Avilamycin in the product Elanco AF0375 Surmax 100 Avilamycin premix

Contents

Foreword

The Australian Pesticides and Veterinary Medicines Authority (APVMA) is an independent statutory authority with responsibility for assessing and approving agricultural and veterinary chemical products prior to their sale and use in Australia.

In undertaking this task, the APVMA works in close cooperation with advisory agencies, including the Department of Health and Family Services (Chemicals and Non-prescription Drug Branch), Environment Australia (Risk Assessment and Policy Section), the National Occupational Health and Safety Commission (Worksafe Australia) and State departments of agriculture and environment.

The APVMA has a policy of encouraging openness and transparency in its activities and of seeking community involvement in decision making. Part of that process is the publication of public release summaries for all products containing new active ingredients and for all proposed extensions of use for existing products.

The information and technical data required by the APVMA to assess the safety of new chemical products and the methods of assessment must be undertaken according to accepted scientific principles.  Details are outlined in the APVMA's publications Vet Manual:  The Requirements Manual for Veterinary Chemicals and Vet Requirements Series.

This Public Release Summary is intended as a brief overview of the assessment that has been completed by the APVMA and its advisory agencies.  It has been deliberately presented in a manner that is likely to be informative to the widest possible audience thereby encouraging public comment.

More detailed technical assessment reports on all aspects of the evaluation of this chemical can be obtained by completing the order form in the back of this publication and submitting with payment to the APVMA.  Alternatively, the reports can be viewed at the APVMA Library, Third floor, 10 National Circuit, Barton, ACT.

The APVMA welcomes comment on the usefulness of this publication and suggestions for further improvement.  Comments should be submitted to the Executive Manager-Registration, Australian Pesticides and Veterinary Medicines Authority, PO Box 6182, Kingston ACT 2604.

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List of abbreviations and acronyms

ADI acceptable daily intake (for humans)
°C Degrees centigrade
kg Kilogram
Kd Distribution Coefficient
L Litre
LD50 Dosage of chemical that kills 50% of the test population of organisms
LOD Limit of Detection
mL Millilitre
MRL Maximum Residue Limit
MSDS Material Safety Data Sheet
oN Degrees latitude
NDPSC National Drugs and Poisons Schedule Committee
Koc Koc= 100K + %OC where K is a coefficient and OC is the concentration of organic matter
NOEC/NOEL No Observable Effect Concentration/Level
PPE Personal Protective Equipment
ppm Parts per Million

 

t.ha-1 Tonnes per hectare
mg.kg-1 Milligram per kilogram
TLC Thin Layer Chromatography
WHP Withholding Period

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Summary

Purpose of application

This application is for the registration of a new product, Elanco AF0375 Surmax 100 Avilamycin Premix. It contains 100g/kg avilamycin as the active ingredient. Avilamycin is the generic name of an oligosaccharide antibiotic of the orthosomycin group. It is an ester of dichloroisoeverninic acid produced by fermentation of Streptomyces viridochromogenes. Avilamycin is composed of a mixture of avilamycin A (>60%) and avilamycin B (>18%), with none of the other avilamycins contributing more than 6% of the total avilamycin content.

Elanco AF0375 Surmax 100 Avilamycin Premix is used to increase weight gain and improve feed efficiency in broiler chickens. It is not indicated for use in laying birds where eggs or egg products are to be used for human consumption or processing. As the product will be mixed with animal feed at feed mills, there will be no on farm mixing.

Public Health Aspects

The NHMRC Working Party on Antibiotics had reviewed Surmax 100 Avilamycin Premix in 1997 and did not object to its registration. Toxicology was reviewed by the Chemicals Policy and Non-Prescription Drug Branch of the Commonwealth Department of Health and Family Services. 

Mycelial avilamycin (14.9% avilamycin equivalents), the activity of which closely resembles that of Surmax 100 Avilamycin Premix (10.5% avilamycin equivalents), was considered to have very low oral toxicity, low dermal toxicity and moderate inhalational toxicity.  Mycelial avilamycin is a slight skin and eye irritant but it is not a skin sensitiser.  Acute toxicity studies with Surmax 100 Avilamycin Premix were not done, however, it was considered that studies done with mycelial avilamycin is likely to adequately reflect the toxicological profile of the product.

Following repeated administration, changes in body weight gain and/or food consumption were the main effects attributable to avilamycin in mice, rats and dogs.  There were no effects on mortality, adverse clinical signs or significant changes in organ weights.  Pathological assessment revealed no changes attributable to treatment with avilamycin.  Avilamycin did not induce cancer in mice and rats and genetic damage was not evident in a range of assays.  A three-generation study in rats did not reveal any abnormality on the reproductive function or on foetal development. 

Based on an assessment of the toxicology, it was considered that there should be no adverse effects on human health from the proposed use of avilamycin as a component of Surmax 100 Avilamycin Premix in accordance with label directions.

The NDPSC had recommended that formulations containing avilamycin be placed in Schedule 4 of the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP), except in animal feed premixes containing 15 per cent or less of avilamycin activity; or in animal feeds containing 50 mg/kg or less of avilamycin activity.  There are provisions for appropriate warning statements and first-aid directions on the product label.

Residues in food

Appropriate residue and metabolism studies were submitted for evaluation in accordance with the Requirements Manual for Veterinary Chemicals and Interim Requirements for the Registration of Agricultural and Veterinary Chemical Products to support use of the product.

The residue data and use pattern indicated that a NIL slaughter withholding period (WHP) is appropriate for poultry. The product should not be used in laying birds where eggs or egg products are to be used for human consumption or processing. The metabolism and residue data show that when the product is used in accordance with Good Agricultural Practice, the proposed MRLs for avilamycin should not be exceeded and consumption of tissues from treated animals is unlikely to result in the ingestion of residues exceeding the established Acceptable Daily Intake (ADI).

