Compiled and edited by Dr Abhinav Gaurav*, Program Director, Bihar Sustainable Livelihood Development (BSLD) ProgramDr Abdus S Sheikh*, Sr. Program Manager – Livestock Technology and One Health, Heifer International India. 9810424836
*Veterinary Community Development Professionalswith more than 15 years ofexperiences in promoting livestock-based livelihoods, especially small ruminants, and backyard poultry value chains; capacity building trainings of para-vets, Community Agro-Vet Entrepreneurs on veterinary first-aid, Animal Wellbeing, and One Health Approach.
Antibiotics are extensively used as growth promoters in livestock sector to control diseases, facilitated feed conversion ratio, and for treatment purposes. As a result, antibiotic resistant bacteria are emerging, which causes serious health hazards. Previous studies also reported that veterinary antibiotics are used vastly in livestock to control disease, enhance growth, promote health, and feed conversion efficiency, as well as to reduce animal susceptibility to stress-related diseases. For these purposes, several antibiotics are extensively used in food animals, including tetracycline, sulfonamides, fluoroquinolones, macrolides, lincosamides, aminoglycosides, beta-lactams, cephalosporin, and so on.
Antibiotics have been reported to accumulate and form residues at varying concentrations in the tissues and organs of food animals, as Billah et al. referred to these antibiotic residues as chemical residues or pharmacologically active substances representing either the parent compound or its degraded products, which are released, gathered, or stored in the edible tissues of the animal, due to their use in the prevention, treatment, and control of animal diseases. Undoubtedly, in Cameroon, Guetiya Wadoum et al. demonstrated the presence of chloramphenicol and tetracycline residues in concentrations above the maximum residue limit (MRL) recommended by the European Union in 2010, in edible chicken tissues (muscle, gizzards, heart, liver, kidney) and eggs. Similarly, Billah et al. detected ciprofloxacin in higher concentration in egg white, but in lower concentration in egg yolk during treatment of the birds. Also, Olufemi and Agboola reported a high oxytetracycline residue in edible beef tissues of cattle slaughtered at Akure, in Nigeria, at violating levels beyond the MRL stipulated by WHO. However, of profound concern are circumstances in which diseased animals and animals undergoing therapy could be sold quickly to save funds or could be slaughtered and used as food or feed for other animals. This causes difficulties in the prophylactic approach to handling epidemic diseases and health risks to consumers, as well as a negative influence on the environment. Van Ryssen reported the use of poultry litter as a feed to farm animals in South Africa since it is considered as a bulky protein supplement.
After using an antibiotic in the human or animal body, it kills bacteria, and the antibiotic is broken down in the body until it becomes a non-functional agent, and finally, it is eliminated from the body. Withdrawal periods of different antibiotics may vary from 1 or 2 days to couple of weeks. The minimum withdrawal period for Oxytetracycline is 3 days, for amoxicillin is 3 days, and for ciprofloxacin is 6 days. In addition, previous studies shown that withdrawal period may vary between different antibiotics, and the minimum withdrawal period maintained for the drugs was 7 days after the last dose of administration. Antibiotics are widely used in veterinary practice, especially for dry cow therapy and mastitis treatment in lactating cows, which may cause the presence of antibiotics. residues in milk. There is a high chance of transmission of antibiotic-resistant organism from animal to human due to indiscriminate use of antibiotics.
2. What is the withdrawal period?
The withdrawal period (clearance or depletion time) defines the length of time required for an animal to metabolize the administered antibiotics under normal conditionsand, also the time needed for the antibiotic concentration in the tissues to reduce to a safe and acceptable level described as tolerance. It can equally be referred to, the time interval necessary between the last administration of the drug under normal conditions of use to animals and the time when treated animals can be slaughtered to produce foodstuff safe for public consumption.Depending on the drug product, route of administration, and dosage form (even with the same active ingredients), the withdrawal periods vary from a day to several days or weeks, and according to the target animals.
When an antibiotic is given to a person or an animal, it starts working in the body. The antibiotic kills bacteria and the body breakdowns the antibiotic. This breakdown takes different times for different antibiotics. It also takes different times in different animals (for instance, cows compared to pigs). Some antibiotics have different breakdown times for different tissues like milk, meat, or liver.
