Tolylfluanid in the product Euparen Multi 500 WG Fungicide

Contents

List of abbreviations and acronyms

ac

active constituent

ADI acceptable daily intake (for humans)
AHMAC Australian Health Ministers Advisory Council
ai active ingredient
BBA Biologische Bundesanalstalt fűr Land- und Forstwirtschaft
bw bodyweight
d Day
DAT Days after treatment
DT50 Time taken for 50% of the concentration to dissipate
EbC50 concentration at which the biomass of 50% of the test population is impacted
EC50 concentration at which 50% of the test population are immobilised
EEC Estimated environmental concentration
ErC50 concentration at which the rate of growth of 50% of the test population is impacted
EUP end use product
F original parent generation
GAP Good agricultural practice
h Hour
HPLC high pressure liquid chromatography or high performance liquid chromatography
id Intradermal
ip Intraperitoneal
IPM Integrated pest management
im Intramuscular
iv Intravenous
in vitro outside the living body and in an artificial environment
in vivo inside the living body of a plant or animal
kg Kilogram
KOC Organic carbon partitioning coefficient
L Litre
LC50 concentration that kills 50% of the test population of organisms
LD50 dosage of chemical that kills 50% of the test population of organisms
LOEC Lowest observable effect concentration
mg Milligram
mL Millilitre
MRL maximum residue limit
MSDS Material Safety Data Sheet
NDPSC National Drugs and Poisons Schedule Committee
ng Nanogram
NHMRC National Health and Medical Research Council
NOEC/NOEL no observable effect concentration/level
po Oral
ppb parts per billion
PPE Personal Protective Equipment
ppm parts per million
Q-value Quotient-value
s Second
sc Subcutaneous
SC suspension concentrate
SUSDP Standard for the Uniform Scheduling of Drugs and Poisons
T-Value a value used to determine the First Aid Instructions for chemical products that contain two or more poisons
TGAC technical grade active constituent
vmd Volume mean diameter
WG water dispersible granule
WHP withholding period

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Summary

Tolylfluanid is a polyvalent sulfamide fungicide with a protective mode of action.  Tolylfluanid is closely related to dichlofluanid, the active ingredient in registered fungicide Euparen.  The activity of tolylfluanid is at least equivalent to, and in most cases better than dichlorfluanid.  The biochemical mode of action has not been fully elucidated although it is assumed that tolylfluanid, like dichlofluanid, interferes with several enzymes by reaction with -SH bonds.

Bayer Australia Limited has applied for registration of the product Euparen Multi 500 WG Fungicide (Euparen Multi), a water dispersible granule formulation containing 500g/kg tolylfluanid.  The product will initially be marketed for the control of black spot and grey mould and suppression of powdery mildew on strawberries in all States.

This publication provides a summary of the data reviewed and an outline of the regulatory considerations for the proposed registration of Euparen Multi 500 WG Fungicide. Responses to this public release summary will be taken into account by the APVMA in deciding whether the product should be registered and in determining appropriate conditions of registration and product labeling

Written comments are invited and should be submitted by 4 July 2000 to the APVMA at the address shown in the Introduction.

Public Health Aspects

Toxicology

Following oral administration tolylfluanid is rapidly and extensively absorbed and quickly excreted, predominantly in the urine. Tolylfluanid has a low acute oral toxicity in rats but is moderately toxic to the guinea pig, rabbit and cat when formulated in an acetone/oil solvent. The acute dermal toxicity is low but the inhalational toxicity is moderate. The skin irritancy of tolylfluanid is slight, the eye irritancy is moderate to severe, and the compound is a skin sensitiser.

In chronic/carcinogenicity studies in dogs, rats and mice there was no evidence of carcinogenicity and although tolylfluanid was positive in two studies on its ability to damage genetic material in vitro, it was negative in 6 other studies and did not cause damage to genetic material when given to hamsters or mice. Four reproduction studies in rats at doses of up to 600 mg/kg bw/day demonstrated that at dose-levels of tolylfluanid that produced clear toxic effects in the parents, no adverse effects on reproduction were observed. Similarly, in two studies on the development of rat pups during pregnancy, the mothers were given doses of up to 1000 mg/kg bw/day of tolylfluanid during the period of foetal organ formation without any increase in malformations observed in the pups, although a reduction in placental and foetal weights was seen. A study in pregnant rabbits that were given up to 70 mg/kg bw/day revealed increased foetal death but no evidence of malformations.