The following amendments to the MRL Standard have been recommended:

TABLE 1

Compound

 

Food

 

MRL (mg/kg)

 

ADD:

Avilamycin

Poultry meat

Poultry, Edible offal of

*0.05

*0.05

and

TABLE 2

Compound Residue

ADD:

Avilamycin

Inhibitory substance, expressed as avilamycin

Trade

Avilamycin is registered in 40 countries worldwide though no MRLs have been set in any of these countries, implying nil residues (Note avilamycin is not registered in USA). Except for Japan which has a 7 day slaughter WHP, the slaughter WHP in these countries is nil. There are no CODEX MRLs for avilamycin in food producing animals.

As the residues expected in poultry products is less than the limit of detection for bioautographic analysis (LOD 0.05 mg/kg), it was concluded that the risk to Australian trade in poultry commodities is small.

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Occupational Health and Safety

The National Occupational Health and Safety Commission has conducted a risk assessment on Elanco AF0375 Surmax 100 Avilamycin Premix as a veterinary feed additive, containing 100 g/kg of avilamycin equivalents, for use in feeds of broiler chickens. The product is  

imported fully packaged in 25 kg capacity multiwall paper sacks with polythene ply (or a similar moisture resistant container).

Based on the toxicity of avilamycin and the non-active ingredients of the product, Elanco AF0375 Surmax 100 Avilamycin Premix can be expected to have low acute oral, dermal and inhalation toxicity and cause slight skin and eye irritation.  It is not expected to be a skin sensitiser.  End users should follow the instructions and safety directions on the product label which include the use of cotton overalls, PVC gloves, and a disposable dust mask when mixing the product with the feed.

It was concluded that Avilamycin and its product, Elanco AF0375 Surmax 100 Avilamycin Premix, can be used safely with the control measures described above.

Environmental aspects

Avilamycin is rapidly hydrolysed under acid conditions but degrades more slowly under alkaline and neutral conditions.  It is rapidly degraded by photolysis.  Based on data from field dissipation studies avilamycin appeared to degrade fairly readily in soil with a half-life, for disappearance of a radioactive label, in the order of 3-4 weeks.  Avilamycin, and in particular its metabolites, exhibited some mobility in soils with the potential for leaching to occur.  Avilamycin would be expected to have a low potential to bioaccumulate based on size and partition coefficient.  As the active is readily hydrolysed and degraded, accumulation in soils is not expected under normal use.

Based on the data provided avilamycin would be considered, at worst, to be slightly toxic to fish and daphnia.  It should not be toxic to earthworms but may have some short term impacts on microorganisms responsible for nitrification in the soil.  There was some evidence of phytotoxic effects on tomatoes grown in soil treated with manure from chickens eating a diet containing avilamycin but other crops tested were not affected.

Environmental exposure from the proposed use of avilamycin is expected via use of contaminated chicken manure as fertiliser.  Concentrations of avilamycin and its metabolites in soil from this use are expected to be low with a maximum estimated concentration of 1.95 mg.kg-1.  Based on the data provided this concentration should have no long term effects on earthworms, soil microorganisms and most plants although data from one test indicates tomatoes may experience some stunting.  Potential exposure of birds and terrestrial mammals to the active is considered to be very low.

Although the short term effect on soil microorganisms of manure containing avilamycin and its metabolites is unclear, the expected environmental concentration of avilamycin in either soil or run-off waters is significantly lower than the concentrations shown to be toxic to earthworms, fish and daphnia tested.

Efficacy and safety

Overseas studies (Europe, US and parts of Asia including Japan) were provided to support the safe and efficacious use of the product in broiler chickens. Two studies were carried out in

Australia. In the Australian field study using avoparcin as a reference, the results demonstrated that  avilamycin was as good as avoparcin in improving performance indices for broiler production and did not unduly harm the birds. Performance indices used included Feed Conversion Efficiency, Days to Closeout and Performance Index Factor between groups.

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Introduction

The purpose of this document is to provide a summary of the data reviewed, and an outline of the regulatory considerations for the proposed registration of the antibiotic avilamycin for use as a growth promotant for broiler chickens. The information provided herein presents only the conclusions reached by the various expert reviewers after consideration of the scientific database.

The Australian Pesticides and Veterinary Medicines Authority (APVMA) has completed an assessment of the data submitted by the applicant in support of the use of avilamycin and now invites public comment before proceeding to approve this product for use in Australia. The information contained in this document is provided for public comment.

The deadline for comments is 7 October 1999.

Comments should be sent to:

Ellen Ho 
National Registration Authority 
PO Box E240 
Kingston  ACT 2604 
Fax: (02) 6272 5249

Applicant's details

Elanco Animal Health 
112 Wharf Road 
West Ryde, NSW 2114 
Tel: (02) 9325 4455 
Fax: (02) 9325 4420

Indications for use

Elanco AF0375 Surmax 100 Avilamycin Premix is intended for use in broiler chickens for increased rate of weight gain and improved feed efficiency.

Product details

Elanco AF0375 Surmax 100 Avilamycin Premix is a light to medium brown, free-flowing premix. It is presented as 25 kg net containing 100kg/kg avilamycin. Formulation of the end use product is carried out at Eli Lilly and Company Ltd, Speke Operations, Liverpool, UK. It will be imported fully finished. Elanco AF0375 Surmax 100 Avilamycin Premix is currently registered in over 40 countries.

