Ractopamine
| Ractopamine | |
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4-[3-[[2-Hydroxy-2-(4-hydroxyphenyl)ethyl]amino]butyl]phenol |
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| Identifiers | |
| CAS number | 97825-25-7  |
| PubChem | 56052 |
| ChemSpider | 50604  |
| MeSH | Ractopamine |
| ChEMBL | CHEMBL509336 |
| Jmol-3D images | Image 1 |
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| Properties | |
| Molecular formula | C18H23NO3 |
| Molar mass | 301.38 g mol−1 |
| Solubility in water | 4100 mg/L |
 (verify) (what is:  / ?)Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) |
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| Infobox references | |
Ractopamine is a drug that is used as a feed additive to promote leanness in animals raised for their meat. Pharmacologically, it is a beta-adrenoceptor agonist. It is the active ingredient in products known as Paylean for swine and Optaflexx for cattle, developed by Elanco Animal Health, a division of Eli Lilly and Company, for use in food animals for growth promotion.
Ractopamine has been banned in the European Union, mainland China and Russia.[1][2]
Contents |
Mode of action [edit]
When used as a food additive, ractopamine added to feed can be distributed via the blood to the muscle tissues, where it will bind to specific beta receptors in the muscle cell membranes. A cascade of events will then be initiated to increase protein synthesis, which results in increase in muscle fiber size. Ractopamine is known to increase the rate of weight gain, improve feed efficiency and increase carcass leanness in finishing swine. Its use in finishing swine yields about three kilograms of additional lean pork and improves feed efficiency by 10%.[3] In steers and heifers, ractopamine use increases hot carcass weight by about 5.5 kilograms and 5 kilograms, respectively.[4][unreliable source?]
Regulation around the world [edit]
Regulatory authorities in 80 countries, including the EU, have banned ractopamine.[5] In 27 countries, including Japan, South Korea, Mexico, Taiwan, Canada, the United States, have determined that meat from animals fed ractopamine is safe for human consumption.[6] In the USA, ractopamine is allowed to be used at a feed concentration of 5–20 mg/kg feed for finishing pigs and in dosages of 5–10 mg/kg feed for finishing pigs heavier than 109 kg. In Canada, ractopamine is allowed in meal or pellet feed for finishing barrows, gilts, finishing beef cattle and finishing heavy turkeys (toms and hens) only. The maximum residues limit of ractopamine is 50 ppb and 10 ppb in the USA and Japan, respectively.
In August 2012 Taiwan's legislature passed amendments to the food safety act allowing ractopamine in beef.[7]
Recently, Russia has restricted beef and pork imports to those that are certified free of the additive ractopamine.[8]
Human use and route of exposure [edit]
Ractopamine is not for use in humans for any medical purposes. The more probable route of exposure to ractopamine in humans is through the consumption of food animals which have been fed ractopamine and its residue remains.
Pharmacokinetics in humans [edit]
A study was conducted to define the pharmacological response of humans to ractopamine. A single oral dose of 40 mg of ractopamine hydrochloride was given to human volunteers. Ractopamine was rapidly absorbed. The mean blood plasma half-life was around 4 hrs and ractopamine was not detected in plasma 24 hrs after dosing. It was shown that <5% of total ractopamine excreted represented the parent drug, while the urinary metabolites were monoglucuronide and monosulfate conjugates, with ractopamine monosulfate being the major metabolite present.[9]
The metabolic fate of ractopamine hydrochloride is similar in the target species (pigs and cattle), laboratory animals and humans. Besides the pharmacology effect, ractopamine may cause intoxication effect, therefore, any consumption by humans of a meat and/or byproducts of animals that consumed ractopamine with feed for growth stimulation, may result in such clinical effects as tachycardia and other heart rate increases, tremor, headache, muscle spasm, high arterial blood pressure.[10] The effect of ractopamine on humans is not entirely known, but consumption of products that contain ractopamine leftovers is not advisable to people with CVD (cardiovasular diseases).
Safety concerns [edit]
Target animal safety [edit]
Ractopamine is safe for finishing pigs heavier than 240 pounds (110 kg) when administered in the diet at concentrations up to 10 ppm and fed for up to 35 days.[citation needed] However, there was an increase in the number of ractopamine hydrochloride–treated animals exhibiting signs of injury during the final drive to slaughter. (FDA)[citation needed]
Some show sheep and goats are illegally given ractopamine to enhance muscle growth. This was the case with Maggie Weinroth's goat at the 2011 Colorado State Fair.