Studies on the neurotoxicity of tolylfluanid in single and repeat dose studies found reversible behavioural and body temperature changes immediately following its acute administration in females, but that no long-lasting signs of neurotoxicity were produced.

Conclusion

Based on an assessment of the toxicology it was considered there should be no adverse effects on human health from the proposed use of tolylfluanid as a component of Euparen Multi 500 WG Fungicide.

Residues in Food and Trade Aspects

Data concerning residues in strawberries, metabolism in plants and animals, environmental fate and chemistry were considered as part of the residue evaluation of the application.

The metabolism studies showed that following oral administration to animals tolylfluanid was rapidly absorbed and excreted, mainly in the urine.

The plant metabolism studies support a residue definition of "tolylfluanid" as being appropriate. Such a definition is adequate for the purposes of monitoring Good Agricultural Practice.

Data from four Australian residue trials were presented. Tolylfluanid appears to be non-persistent and the number of applications does not significantly affect the residues observed at sampling. Overall the highest residue at the proposed withholding period (1 day) was 1.92 mg/kg. The Australian residue data submitted with the application support a MRL of 3 mg/kg and a withholding period of 1 day when Euparen Multi 500 WG Fungicide is used according to proposed Australian GAP.

No feed commodities in which tolylfluanid residues are expected are fed to animals in commercial situations. It is considered unlikely that detectable residues of tolylfluanid would occur in animals as a result of the use of Euparen Multi 500 WG Fungicide on strawberries and consequently no recommendations on animal feed commodity MRLs or animal commodity MRLs are being made at this time.

Due to the rapid breakdown and immobility in soil and rapid metabolism and excretion in animals, the use of tolylfluanid does not pose a significant risk of bioaccumulation in animals.

The theoretical maximum daily intake of tolylfluanid from the proposed use pattern is approximately 0.1% of the ADI of 0.1 mg/kg body wt/day.

Trade aspects

Although the quantities of strawberries exported are not insignificant they can be considered a minor export commodity in relation to Australia's overall export of horticultural commodities. The residue trials submitted with the application demonstrate that residues of tolylfluanid are unlikely to exceed the proposed Australian MRL when the product is used according to GAP. In addition, the proposed Australian MRL and residue definition are the same as those recommended by CODEX.  Under the GATT agreement an MRL in place under CODEX should be adopted by importing countries even when there is a local MRL lower than the CODEX MRL.  It is noted that some of the potential importers of Australian strawberries do not have national MRLs in place.  It should be the Australian exporter's responsibility to determine whether the CODEX MRL is acceptable in such situations.

Occupational Health and Safety Aspects

NOHSC has conducted a risk assessment on Euparen Multi 500 WG Fungicide for use on strawberries.  Euparen Multi 500 WG Fungicide can be safely used by workers when handled in accordance with the control measures indicated in this assessment.

Tolylfluanid is not currently listed in the NOHSC List of Designated Hazardous Substances.  Bayer Australia Limited has classified tolylfluanid as a hazardous substance according to NOHSC Approved Criteria for Classifying Hazardous Substances.  This classification is based on its acute inhalational toxicity, and irritant and sensitising effects.  Euparen Multi 500 WG Fungicide was also classified by Bayer Australia Limited as a hazardous substance based on its skin sensitising effects.

Euparen Multi 500 WG Fungicide will be imported fully formulated.  It is packaged in 400 g polybags.  Transport, storage and retail workers will handle the packaged product, and could only become contaminated in the event of a packaging breach.

There were no studies available on the acute oral, dermal, and inhalational toxicity of Euparen Multi 500 WG Fungicide.  The product is a moderate skin and slight eye irritant and causes skin sensitisation.