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Chemistry and Manufacture

Active constituent

The chemical active constituent avilamycin has the following properties:

Common name (ISO): Avilamycin

Factor Composition:    Avilamycin A        Not less than 60%

        Avilamycin B        Not more than 18%

        Avilamycin A + B     Total of not less than 70%

        Avilamycin C, D1, D2 & E    Not more than 6% (for each type)

Product name: Elanco AF0375 Surmax 100 Avilamycin Premix

CAS Registry Number: 11051-71-1

Physical form: Powder

Melting Point: 181-182 ˚C

Colour: Light to medium brown

Odour: Musty smell

Structural formula:

Structural formula

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Toxicological Assessment

The toxicological database for avilamycin, which consists primarily of toxicity tests conducted using animals, is extensive.  In interpreting the data, it should be noted that toxicity tests generally use doses which are high compared to likely human exposures.  The use of high doses increases the likelihood that potentially significant toxic effects will be identified.  Findings of adverse effects in any one species do not necessarily indicate such effects might be generated in humans.  From a conservative risk assessment perspective however adverse findings in animal species are assumed to represent potential effects in humans unless convincing evidence of species specificity is available. Where possible, considerations of the species specific mechanisms of adverse reactions weigh heavily in the extrapolation of animal data to likely human hazard.  Equally, consideration of the risks to human health must take into account the likely human exposure levels compared with those, usually many times higher, which produce effects in animal studies.  Toxicity tests should also indicate dose levels at which specific toxic effects are unlikely to occur.  Such dose levels as the No-Observable-Effect Level (NOEL) are used to develop acceptable limits for dietary or other intakes at which no adverse health effects in humans would be expected.

Acute Studies

Toxicity studies were done with crystalline or pure avilamycin (92.5% pure, the antimicrobial activity is taken as 100%) and mycelial avilamycin.  The concentrations of the mycelial avilamycin varied and their potencies were expressed as a % of the antimicrobial activity (referred to as avilamycin equivalents) of crystalline avilamycin.  Surmax 100 Avilamycin Premix contains 10.5% of avilamycin equivalents.

Crystalline avilamycin had very low oral toxicity in rats (LD50 >4640 mg/kg) and mice (LD50 >6000 mg/kg).  It was not a skin or eye irritant.  Mycelial avilamycin (14.9% avilamycin equivalents), the activity of which closely resembles that of the product Surmax 100 Avilamycin Premix had very low oral toxicity in rats and mice (LD50 >5000 mg/kg), low dermal toxicity in rabbits (LD50 >2000 mg/kg) and moderate inhalational toxicity in rats (LC50>770 mg/m3).  Mycelial avilamycin was a slight skin and eye irritant but it was not a skin sensitiser.

Short-Term Studies

In mice the effects of 28-day oral administration (in diet) of mycelial avilamycin at 0, 30, 300, 3000 and 30000 parts per million (ppm, doses in males/females: 0, 4.7/5.2, 46/51, 415/618 and 6100/6100 mg/kg bw/day) were investigated.  The mean body weight gain was increased in males at 300, 3000 and 30000 ppm but not in females.  The food intake was increased in males and females at 300 and 3000 ppm.

In rats the effects of 14 and 28-day oral administration (in diet) of mycelial and crystalline avilamycin (up to 10%, equivalent to 8593/8084 mg/kg bw/day in males/females; or up to 30000 ppm, equivalent to 3459/3685 mg/kg bw/day in males/females) were investigated.  At 5414 mg/kg bw or above, mycelial avilamycin increased blood urea nitrogen and creatinine which are suggestive of altered kidney function, and increased bilirubin (increased breakdown of red blood cells or altered liver function).  At 307 and 3459 mg/kg bw/day (mycelial avilamycin), blood urea nitrogen was increased and lactate dehydrogenase (a marker of heart and skeletal muscle function) was decreased in males.  Food consumption and body weight gain were increased in females at 3459 mg/kg bw/day (mycelial avilamycin) in the last week.  Changes in blood cell parameters were observed at 3459 mg/kg bw/day (mycelial avilamycin): in females, packed cell volume (haematocrit) was decreased and the white blood cell count increased, and platelet count was increased in males and decreased in females.  Crystalline avilamycin increased the enzyme alanine amino transferase (a marker of liver toxicity) at 2326 and 4652 mg/kg bw/day in females and decreased total bilirubin in these treated groups. 

A 6-month subchronic oral toxicity study was done in beagle dogs with mycelial avilamycin at 0, 20, 200 and 1000 mg/kg/day (0, 3.6, 36 and 178 mg/kg bw/day of avilamycin equivalents).  In males, there was an increase in the overall mean body weight gain in the treated groups.  Gross inspection and microscopic examination did not reveal any treatment related abnormality.  The NOEL for this study was 1000 mg/kg bw/day mycelial avilamycin (178 mg/kg bw/day of avilamycin equivalents), the highest dose used.

Long-Term Studies

Mice were treated with 0, 30, 300 and 3000 ppm mycelial avilamycin (0, 3, 30 and 310 mg/kg bw/day avilamycin equivalents in males and females) for 24 months in the diet.  Another group received 3000 ppm of crystalline avilamycin (310/324 mg/kg/day in males/females) in the diet.  Body weight gain in males was slightly increased at 300 and 3000 ppm (mycelial avilamycin) over the first 6 months but during the last 6 months of the study weight loss was seen in all male and female groups, including control, but the weight loss was slightly increased in the treated groups.  The overall food intake was increased slightly in females but decreased in males.  The number of cells in the pancreas was increased in a few males and degeneration of the eye lens occurred in a few females, but the effects were not dose dependent and therefore not considered treatment related.  Avilamycin did not induce cancer in mice.  The NOEL for this study was 3000 ppm (310 mg/kg bw/day of avilamycin equivalents), the highest dose used.

A rat chronic study was done in three phases with mycelial avilamycin administration (0, 30, 300 and 3000 ppm) during premating and reproductive phases in the parents and for 24 months in the offspring.  Approximate actual achieved doses during the main phase were 0, 1/1, 11/12 and 111/128 mg/kg bw/day in males/females.  Another group received 3000 ppm of crystalline avilamycin (108/127 mg/kg/day in males/females).  There was no adverse effect of treatment on survival or clinical signs.  The overall body weight gain was reduced in the female group given crystalline avilamycin at 3000 ppm, but not with the mycelial form.  The overall food intake was not altered.  Water consumption, measured in the 3000 ppm mycelial and crystalline groups up to week 24, was increased only at week 24 in males in the mycelial group but not in the crystalline group, and urinary volume was increased at 3000 ppm in females (mycelial group) and at 300 and 3000 ppm in males (mycelial and crystalline groups) at some time points.  Organ weights and pathology were not altered by treatment and tumour incidences were not increased.  In the reproductive phase of the study, pregnancy rate, litter size and pup mortalities were not altered.  The NOEL for this study was 3000 ppm (108 mg/kg bw/day of avilamycin equivalents), the highest dose used.