The time the body takes to breakdown the antibiotic until it is no longer functional, or present is called the withdrawal timeor withdrawal period. Once the withdrawal period has passed the antibiotic has been eliminated from the animal’s system.
Every antibiotic has a withdrawal period. Some withdrawal periods are very short, 1 or 2 days. Some are longer, 7-10 days. Some are even longer, up to weeks.
The withdrawal period must be determined for every species of animal the antibiotic can be used on. If the antibiotic is used in a lactatinganimal, the withdrawal period must be determined for both meat and milk.The withdrawal period for milk is usually shorter than the withdrawal period for meat.
3. Maximum Residue Limits (MRLs) and withdrawal periods
Pharmacologicallyactive residuesor degradation products and their metabolites, which remain in foodstuffs obtained from animals treated with a veterinary medicinal product.
The MRL is the maximum concentration of residue accepted by the European Union (EU) in a food product (e.g., meat, milk, eggs) obtained from an animal that has received a veterinary medicine.
In the process of establishing an MRL, firstly a No Observed (Adverse) Effect Level (NO(A)EL) is identified through scientific studies with the active substance. The NO(A)EL is the highest dose that does not cause adverse effects. This figure is then divided by an ‘uncertainty’ or ‘safety factor’ e.g., by 100-1000 to determine the Acceptable Daily Intake (ADI). The ADI is the amount of the residue that is considered safe for an individual to eat every day for their lifetime considering several safety factors.
When an MRL is determined for a veterinary medicine, the withdrawal period is then calculated by considering the rate of residue depletion, to below the MRL, in all edible tissues and products.
The use of animal medicines is strictly controlled by Indian law, and requires observance of the withdrawal period, which must have elapsed before an animal, or its products can be used for human consumption. The withdrawal periods have been calculated using rigorous scientific processes so that veterinary medicines can be authorised and administered to food producing animals, whist at the same time consumer safety is protected.
Every medicine that is given to animals, including antibiotics, has a withdrawal period. Farmers must follow these withdrawal times to be sure no antibiotics are in our food.
4. Why does the withdrawal period matter?
It simply takes time for the body to break antibioticsor any medicationdown to a form where the medicines are no longer functional and leave the body.Therefore, withdrawal periods are so important. Following withdrawal periods means that we know there are no traces of antibiotics in the meat or milk you buy for consumption. It implieswe know that you and your families are not exposed tounnecessary antibiotics. It means that farmers aredoing everything they can to prevent the development of antibiotic resistance.
Withdrawal period refers to the minimum period from administering the last dose of medication and the production of meat or other animal-derived products for food.
The withdrawal period is different for each veterinary medicinal product, animal species and food type, meaning there are different withdrawal periods for meat, fish, eggs, milk, and honey.
For example, if mastitis is treated with a medicine that requires a withdrawal period of 6 days for milk, the treated cow’s milk may be produced for delivery to a dairy on the 7th day after the last dose, at the earliest.
The purpose of the withdrawal periods is to ensure that foods do not contain residues of pharmacologically active substances more than the maximum residue limit (MRL).
5. What are withdrawal periods for meat and milk, and where can they be found?
Withdrawal periods reflect the amount of time necessary for an animal to metabolize an administered product and the amount of time necessary for the product concentration level in the tissues to decrease to a safe, acceptable level. Every federally approved drug or animal health product has a withdrawal period printed on the product label or package insert. Products carry meat withdrawal periods ranging from 0 to 60 days.Examples for meat range from no withdrawal period with ceftiofur, 4-15 days with different penicillin products, to 28 days with Pirlimycin. Animals treated with a product that has a withdrawal period of 45 days should be withheld from sale or slaughter for at least 45 days.
Withdrawal periods are not the same for all drugs. Examples for milk include: Pirlimycin, 36 hours; Cloxacillin, 48 Hours, Amoxicillin, 60 hours, Penicillin, 72 hours, and Cephapirin, 96 hours. Milk produced during that period must be disposed of. Dairy animals to be slaughtered must be withheld for the meat withdrawal period specified.
