrawal of the approval for Histostat and two combination products containing Histostat, there will no longer be any FDA-approved arsenic drugs for use in food animals. The approvals for three other arsenic-based animal drugs, 3-Nitro (roxarsone), carbasone and arsanilic acid, were formally withdrawn in February 2014, in response to an FDA study of 100 broiler chickens that detected inorganic arsenic, a known carcinogen, at higher levels in the livers of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.
What is arsenic and why would it be used in animals?
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. 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 was the active ingredient in approved arsenic-based animal drugs.
The scientific understanding at the time these drugs were approved was that the organic arsenic 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 was the purpose for these drugs?
These drugs were approved to help prevent certain diseases in poultry. Roxarsone was approved to help prevent coccidiosis, a parasitic disease that infects the intestinal tracts in poultry and can lead to death in poultry, and was also approved for weight gain, feed efficiency and improved pigmentation in chickens. Nitarsone is approved for the prevention of blackhead disease (histomoniasis) in turkeys and chickens, but is primarily used in turkeys. Blackhead is a significant cause of mortality in turkeys.
When were these animal drugs approved?
FDA first approved the use of animal drug products containing arsenic many years ago. The first such approval was for 3-Nitro (roxarsone), which was approved on March 21, 1944.
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.
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. FDA scientists 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 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.
What studies did FDA conduct?
FDA issued a report in 2011 for a study conducted 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).
In 2015, FDA also published the reports for three additional follow-up studies that were conducted to address certain questions raised about FDA’s 2011 study, such as whether the study provided complete analyses to affirm the frozen storage stability and freeze-thaw stability of tissue samples for arsenical speciation. FDA believes the findings of these additional studies adequately address the questions raised and affirm the results of the 2011 study.
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, it 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 chicken liver when it developed and validated its method for detecting inorganic arsenic in edible tissue.
Where can I obtain a copy of FDA’s studies?
The study reports are available on CVM’s website.