What are the risks of residues and milk/meat withdrawal times for each ivermectin formulation?
Executive summary
Ivermectin residues vary markedly with formulation, route, and species: injectable and long‑acting preparations produce the highest and most persistent tissue and milk residues requiring weeks to months of meat withholding and often precluding use in lactating animals, while topical (pour‑on) and some oral uses generally give lower milk transfer though withdrawal rules differ by jurisdiction; eprinomectin was developed to minimize milk excretion and is licensed for dairy use in many places [1] [2] [3]. Regulatory maximum residue limits (MRLs) and recommended withdrawal intervals are formulation‑ and country‑specific, and extralabel or long‑acting uses substantially increase residue risk and uncertainty [4] [5].
1. Injectable (subcutaneous) — deep tissue persistence and long meat withdrawals
Subcutaneous injectable ivermectin concentrates in fat and liver and shows slow depletion, producing the highest risk of residues in edible tissues and requiring lengthy slaughter withholding periods that have been set in many jurisdictions at multiple weeks to months (for example, EU rules supporting ~49 days after single‑dose injectables) [1] [6]. Injectables also result in measurable residues at injection sites and erratic depletion kinetics that complicate precise withdrawal estimates across breeds and studies, so regulators and analysts recommend conservative intervals for meat and often bar use in lactating animals because milk withdrawal times are not well‑established [7] [8]. Historical residue studies led to suggested edible tissue withdrawals of roughly 21–28 days in some older studies, but modern regulatory assessments and the EMA set longer intervals based on fat and liver accumulation [6] [1].
2. Pour‑on/topical formulations — lower milk transfer but variable rules
Topical “pour‑on” formulations have lower systemic bioavailability in cattle and tend to deposit more drug in skin and fat, which can reduce milk concentrations below some national MRL thresholds if sufficient time elapses between treatment and milking, but trace residues can persist and rules differ by country (for example, a study found no detectable milk residues when pour‑on was given >10 days before calving under China’s 10 ng/mL MRL, while other jurisdictions treat any detectable residue as a violation) [9] [10]. Pour‑on administration still results in systemic absorption in some species (eg, chickens and hens), producing prolonged residues in eggs or milk in nonbovine species, so topical use cannot be assumed safe for all food animals [11]. Merck Veterinary Manual warns that long‑acting topical products can still require extended withholding depending on formulation [2].
3. Oral formulations — species and dose matter
Oral ivermectin can produce residues that vary by species; goats and cattle differ markedly in milk excretion and required withdrawal times, with literature showing much shorter milk depletion in some goats versus longer intervals in cattle, and country‑by‑country differences apply (a Brazilian goat study reported no detectable milk residues by 42 days for a specific oral protocol, but lack of dosage/context limits generalizability) [12]. Because oral absorption and milk partitioning depend on the molecule and formulation, regulators typically set withholding periods per species and product; extralabel oral use is discouraged when animals produce milk for human consumption [2] [13].
4. Long‑acting or slow‑release formulations — new risks, likely longer withdrawals
Long‑acting injected formulations designed to release ivermectin over months pose qualitatively different accumulation and environmental exposure risks and would likely necessitate increased withdrawal times compared with classical products; proof‑of‑concept research flags the need for careful residue characterization and probably exclusion of gestating or lactating food animals during the release period unless non‑consumption guarantees exist [5]. Regulatory frameworks (FAO/WHO/JECFA) are specifically cited as needed guides for defining safe withdrawal intervals for such novel formulations [5] [4].
5. Regulatory context, MRLs and practical guidance
Codex/FAO/WHO and regional bodies set MRLs (eg, historic Codex discussions and EU limits for fat, liver, kidney) that determine whether detected residues are violations and underpin withdrawal intervals; where no milk MRL or label milk withdrawal is provided, use in lactating dairy animals is effectively contraindicated and extralabel use discouraged [4] [3] [8]. In practice, producers should follow product labels and national regulations because studies show wide variability by formulation, species, breed, dose and injection site that make one‑size‑fits‑all withdrawal statements unreliable [7] [1].