Withdrawal periods may be extended when combinations of drugs are used or when drugs are used in an extra-label manner. In these situations, or at any time a producer is uncertain of a specific drug withdrawal period, a veterinarian should be consulted.
6. Withdrawal periods after anthelmintic treatment
Most anthelmintics have withholding periods if milk or meat from treated animals is intended for human consumption; the specific requirements for each must be observed. Of the benzimidazoles, thiabendazole is absorbed and excreted most quickly; fenbendazole, oxfendazole, and albendazole are absorbed and excreted over a longer period, which necessitates withholding periods of 8–14 days before slaughtering for meat and 3–5 days before milking for human consumption. Other members of the group have withholding periods between these extremes, but withholding periods are longer for bolus formulations.
A similar relationship between the rate of metabolism and activity against immature parasites also exists with certain fasciolicides. Closantel, rafoxanide, and nitroxynil bind more strongly to blood proteins than does oxyclozanide, and therefore remain in the blood for longer periods. While this greater persistence is associated with greater activity against immature liver flukes, the withholding period for slaughter is also longer: 21–77 days for closantel, rafoxanide, and nitroxynil, compared with 3–14 days for oxyclozanide. The low plasma-protein binding of diamfenetide, coupled with the rapid excretion of its active metabolite, necessitates only a short withdrawal time. Similarly, withholding periods for milk vary widely. Closantel and nitroxynil cannot be used in lactating animals when milk is intended for human consumption, whereas oxyclozanide has a withdrawal time of only 60 hr.
Levamisole and morantel are rapidly excreted; thus, withholding periods for meat are short, and frequently there is no, or only a short, withholding period for milk. However, in some countries, levamisole cannot be used in lactating animals when milk is intended for human consumption.
Ivermectin and doramectin are excreted in milk and are not recommended when milk is intended for human consumption. Commensurate with the long period of activity of macrocyclic lactones, ivermectin, abamectin, doramectin, and moxidectin have significant withholding periods before slaughter (e.g., 35 days), which vary with the formulations and local regulations. Residual concentrations of moxidectin in milk after topical administration are below threshold limits, resulting in no milk withholding period in many countries.
Monepantel has a withdrawal period of 7–14 days for meat and is not approved for use in lactating animals producing milk for human consumption.
In combination with abamectin, derquantel has a withholding period of 14 days for meat and is not approved for use in lactating animals producing milk for human consumption.
7. How antibiotic withdrawal period affects your health
Antibiotic residues can lead to allergy, cancer, antibiotic resistance, and other health effects. Residual penicillin in animal products can cause allergic reaction in some people. Other antibiotic residues like tetracycline, sulphonamides and aminoglycosides can also cause allergic reactions.
One of the most important concerns is antibiotic resistance. Animal products containing antibiotic residues can cause antibiotic resistance in man. The resistant bacteria can then cause diseases in man and such diseases are difficult and expensive to treat.
These effects may be direct or indirect, owing to the high dose of the residues, which must have accrued over a prolonged period. They can be exhibited as drug hypersensitivity reactions, aplastic anaemia, carcinogenic, mutagenic, immunologic and teratogenic effects, nephropathy, hepatotoxicity, disruption of the normal flora of the intestines, a reproductive disorder, as well as the development of antibiotic-resistant bacteria in the gut.
Presence of antibiotic residues in the different animal-derived products and their consequences in humans and animals.
Presence antibiotic residues in the different animal-derived products in some developing countries and their consequences in humans and animals.