Euparen Multi 500 WG Fungicide is to be applied to strawberries at the rate of 200-1333 g/100 L water.  The maximum application rate is 2 kg/ha.  The water volumes will vary between 150 L/ha for low volume application and 2000 L/ha for high volume application.  Spraying is to commence from flowering until the end of harvest at 7 to 10 day intervals.  A one-day withholding period for harvesting strawberries is proposed.

No worker exposure data were available for tolylfluanid or Euparen Multi 500 WG Fungicide.  The occupational health and safety risk assessment was based on estimates obtained from exposure models.

Instructions and Safety Directions are provided on the product label to minimise exposure to the product.  Mixer/loaders and applicators need to wear cotton overalls buttoned to the neck and wrist and a washable hat and elbow length PVC gloves when opening the container, preparing spray and using the prepared spray.  The following re-entry statement should appear on the product label and Material Safety Data Sheet: 'Do not allow entry into treated areas until the spray has dried.  When prior entry is necessary, wear cotton overalls buttoned to the neck and wrist and a washable hat and chemical resistant gloves'.  Additional information is available on the product Material Safety Data Sheet.

Environmental Aspects

The environmental hazard of tolylfluanid will be highest to organisms living in the vicinity where it will be applied.  Residues would be expected on strawberry plant surfaces including the interrow plant cover and soil.  Surface water, uncultivated land and nearby non-target plants (e.g. trees and grasses) may be contaminated through overspray, spray drift and/or run-off.

Tolylfluanid hydrolyses rapidly to dimethylaminosulfotoluidide (DMST) at alkaline pH with a half-life of <<10 min.  The hydrolysis half-life increases progressively to 11.7 d as the pH decreases to 4.  Photolysis is not likely to be a major route of transformation while metabolism in aerobic soil is initially rapid with DT50 values of <1-12 d.  However, a significant lag phase is observed as small but detectable amounts (up to 7.7% of that originally applied) were found up to 99 DAT.  The metabolite DMST also follows a rapid initial degradation with DT50 of 1.9-7.4 d followed by a lag phase. 

Degradation of tolylfluanid in two natural sediment/water systems was rapid with undetectable concentrations by 14 DAT.  However, DMST partitioned preferentially to the water phase with half-lives in the whole system of 42.1-76.4 d.  Tolylfluanid is expected to be slightly mobile in soil but no parent or DMST were detected in leachate in several studies.  After 40 d aging of parent compound in soil, 4.9% of the originally applied radioactivity (undetectable parent and 0.2% DMST) leached through 27 cm of soil while 75.1% remained bound in the top 9 cm of soil (68.5% was unextractable).  Based on poorly described field dissipation studies, the half-life of tolylfluanid in one soil was 4.5 d with both parent and DMST nondetectable at 59 DAT.  Other soils had DT50 values of 8.2-14 d with nondetectable concentrations by 59-60 DAT.  In the best case aerobic soil DT50 of <1 d, Environment Australia modeled there would be no accumulation of tolylfluanid in soil.  However, a worst case DT50 of 12 d would result in peak soil concentrations of about 2.5 mg a.i./kg soil after 10 weekly applications. 

In water, the hydrolysis half-life would result in no accumulation from weekly sprays but the concentration of the metabolite DMST could continue to increase in the unlikely worst case direct overspray for 25 consecutive weeks and half-life of 76.4 d.

Tolylfluanid was practically nontoxic to Japanese quail in a 5-d dietary test which was supported by an unacceptable single dose acute oral study.  The single oral dose LD50 to bobwhite quail was > 2,000 mg a.i./kg bodyweight which was practically nontoxic.  The NOEC and LOEC to bobwhite quail in a one generation dietary toxicity study were 888 and 2,800 mg a.i./kg food, respectively, based on high mortality. 