Reproduction and Developmental Studies

A three-generation study with crystalline (3000 ppm) and mycelial avilamycin (0, 30, 300 and 3000 ppm, equivalent to 0, 1.5, 15 and 150 mg/kg bw/day) was done in rats.  The reproductive study also had a component on developmental toxicity.  In all generations, no treatment related effects were seen on parent mortality, clinical signs, body weight gain, and food and water consumption.  The parental reproductive parameters (male and female mating and fertility indices, maternal gestation and parturition indices, and the duration of gestation) were unaffected by treatment.  No dose dependent or consistent effect of avilamycin could be seen on foetal development, litter size or litter survival.  The NOEL for this study was 3000 ppm (150 mg/kg bw/day), the highest dose tested.

A developmental study was performed in rabbits with mycelial avilamycin administered orally in daily doses of 0, 44, 127 and  356 mg/kg bw/day on gestation days 6 through 18.  Food intake was decreased by treatment.  One rabbit in the high dose group (356 mg/kg bw/day) died on gestation day 17 following tonic and clonic convulsions.  Diarrhoea occurred in a few treated animals.  The urine of the treated groups had orange colour.  Abortions occurred in 2 rabbits of the 44 mg/kg bw/day group and in one rabbit of the 127 and 356 mg/kg bw/day groups.  The rabbits which aborted had diarrhoea and/or loss of appetite.  The other parameters tested were not affected by treatment.  Since toxic effects in the rabbit are likely to be associated with gross alteration of the intestinal microflora, caution should be used in extrapolating this toxicity to circumstances where the microflora would be unaffected.

Genotoxicity studies

Negative results were obtained in a range of studies to assess gene toxicity.  The assays conducted were gene mutation (S. typhimurium strains TA98, TA100, TA1535, TA1537 and TA 1538; L5178Y mouse lymphoma cells), unscheduled DNA synthesis (rat hepatocytes) and sister chromatid exchange (bone marrow of Chinese hamsters).

Public Health Standards

Poisons Scheduling

The National Drugs and Poisons Schedule Committee (NDPSC) considered the toxicity of the product and its active ingredient and assessed the necessary controls to be implemented under States' poisons regulations to prevent the occurrence of poisoning.

The NDPSC recommended that formulations containing avilamycin be placed in Schedule 4 of the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP), except in animal feed premixes containing 15 per cent or less of avilamycin activity; or in animal feeds containing 50 mg/kg or less of avilamycin activity.  There are provisions for appropriate warning statements and first-aid directions on the product label.

NOEL/ADI

In mice, rats and dogs, avilamycin did not have any significant toxicity and hence the highest doses used in these species represented the NOEL.  Avilamycin had a NOEL of 108 mg/kg bw/day in rats, 178 mg/kg bw/day in dogs and 324 mg/kg bw/day in mice.  The lowest NOEL (108 mg/kg bw/day in rats) was used for ADI calculation.  In order to calculate an Acceptable Daily Intake (ADI) for humans, a safety factor is applied to the NOEL in the most sensitive species.  The magnitude of the safety factor is selected to account for uncertainties in extrapolation from animal data to humans, variation within the human population, the quality of the experimental data, and the nature of the potential hazards.  Using a safety factor of 100, an ADI of 1 mg/kg bw/day was established for avilamycin.

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Metabolism and Toxicokinetics Assessment

In the rat after 3 days oral administration of avilamycin (100mg/kg/day), 91 - 99% of the absorbed compound was excreted in the faeces within 24 h after the last dose, with 0.2% excreted in the urine.  Three major metabolites were identified in the faeces: avilamycins A and B, and flambalactone.  Flambic acid, a polar metabolite, was the major metabolite of the remaining fraction which is relatively unstable and readily cyclized to flambalactone. Data from the pig indicated that excretion and metabolism are similar in rats and pigs.

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Residues Assessment

This section provides evaluation of the data submitted by the applicant to support establishment of MRLs for avilamycin in poultry meat and edible offal. The proposed dose rate is 2.5 to 15 mg/kg in the feed for broiler chickens.

Metabolism studies

Studies were conducted in rats, poultry and pigs. The metabolic patterns in rats and pigs showed similar patterns for degradation although the distribution of individual metabolites is different. There is extensive metabolism of avilamycin in pigs and excretion is rapid in rats, pigs and poultry. The major residue detected in the liver of both rats and pigs was flambic acid.

Rats

In rats dosed by gavage for 3 consecutive days with 14C- labelled avilamycin at 100 mg/kg bodyweight, >90% of the dose excreted in the faeces with less than 0.25% recovered in the urine. Most of the faecal radioactivity was unchanged avilamycin which accounted for approximately 50% of the radioactive residue. The other major components were an unidentified polar metabolite, probably flambic acid,  and flambalactone.

Poultry

Chickens pretreated by feeding with unlabelled avilamycin followed by a single dose of 14C-avilamycin excreted most of the dose within 4 days with greater than 50% excreted in the first 24 hours post dose. The target tissue for chickens was the liver.

Pigs

Pigs fed ad libitum 14C-avilamycin rations excreted most of the dose within 5 days Approximately 90 and 8% of the dose was excreted in the faeces and urine respectively. Unchanged avilamycin accounted for <10% of the radioactivity in the faeces with the major metabolite, flamalactone, accounting for approximately 40% of the radioactivity. The major metabolite in liver was flambic acid. Saponification and esterification of fat tissues demonstrated that most of the radioactivity was incorporated into natural fatty acids rather than occurring as avilamycin related residues.