Human safety [edit]
On 6 July 2012, the Codex Alimentarius Commission approved safe limits of residual ractopamine in meats.[11] In the United States, as codified under 21 CFR 556.570, the safe concentrations for total residues of ractopamine hydrochloride are: 0.25 ppm in muscle, 0.75 ppm in liver, and 1.5 ppm in kidney and fat. The acceptable daily intake for total residues of ractopamine is 1.25 micrograms ractopamine hydrochloride per kilogram of body weight per day. The human safety of meat products derived from food animals fed ractopamine has been confirmed by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 2004, 2006, and 2010 and by 27 regulatory authorities from around the world.[12][13][14]
Adverse effects [edit]
Acute toxicity [edit]
Oral LD50 in mouse and rat are 3547–2545 mg/kg bw (male and female) and 474–365 (male and female), respectively.[15]
Genotoxicity and mutagenicity [edit]
Mutation studies in prokaryotes and eukaryotes show that ractopamine is non-mutagenic. However, the results of several in vitro studies, including chromosome aberration tests in human lymphocytes, are positive. The positive genotoxic results are explained with limited evidence to be due to a secondary auto-oxidative mechanism from ractopamine-catechol producing reactive intermediates.[which?]
Carcinogenicity [edit]
Ractopamine is considered not to be a direct carcinogen. It is not listed by IARC, NTP, ACGIH, or OSHA. The induction of benign leiomyomas (tumors of smooth muscle) in mice and rats can possibly be due to a general feature of beta-adrenergic activity of ractopamine.
Cardiovascular effects [edit]
Dose-dependent changes of heart rate and cardiac output are observed within the first hour after administration of ractopamine and gradually return to baseline values. The systolic blood pressure will also increase in a dose-dependent manner, while the diastolic pressure remains unchanged.
Musculo-skeletal effects [edit]
Skeletal muscle tremor is the most common adverse effect of beta-agonists, and is more likely to be seen after oral administration than after inhalation. Tremor results from an imbalance between fast- and slow-twitch muscle groups of the extremities, and its severity varies greatly between individuals. No such effects were recorded at the NOEL determined in the toxicological studies conducted in laboratory animals given ractopamine or in the study in humans on cardiovascular effects of ractopamine.
Behavioral changes [edit]
Feelings of restlessness, apprehension, and anxiety were reported effects after the use of various beta-agonists, particularly after oral or parenteral treatment. In pilot clinical trials with ractopamine, four patients showed little evidence for central nervous system stimulation. It is unclear whether long-term treatment with these drugs results in the development of tolerance to these adverse effects.
Analytical method for residues in meat [edit]
The determinative procedure for the analysis of ractopamine residues in tissue can be performed, using liver or muscle as the target tissues, by high performance liquid chromatography (HPLC) with fluorescence detection. The confirmatory method include reversed-phase HPLC/electrospray ionization triple tandem quadrupole mass spectrometry (LC/ESI-MS-MS). The limit of quantification (LOQ) of the drug using LC/MS was shown to be 1 ng/g.[16]
International controversies [edit]
Mainland China [edit]
In July 2007 officials of the People's Republic of China seized U.S. produced pork for containing ractopamine residues.[17] Further shipments of ractopamine fed pork were seized in September, though this time they were Canadian in origin.[18]
Republic of China (Taiwan) [edit]
Ractopamine has been banned in Taiwan since 2006.[19] In the summer of 2007, two U.S. shipments including ractopamine-laced pork were rejected by Taiwan's health authorities, while the Taiwan government had been considering lifting the ban on such imports.[20] This resulted in mass protests in the capital city Taipei by swine farmers insisting that the ban remain in place. Health Minister Hou Sheng-mou (侯勝茂) declared that there would be no lifting of the ban unless related laws were amended.
Malaysia [edit]
According to the Malaysian Food Act 1983 and Regulations (as of 5 January 2010), ractopamine is allowed in pig muscle and fat (MRL of 10 ppb), pig liver (MRL of 40 ppb) and pig kidney (MRL of 90 ppb).[21] Ractopamine is allowed as its half-life is lower, leading to reduced residues in the food, and the dose required to affect in humans is much higher than other beta agonists.[22] On 30 December 2008, the Malaysian Veterinary Services Department quarantined 10 out of the 656 pig farms in Malaysia, as the livestock were found to contain the banned chemical.[23][24]
Russia [edit]
On 6 June 2011, Russian Rosselkhoznadzor notified key meat exporters in Russia on coming prohibition on use of ractopamine in meat that is exported to Russia and on requirement of submission of compliance certificates (confirming absence of ractopamine in meat) that accompany such exported meat.
On 7 December 2012, the above said prohibition had come into force and the pig and cattle meat export supply became possible only upon check that confirm that such meat is ractopamine free.
