Ractopamine

Ractopamine
Identifiers
CAS number 97825-25-7 N
PubChem 56052
ChemSpider 50604 YesY
MeSH Ractopamine
Jmol-3D images Image 1
Properties
Molecular formula C18H23NO3
Molar mass 301.38 g mol−1
Solubility in water 4100 mg/L
 N (verify) (what is: YesY/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Ractopamine is a drug used as a feed additive to promote leanness in animals raised for their meat. Pharmacologically, it is a beta-adrenergic 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]

Mode of action

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 increased 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 and 5.0 kg, respectively.[4][unreliable source?]

Regulation around the world

Russia and China have both banned ractopamine in beef, deeming it unfit for human consumption.[5] Twenty-seven other countries, including Japan, South Korea, Mexico, Taiwan, Canada, and 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, beef cattle and heavy turkeys only. The maximum residues limit of ractopamine is 50 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

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

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. The drug was rapidly absorbed; the mean blood plasma half-life was around 4 hrs and it was not detected in plasma 24 hrs after dosing. Less than 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, or high arterial blood pressure.[10] The effect of ractopamine on humans is not entirely known, but consumption of products that contain ractopamine residues is not advisable to people with cardiovascular diseases.

Safety concerns

Target animal safety

Ractopamine is safe for finishing pigs heavier than 240 lb (110 kg) when administered in the diet at concentrations up to 10 ppm and fed for up to 35 days. However, the number of ractopamine hydrochloride–treated animals exhibiting signs of injury increased during the final drive to slaughter. (FDA)

Some show sheep and goats are illegally given ractopamine to enhance muscle growth.

Human safety

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 in 2004, 2006, and 2010 and by 27 regulatory authorities from around the world.[12][13][14]

Adverse effects

Acute toxicity

Oral LD50 levels in mice and rats are 3547–2545 mg/kg body weight (male and female) and 474–365 (male and female), respectively.[15]

Genotoxicity and mutagenicity

Mutation studies in prokaryotes and eukaryotes show that ractopamine is not 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

Ractopamine is not considered 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

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.

Musculoskeletal effects

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

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

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 with fluorescence detection. The confirmatory method include reversed-phase HPLC/electrospray ionization triple tandem quadrupole mass spectrometry. The limit of quantification of the drug using this LC/MS instrument was shown to be 1 ng/g.[16]

International controversies

Mainland China

In July 2007, officials of the People's Republic of China seized US-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)

Ractopamine has been banned in Taiwan since 2006.[19] In the summer of 2007, two US 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 there would be no lifting of the ban unless related laws were amended. In August 2012, Taiwan's legislature passed amendments to the food safety act allowing ractopamine in beef.

Malaysia

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 humans is much higher than other beta agonists.[22] On 30 December 2008, the Malaysian Veterinary Services Department quarantined 10 of the 656 pig farms in Malaysia, as the livestock were found to contain the banned chemical.[23][24]

Russia

On 6 June 2011, the Russian Ministry of Agriculture notified key meat exporters in Russia of the coming prohibition on the use of ractopamine in meat exported to Russia, and the requirement of submission of compliance certificates (confirming absence of ractopamine) that accompany such exported meat.

On 7 December 2012, the above prohibition went into force, and the pork and beef export became possible only upon checks that confirm such meat is ractopamine-free.


Comparison to clenbuterol

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, 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, and Hong Kong.

See also

References

External links

  • Ractopamine page
  • Ractopamine study