Collectively the submitted metabolism studies indicated that avilamycin is extensively metabolised and rapidly excreted in rats, poultry and pigs.

Residue definition

The metabolic profiles of avilamycin in rats and pigs are qualitatively similar. Avilamycin undergoes rapid metabolism and excretion. The major metabolite detected was flambic acid. The level of microbiologically active residue detected in tissues were low in contrast to the higher levels detected by GC (parent plus sum of metabolites containing the

dichloroisoeverninic acid). For some antibiotics where there is little metabolism, it is possible to relate microbiological assay results to chromatographic methods such as HPLC or GC. This is not the case for avilamycin. As microbiologically active residues can be quantitated by bioautographic analysis it is appropriate to define the residue as:

    Avilamycin        Inhibitory substance identified as avilamycin

Analytical methods

Samples of homogenised tissue were extracted with acetone and an aliquot of the acetone purified by liquid-liquid partitioning (hexane followed by dichloromethane). The combined dichloromethane extracts were evaporated to dryness and the residue redissolved in acetone and spotted on a TLC plate (Silica Gel G). After development of the TLC plate with ethyl acetate:toluene:methanol, 95:5:5, the solvent was removed under vacuum and the plate was subjected to bioautographic analysis using Micrococcus flavus. The plate was sprayed with a visualiser (0.2% 2-(p-iodophenyl)-3-(p-nitrophenyl)-5-phenyl tetrazolium chloride) to enhance the appearance of the zones of inhibition. The avilamycin was determined by comparison with a reference standard analysed in the same manner (LOD 0.05 mg/kg).

Validation was by analysis of control samples and samples of liver, kidney, fat and muscle fortified at 0.05 mg/kg. Zones of inhibition corresponding to the same Rf values as standard curves were detected for all fortified samples.

Residue trials

Two residue trials for chickens were conducted that addressed the proposed use pattern. The levels of total radioactive residue were greatest in the liver followed by fat, kidney and muscle. The target tissue is the liver.

Broiler chickens fed 14C-avilamycin in the feed for 4 to 10 days had low levels of radioactivity in liver, skin and fat. The levels of radioactivity were <LOD for muscle and kidney.

In a separate study on broiler chickens fed unlabelled avilamycin for 56 days, no residue was detected in muscle, liver, kidney, fat or skin tissues. The LOD for the analytical method was 0.05 mg/kg.

Withholding Period Statements

Recommended label statements are:

MEAT: NIL

EGGS: DO NOT USE in laying birds where eggs or egg products are to be used for human consumption or processing.

Dietary intake

Dietary intake calculations indicate that the theoretical maximum daily intake of avilamycin from pig and poultry meat and offal does not exceed the Australian ADI for avilamycin of 1 mg/kg/day, and is thus safe for human consumption.

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Assessment of Overseas Trade Aspects of Residues in Food

Avilamycin is registered in 40 countries worldwide though no MRLs have been set in any of these countries, implying nil residues (e.g. EU, Japan, NZ. Note avilamycin is not registered in USA). Except for Japan which has a 7 day slaughter WHP, the slaughter WHP in these countries is nil. The major markets for Australian domestic pig exports valued at A$12.2 million dollars are New Zealand, Japan, Philippines, Hong Kong and Nauru. The value of Australian poultry exports in 1995/1996 was A$10 million dollars with major markets in Hong Kong, China and South Africa.

Codex MRLs

There are no CODEX MRLs for avilamycin in food producing animals.

Australian MRLs

The MRLs proposed herein for Australia are:

    Poultry Meat            *0.05 mg/kg

    Poultry, Edible offal of      *0.05 mg/kg

Limits of Quantitation

The limit of detection for bioautographic analysis is 0.05mg/kg.

Implications for trade

As the residues expected in poultry products is less than the limit of detection for bioautographic analysis (LOD 0.05 mg/kg) the risk to Australian trade in poultry and pig commodities is considered small. However differences in the residues definition overseas may need to be considered by exporters if the screening program defines residues as the sum of avilamycin and its metabolites containing dichloroisoeverninic acid. Microbiologically active residues apparently account for 2 - 15% of the dichloroisoeverninic acid containing residue.

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Occupational Health and Safety Assessment

The National Occupational Health and Safety Commission (NOHSC) has conducted a risk assessment on Elanco AF0375 Surmax 100 Avilamycin Premix as a veterinary feed additive, containing 100 g/kg of avilamycin equivalents, for use in feeds of broiler chickens. 

Avilamycin is not on the National Occupational Health and Safety Commission List of Designated Hazardous Substances. In assessing the potential hazards associated with the use of Elanco AF0375 Surmax 100 Avilamycin Premix, NOHSC has considered the following:

Active constituent

Crystalline avilamycin has very low oral toxicity in rats.  It is not a skin or eye irritant.  Mycelial avilamycin (14.9% avilamycin equivalents), the activity of which closely resembles that of the product Elanco AF0375 Surmax 100 Avilamycin Premix, has low acute oral, dermal and inhalation toxicity.  It is a slight eye and skin irritant but not a skin sensitiser.

End use product (EUP)

Based on the amount of avilamycin in the EUP, the Therapeutic Goods Administration (TGA) predicts that Elanco AF0375 Surmax 100 Avilamycin Premix may be of low oral, dermal and inhalation toxicity and a slight skin and eye irritant.

Transport, storage and retailing

The product will be formulated overseas and imported fully packed in 25 kg multi-wall paper sacks with a polythene ply (or a similar moisture resistant container).  Transport and storage workers could only be exposed to the product if packaging is breached.