Rosselkhoznadzor on February 11, 2013 introduced prohibitions to the supply of frozen meat and meat products from the United States. This is due to the fact that the American Veterinary Service does not observe the rules of ractopamine. Supply of chilled meat for that reason was prohibited on February 4. The head of Rosselkhoznadzor, Sergey Dankvert, said "Because the violations continue and we identify ractopamine in meat shipped from the U.S., we plan on February 11, to impose restrictions on the import of these products". According Rosselkhoznadzor, laboratory monitoring of imported meat products to Russia from the United States had found another case of ractopamine. This stimulant is found in lots of pork, the company-generated N17D, and beef liver, received from the company N235. This is a gross violation of animal health requirements of the Customs Union and Russia, the report underlines. The use of ractopamine in Russia is prohibited. Rosselkhoznadzor notified the case management of the Food Safety and Inspection Service, USDA.
Comparison to clenbuterol [edit]
Similar to ractopamine, clenbuterol is a growth promoting compound belonging to the beta-agonist family. It is known to have the effect of enhancing weight gain and proportion of muscle to fat. However, clenbuterol is known to have a much longer half-life in blood than ractopamine and thus has a greater potential for bioaccumulation.
Clenbuterol is reported to induce unintended side effects on humans, such as increased heart rate, muscular tremors, headache, nausea, fever, and chills. The US FDA has concluded these side effects to be unacceptable. The use of clenbuterol in food animals has been prohibited in almost all countries, including the USA, Canada, Taiwan, Hong Kong. In contrast, ractopamine is allowed to be used at the recommended concentrations in food animals for growth promotion in some countries such as the United States, Canada, Australia.
See also [edit]
References [edit]
- ^ Bottemiller, Helena (January 25, 2012). "Dispute over drug in feed limiting US meat exports". Bottom Line.
- ^ Garina, Anastasia. "Russia throws poisonous meat back to US". Pravda.ru. Retrieved 14 December 2012.
- ^ Apple JK et al. (2007). "Meta-analysis of the ractopamine response in finishing swine". Prof. Anim. Sci. 23: 179–196.
- ^ Elanco Study Nos. T4V200321, T4V080342, T4V160328, T4V480326, T4V080325 & T4V200324. Projection based upon a summary of Optaflexx Post-approval Research in Heifers. October 2006. Data on file.
- ^ "British expert explains the EU ban on ractopamine". Retrieved 4 Decembre 2012.
- ^ "The Facts about U.S. Beef and Ractopamine". American Institute in Taiwan. Retrieved 5 March 2012.
- ^ http://www.taipeitimes.com/News/taiwan/archives/2012/08/02/2003539254
- ^ http://beefmagazine.com/foreign-trade/russian-ban-ractopamine-boosts-brazilian-exports
- ^ RACTOPAMINE (addendum). WHO FOOD ADDITIVES SERIES: 53
- ^ "Safety evaluation of ractopamine EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP)". EFSA Journal. 7 April 2009. doi:10.2903/j.efsa.2009.1041. Retrieved 2013-03-21.
- ^ http://www.fao.org/news/story/en/item/150953/icode/
- ^ Evaluation of Certain Veterinary Drug Residues in Food (Sixty-second report of the Joint FAO/WHO Expert Committee on Food Additives). WHO Technical Report Series. No. 925, 2004.
- ^ Evaluation of Certain Veterinary Drug Residues in Animals and Foods (Sixty-sixth report of the Joint FAO/WHO Expert Committee on Food Additives). WHO Technical Report Series. No. 939, 2006.
- ^ Residue Evaluation of Certain Veterinary Drugs. Joint FAO/WHO Expert Committee on Food Additives. FAO JECFA Monographs 9. 2010.
- ^ Safety evaluation of ractopamine. 2009. p. 10.
- ^ Sakai T et al. (2007). "Determination method for ractopamine in swine and cattle tissues using LC/MS". Shokuhin Eiseigaku Zasshi 48 (5): 144–147. doi:10.3358/shokueishi.48.144. PMID 18027547.
- ^ "China fights back, goes after U.S. meat", USA Today, July 14, 2007.
- ^ "China stops imports from Canadian pork plant over banned additive", Canada Press (2007-09-19)[dead link]
- ^ Lin, Hermia (August 22, 2007). "Swine farmers get rowdy over ractopamine issue". Taiwan News. Retrieved January 25, 2012.[dead link]
- ^ "Taiwanese farmers urge continuation of US pork import ban". Associated Press. August 21, 2007. Archived from the original on January 25, 2012.
- ^ Fifteenth A Schedule, Table 1, Maximum Permitted Proportion of Drug Residues in Food.
- ^ "Beta-agonists hog the limelight". The Star. November 5, 2006. Retrieved January 25, 2012.
- ^ "Vet Dept seals 10 pig farms". The Star. December 31, 2008. Retrieved January 25, 2012.
- ^ "10 pig farms under quarantine". The Star. December 30, 2008. Archived from the original on January 25, 2012.