|SN||Antibiotic residues||Consequences in Humans/Animals|
|1||Tetracyclines||Primary and permanent teeth discolouration in children and infants, allergic reactions, and teratogenicity during the first trimester of pregnancy, nephrotoxicity, carcinogenic, hepatoxicity, and disturbance of the normal microflora of the intestines. It equally causes skin hyperpigmentation of areas exposed to the sun, proximal and distal renal tubular acidosis, hypersensitivity reactions.|
|2||Oxytetracyclines||Carcinogenicity and cytotoxicity in bone marrow of broiler chickens|
|3||Sulfadimidine||Carcinogenicity and allergic reactions.|
|5||Enrofloxacin||Allergic hypersensitivity reactions or toxic effects, phototoxic skin reactions, chondrotoxic), and tendon rupture.|
|6||Chloramphenicol||Bone marrow toxicity, optic neuropathy, brain abscess|
|7||Penicillin||Allergy, affect starter cultures to produce fermented milk product|
|8||Quinolones||Allergic hypersensitivity reactions or toxic effects (phototoxic skin reactions, chondrotoxic) and tendon rupture.|
|9||Amoxicillin||Carcinogenic, teratogenic, and mutagenic effects.|
|10||Penicillin G||Allergy (hypersensitivity reaction) ranging from mild skin rash to life-threatening anaphylaxis.|
8. Strategies to minimize cost of withdrawal periods
Obeying drug withdrawal periods can be costlier for the farmers. For example, if your egg layers or cows get sick, and you have no other option than to give them an antibiotic with a 7-day withdrawal period. This means that all the eggs or milk produced throughout these 7 days will be thrown away. Many farmers therefore in developing countries find it difficult to obey withdrawal periods.
The cost resulting from obeying withdrawal periodscan be minimized by following good management practices. This entails following production techniques that help to maximize efficiency and eliminate or reduce infections. It includes proper housing, putting farm biosecurity measure in place, good nutrition, proper vaccination, etc.
Herbs and probiotics can help prevent diseases in animals. Various research on herbs and plant extracts show that they can be used to prevent and treat diseases in animals. With herbs and probiotics, there are no withdrawal periods unlike antibiotics.
In India, laws may exist about antibiotic withdrawal period, but steps are not usually taken to enforce them. As a result, many farmers don’t observe withdrawal periods. Antibiotic and pesticide residues are among the reasons why the countries like India are denied access into American and Europe livestock market.
Despite the cost associated with obeying antibiotic withdrawal period, it is still necessary that farmers adhere to it. If not, it can jeopardize the health of consumers. The best way to avoid the cost is by following best management practices that prevent or minimize infections Herbs and probiotics can help as alternatives to antibiotics. The veterinary professionals can play a vital role by making the livestock farmers aware about the importance of withdrawal period. In India, drugs rules and regulations are controlled by Central Drugs Standard Control Organization (CDSCO). There is need of enforcing strict regulation regarding withdrawal period on farm animals by CDSCO.
Proper maintenance of withdrawal period after antibiotic treatment would minimize the risk of antibiotic residues in animal products. Therefore, awareness regarding the proper maintenance of withdrawal period after antibiotic treatment is one of the best strategies that may positively reduce the risk of antimicrobial drugs residues in animal products.
Annex 1: Maximum permissible level of antibiotics in meat:
|Antibiotics||Animal species||Level (mg/kg)|
|Tetracycline||Calves, sheep, goat, pig||0.25|
|Tylosine||Cattle, calves, pigs||0.20|
|Oxytetracycline||Cattle, calves, pigs||0.10|
|Chlortetracycline||Cattle, calves, and pig||0.10|
|Chlortetracycline||Calf liver and kidney||4.00|
Annex 2: Age restriction on feeding antibiotics:
|Swine||4 – 6 months|
|Poultry||8 -10 months|
|Fur bearing animals||2 – 3 months|
|Beef cattle||18 months|
Annex 3: Withdrawal time and tolerance level of antibiotics in cattle:
|Drugs||Pre-slaughter withdrawal time (days)|
|Oral||Injectables||Tolerance level (ppm)|
Annex 4: Withdrawal time and tolerance level of antibiotics in sheep and goats
|Drugs||Pre-slaughter withdrawal time (days)|
|Oral||Injectables||Tolerance level (ppm)|
|Procaine penicillin G||–||9||0|
Annex 5: Withdrawal time and tolerance level of antibiotics in chickens
|Drugs||Pre-slaughter withdrawal time (days)||Tolerance level (ppm)|
Annex 6: Recommended withdrawal periods for some of the antimicrobial substances used in poultry industry.
|Antimicrobial substances||Feed withdrawal period (days)|