End use

Elanco AF0375 Surmax 100 Avilamycin Premix will be mixed with the animal feed. Mixing of the product with the feed will be carried out at feed mills by operators.  In these situations, most exposure would occur at the time of sampling and weighing out the premix and when adding it to the mixer.  There will be no on-farm mixing of the product.  

The primary routes of occupational exposure will be through skin contamination and inhalation of product/feed dust.

No worker exposure studies were available, so a qualitative risk assessment was conducted.  The EUP is a slight eye irritant and workers will require eye protection when handling the premix.   The average particle size of the EUP is above the inspirable range, however, the dust may be a physical irritant, so a dust mask is also recommended when handling the premix.

From the assessment of health risk, it is recommended that overalls and gloves be worn when handling the premix to minimise skin contamination.

Re-handling of treated animals

Elanco AF0375 Surmax 100 Avilamycin Premix is to be given orally, so no restricted handling interval is necessary.

Recommendations for safe use

Based on the above considerations, NOHSC has concluded that Elanco AF0375 Surmax 100 Avilamycin Premix can be used safely if handled in accordance with the instructions on the product label.  End users should follow the instructions and Safety Directions on the product label. The Safety Directions include the use of overalls, elbow-length PVC gloves and a disposable dust mask during mixing.

The Personal Protection Equipment (PPE) recommended should meet the relevant Standards Australia standard specified below:

AS 2161-1978 Industrial Safety Gloves and Mittens (Excluding Electrical and Medical Gloves)

AS/NZS 1715-1994 Selection, Use and Maintenance of Respiratory Protective Devices and AS/NZS 1716-1994 Respiratory Protective Devices

AS 3765-1990 Clothing for Protection Against Hazardous Chemicals

Avilamycin should be labelled in accordance with NOHSC National Code of Practice for Labelling of Workplace Substances.  Elanco Animal Health has produced MSDS for Elanco AF0375 Surmax 100 Avilamycin Premix containing information relevant to Australian workers, as outlined in the NOHSC National Code of Practice for the Preparation of Material Safety Data Sheets.  Employers should obtain the MSDS from the supplier and ensure that their employees have ready access to it.

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Environmental Assessment

Environmental Fate

Avilamycin is produced by fermentation of a strain of the bacterium Streptomyces viridochromogenes.  The strain used is stated by the applicant to be non-spore forming.  The active is added as fermentation solids which were initially innoculated with the bacterium and have been recovered after the fermentation process by centrifuging the fermentation medium.  The processing of the fermentation solids involves drying at 70 ˚C and according to the applicant this is unlikely to permit the survival of vegetative organisms although no data were provided to indicate the finished product contained no viable material.  However, the applicant has also provided expert reports to indicate that the bacterium is likely to be present in Australian soils.  So, in the unlikely event that any viable material from Streptomyces viridochromogenes was imported into Australia there should be minimal, if any, environmental hazard.

The product contains granular avilamycin equivalent to 10% avilamycin.  The product is mixed with feed at a rate of 2.5-15 ppm for chickens and is used on a continual basis. Environmental exposure is from spreading contaminated manure on fields as a fertiliser.

1.  Metabolism

No metabolism data were provided for chickens.  Studies with rats and pigs using diets containing radio labelled avilamycin showed rapid excretion.  In rats 90% of radioactivity was excreted within 24 hours whilst in pigs excretion was slower and occurred over 72 hours.  In pigs 92% of radioactivity was excreted in faeces with 8% in urine.  The metabolites found in the urine and faeces of pigs and rats were similar and consisted mainly of avilamycin A, flambalactone and flambic acid.

2.  Hydrolysis

Hydrolysis of avilamycin was studied in buffered, sterilised solutions at pH 5, 7 and 9.  The solutions were held in dark conditions at 24˚C for up to 10 days and avilamycin concentrations were measured by microbiological assay. Avilamycin degraded in all the solutions but the rate of degradation was markedly influenced by pH.  The half-life for loss of biological activity at pH 5 was 12 hours but this increased to 52 hours at pH 9 with the slowest degradation occurring at pH 7 where the half-life was 230 hours.

3.  Photolysis

Test solutions were held in a buffer solution of pH 7 at 28˚C for 24 hours and exposed to artificial light designed to replicate natural sunlight. Avilamycin concentrations were measured by microbiological assay.  There was no degradation in control solutions held in the dark but the illuminated solutions showed rapid degradation with a half life of 1.2 hours.  In a study using natural sunlight rapid degradation also occurred with the half life for loss of biological activity estimated at 0.95 days.  Based on the data from this experiment the photolysis half-life of avilamycin under summer and winter conditions for various latitudes were estimated.  These varied from 0.086 days in summer at latitude 20 ˚N to 1.33 days at latitude 50 ˚N in winter.

4.  Degradation in soil and water

No degradation studies were provided.  However, data from field dissipation experiments  involving the application of manure containing avilamycin residues indicated that the half life of avilamycin in soil was less than four weeks.

5.  Mobility in soil

The soil adsorption characteristics of avilamycin were tested on sandy loam, loam and clay loam soils.  The soil/water distribution coefficients (Kd) ranged from 23 to 109 and the KOC values ranged from 1802 to 3685.  Tests of soil mobility using TLC indicated avilamycin would be immobile or of low mobility in soils.  However, the major metabolite, Metabolite A, was mobile and very mobile in medium and fine textured soils respectively but only showed low mobility in a coarse textured soil.  In laboratory leaching studies, radio labelled aged avilamycin was found to leach with 84% of added radioactivity found in the leachate in one study.  In a further study the proportion of freshly applied radioactivity found in leachate ranged from 22 to 53%.  These results indicate avilamycin and, in particular, its metabolites have the potential to leach.

6.  Field dissipation

Studies were conducted using the application of manure from both chickens and pigs on diets containing avilamycin.  The pig manure containing radio labelled avilamycin residues was applied at a rate equivalent to 17.4 t.ha-1 of manure from pigs on a diet containing 40 ppm avilamycin.  After four weeks less than 50% of the applied radioactivity remained.  In a similar experiment, chicken manure was applied at a rate equivalent to 15.4 t.ha-1 of manure from chickens eating a diet containing 30 ppm avilamycin.  Residues again dissipated quickly with less than 50% of the applied radioactivity remaining after four weeks.

7.  Accumulation and bioaccumulation

No data were available but accumulation in soils and bioaccumulation are not expected with normal use.

Environmental Effects

1.  Avian toxicity

Tests were conducted on Bobwhite quail (Colinius virginianus) and Mallard duck (Anas platyrhynchos).  In a fourteen day oral toxicity study with Bobwhite quail, doses up to 372.5 mg.kg bodyweight-1 resulted in no deaths and only one bird showed some short term ill effects.  Consequently based on this experiment the LD50 would be > 372.5 mg.kg bodyweight-1, the NOEC would be 186.3 mg.kg bodyweight-1 and avilamycin would be

considered, at worst, moderately toxic.  In five day dietary tests with both species no deaths or ill effects were observed with avilamycin concentrations of up to 745 ppm in the feed.  Consequently the dietary LD50 would be > 745 ppm, the NOEC would be 745 ppm and avilamycin would be considered, at worst, moderately toxic to both species.

2.  Aquatic species

Tests were conducted on two fish species and an aquatic invertebrate.  In a static test with Rainbow trout (Oncorhynchus mykiss) no deaths or signs of sublethal toxicity were observed at the concentrations tested and the NOEC was 47.8 mg.L-1.  In a similar test with Bluegill sunfish (Lepomis macrochirus) no deaths or sublethal effects were observed at the concentrations tested and the NOEC was 35.4 mg.L-1.  In a static test with Daphnia magna  no deaths or sublethal effects were observed and the NOEC was 23.8 mg.L-1.  Avilamycin would be considered, at worst, slightly toxic to fish and daphnia.

3.  Terrestrial invertebrates

Earthworms were exposed to avilamycin concentrations of 10 and 100 mg.kg-1 in a sandy loam soil with dried rabbit faeces added as a food supply.  No signs of toxicity were observed and the bodyweights of the worms in the treated soil did not differ from those in control treatments.  The NOEC was therefore concluded to be 100 mg.kg-1.  Tests on the nitrification process in soil showed that the application of 25 t.ha-1 of pig manure, from pigs eating a diet containing 80 ppm avilamycin, containing avilamycin appeared to have short term impacts with ammonium concentrations being slightly higher and nitrate concentrations slightly lower.  However, such effects are expected to be short term only.  Tests conducted to examine the effects of avilamycin on the microorganisms responsible for the degradation of sewage sludge and anaerobic digestion of pig and poultry manure showed minimal effects with avilamycin concentrations up to 102 mg.kg-1.

4.  Mammals

Summaries of a range of studies were provided in the submission overview.  No ill effects were observed in rats fed a diet containing 10% avilamycin for two weeks.  A six month test on dogs indicated a NOEL of > 178 mg.kg bodyweight-1.  Risk to mammals would appear minimal.

5.  Plants

Laboratory germination tests on pinto bean, soybean, maize, wheat, sweet pepper and tomato showed no effect from avilamycin at rates equivalent to the application of up to 1.35 kg.ha-1 of avilamycin.  A further study measured the effect on the growth of maize, wheat , soybean and tomato from the application of chicken manure at 20 t.ha-1 from chickens eating a diet containing 20 mg.kg-1 of avilamycin.  The only effects observed were a slight reduction in the shoot height of tomatoes and a significant reduction in the biomass of tomatoes although the plants were morphologically normal.

Environmental Hazard

Environmental exposure from the proposed use of avilamycin is expected via use of contaminated chicken manure as fertiliser. Concentrations of avilamycin and its metabolites in soil from this use are expected to be low.  A maximum estimated soil concentration of 0.57 mg.kg-1 is expected from the use of chicken manure. Based on the data provided this concentration should have no long term effects on earthworms, soil microorganisms and most plants although data from one test indicates tomatoes may experience some stunting. In addition studies have indicated a half-life of approximately 3-4 weeks for avilamycin in soil.  There appears to be some potential for avilamycin and, more likely, its metabolites to leach when applied to soil in contaminated manure.

The potential exposure of birds and terrestrial mammals to the active is considered to be very low.  The expected environmental concentration of avilamycin in either soil or run-off waters is significantly lower than the concentrations shown to be toxic to earthworms, fish and daphnia tested although the short term effect on soil microorganisms of manure containing avilamycin and its metabolites is unclear.

Avilamycin would be expected to have a low potential to bioaccumulate based on size and partition coefficient.  The active is also readily hydrolysed and degraded in the environment. Accumulation in soils is not expected under normal use.

Conclusions

The use of avilamycin sodium is not expected to have a significant impact on the environment when used as directed by the manufacturer.  However, the potential exists for some adverse effects where contaminated manure is applied, particularly at high rates, to some soils through leaching to groundwater.  While this appears unlikely the applicant is expected to keep the National Registration Authority and Environment Australia informed if any such incidents occur in Australia.

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Efficacy and Safety Assessment

Overseas studies

Results from trials conducted overseas were provided to support registration. The trials were done using avilamycin in comparison with untreated controls and with other growth promotants. Some of the trials have also incorporated coccidiostats. They are summarised below:

European studies (twelve trials in six European countries): The effects of feeding different levels of avilamycin on the growth performance of commercial broilers compared with untreated controls were examined. The results demonstrated improvements in average final liveweights and feed conversion ratios compared to untreated controls, the optimum improvement being at 15ppm avilamycin. At this level, feed consumption also increased by 0.88% compared with untreated controls.

US Studies: Treatments with 2.5, 5 and 10 ppm avilamycin were compared to a control treatment. Monensin was included at 10 ppm for all treatments. Results indicated that avilamycin treatments improved weight gain and feed efficiency compared to controls at all levels.

South African studies: Four trials were carried out in South Africa using avilamycin (5ppm) in comparison with treatments using Roxarsone (50ppm), Bambermycin 5 (3ppm), Olaquindox (15ppm) and Virginiamycin 10 (5ppm). Data collected at 42 days indicated that avilamycin treatment was comparable to the other growth promotant used in terms of feed conversion and weight gain improvements and was significantly better compared to untreated controls.

Japan studies: Avilamycin was included in both starter and finisher diets fed to broiler chickens at levels of 0, 2.5, 5 and 10ppm. A comparative group was fed 5.0ppm virginiamycin. The results indicated that percent mortality was slightly higher in the avilamycin treated group than the group treated with virginiamycin but both treated groups had significantly lowered mortality compared to the untreated group. There was little difference in feed consumption between the treated groups but feed to gain ratio of the group treated with avilamycin at 5 and 10 ppm was better than the group treated with virginiamycin. 

Others:  Trials were also carried out in Taiwan, Korea and the Philippines. Avilamycin improved weight gain and feed conversion efficiency when compared to non-medicated controls.

Studies in Australia

The results of a single study was initially submitted in support of the application. However, as the study was undertaken at a research station, further confirmatory trials under Australian field conditions were recommended by the reviewer. After some negotiation, an additional study on a broiler operation was undertaken. Avoparcin was used as a comparison in this study.

The parameters measured were feed conversion efficiency, feed conversion efficiency corrected to 2.1kg live weight, performance index factor between groups, days to closeout and  days to closeout corrected to 2.1 kg live weight. Mortality was also compared between the groups. The results demonstrated that avilamycin is as good as avoparcin in improving performance indices as specified above for broiler production and will not unduly harm broiler chickens when used as recommended.

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Labelling Requirements

READ SAFETY DIRECTIONS BEFORE OPENING OR USING

FOR ANIMAL TREATMENT ONLY

Labelling Requirements

ACTIVE CONSTITUENT: 100g/kg AVILAMYCIN

For increased rate of weight gain and improved feed efficiency in broiler chickens.

                        25 kg NET

DIRECTIONS FOR USE:

DO NOT USE in laying birds where eggs or egg products are to be used for human consumption or processing.

FOR USE IN BROILER CHICKEN FEEDS ONLY

Mixing and feeding directions:

Surmax 100 Premix must be thoroughly mixed in feeds before use and should be thoroughly mixed with a small quantity of feed ingredient (20 to 50kg) before it is incorporated into the bulk of the feed to be prepared.

BROILER CHICKENS: Thoroughly mix 25 to 150 grams of SURMAX 100 into 1000kg of feed to provide 2.5 to 15 grams avilamycin per ton or 2.5 to 15 ppm.  Feed continuously as the only ration.

WITHHOLDING PERIOD

MEAT: NIL       

EGGS: DO NOT USE in laying birds where eggs or egg products are to be used for human consumption or processing.

An Export Slaughter Interval may apply to this product.  Contact Elanco Animal Health before using this product in poultry destined for the export market.

SAFETY DIRECTIONS: May irritate the eyes and skin.  Avoid contact with the eyes and skin.  When opening the container and mixing into stock feed, wear cotton overalls

buttoned to the neck and wrist (or equivalent clothing), elbow-length PVC gloves, and a disposable dust mask.  Wash hands after use.

FIRST AID: If poisoning occurs, contact a doctor or Poisons Information Centre.  Phone 13 1126.

DISPOSAL OF BAGS: Shake and empty contents into medicated feed.  Do not dispose of undiluted chemicals on site.  Puncture or shred and bury empty bags in a local authority landfill.  If not available bury the bag below 500 mm in a disposal pit specifically marked and set up for this purpose clear of waterways, vegetation and roots.  Empty bags and product should not be burnt.


APVMA Approval No.   49376/



            USE NO HOOKS     
 

Manufactured in U.K. for:

ELANCO ANIMAL HEALTH 
A DIVISION OF ELI LILLY AUSTRALIA PTY. LIMITED 
A.C.N. 000 233 992 
112 WHARF ROAD, WEST RYDE, N.S.W. 2114 
TEL: (02) 9325 4455 OR 1800 226 324

Member Avcare (logo)

Store below 30oC (Room Temperature) in a dry place

Expiry date:            

Batch number:

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Glossary

Active constituent The substance that is primarily responsible for the effect produced by a chemical product.
Acute Having rapid onset and of short duration.
Carcinogenicity The ability to cause cancer.
Chronic Of long duration.
Codex MRL Internationally published standard maximum residue limit.
Efficacy Production of the desired effect.
Formulation A combination of both active and inactive constituents to form the end use product.
Genotoxicity The ability to damage genetic material
Half-life The time required for half the amount of a drug introduced into an animal to be metabolised or excreted.
Hydrolysis Reaction with water
Koc The Koc will give the degree with which the chemical is expected to adsorb to soil in relation to organic matter.
Leaching Removal of a compound by use of a solvent.
Metabolism The conversion of food into energy
Metabolite A product of metabolic change
Microbial Pertaining to the actions of microscopic forms of life

 

Radio labelled A molecule that has had an atom replaced by a radioactive version of that atom to allow the tracing of the movement of that molecule during scientific experiments
Toxicokinetics The study of the movement of toxins through the body.
Toxicology The study of the nature and effects of poisons.

References

Australian Pesticides and Veterinary Medicines Authority 1996,  MRL Standard: Maximum Residue Limits in Food and Animal Feedstuffs, APVMA, Canberra.

Australian Pesticides and Veterinary Medicines Authority 1997, Vet Labelling Code-Code of Practice for Labelling Agricultural Chemical Products, APVMA, Canberra.

Australian Pesticides and Veterinary Medicines Authority 1996, Vet Manual, The Requirements Manual for Veterinary Chemicals,  APVMA, Canberra.

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