Technical and formulated (expected to behave similarly to the proposed formulation) tolylfluanid were very highly toxic to juvenile rainbow trout and golden orfe in acute 96-h exposures.  The DMST metabolite was apparently slightly toxic but this result must be treated with extreme caution as it was a preliminary test.  In chronic 21-d exposures, technical tolylfluanid was highly toxic to juvenile rainbow trout even though parent compound had hydrolysed completely to DMST by 21 DAT.  When formulated, tolylfluanid was very highly toxic to trout after 21 d while DMST was only slightly toxic.  Technical and formulated tolylfluanid were highly and very highly toxic to daphnids in standard 48-h experiments.  However, only moderate to high toxicity was observed in two chronic 21-d exposures.

DMST was only slightly and very slightly toxic to daphnids in 48-h and 21-d exposures.  Moderate to slight toxicity was observed when technical and formulated tolylfluanid were tested with algae for 72 h.  DMST was slightly toxic in a 96-h test.

For earthworms, tolylfluanid alone and in a 4:1 mixture with tebuconazole were only very slightly toxic in 14-d exposures.  Ten summaries on testing with honey bees were submitted, but were lacking study details and not used; a supplementary study was acceptable indicating relative nontoxicity after 48-h in oral and contact exposures.  Formulated tolylfluanid at 2.58 kg a.i./ha was harmful to predatory mites but harmless to predatory heteropteran bugs at up to 2.42 kg a.i./ha. 

Laboratory tests with a parasitic wasp showed a harmful effect at 200 g a.i./ha (5X lower than the proposed rate) but a 1.12 kg a.i./ha treatment on apple trees had no significant effect on the parasitisation efficiency of a different wasp.  Formulated tolylfluanid was harmless to staphylinid, carabid and ladybird beetles at up to 2.64 kg a.i./ha while the green lacewing was unaffected by low application rates of 139-176 g a.i./ha. 

Two loamy sands treated at 1.3 and 13.0 mg a.i./kg dw soil (with or without lucerne amendment) showed no lasting adverse effects on microbial carbon mineralisation by 28 DAT.  When these soils were amended with ammonium sulphate and glucose, an adverse but tolerable reduction in nitrification was evident by 56 DAT.  Ammonification processes were not measured.

There is no expected hazard to bobwhite quail from short term exposure to tolylfluanid residues in their food resulting from the proposed application.  Even with the worst-case accumulation in soil from repeated spraying at 7 d intervals, the NOEC from chronic dietary studies is 2.8X higher than the EEC.  Coupled with the birds' ability to leave the treated area and feed on noncontaminated items, the hazard to quail is expected to be acceptable.  As toxicity studies on mallard ducks were not submitted, the hazard cannot be assessed. 

Earthworms are expected to be adequately protected from both acute and chronic toxicity as are honey bees, predatory heteropteran bugs, the parasitic wasp Trichogramma dendrolimi and staphylinid, carabid and ladybird beetles.  However, the hazard to the predator Phytoseiulus persimillios (used in IPM against the two spotted mite), wasps T. cacoeciae and Aphidius rhopalosiphi, green lacewings and predatory mites at the proposed application rate is unclear. 

Growers intending to use Euparen Multi 500 WG Fungicide in IPM programs (e.g. release of predatory mites) should be made aware of the potential hazard to these organisms.  Carbon mineralisation processes are not expected to be adversely affected even in the worst case soil accumulation, however, an adverse but tolerable reduction in nitrification may occur and the hazard to ammonification processes could not be assessed.

Water bodies adjacent to strawberry plots may be contaminated by tolylfluanid through direct overspray.  Contamination outside the target area is likely to result from spray drift, particularly where sprayers producing small (vmd < 100 m) droplets are used, and from run-off of material sorbed to soil and organic matter particles.  In the worst-case scenario of a direct overspray of a 15 cm deep body of water with Euparen Multi 500 WG Fungicide, the expected environmental concentration of 0.67 mg a.i./L would result in Q-Values of 14 and 19 for fish and daphnids, indicating unacceptable risk for both.  The Q-Value of 0.21 for algae indicates a risk that may be mitigated by restricted use but the hazard for macrophytes cannot be assessed due to lack of data. 

The rapid hydrolysis of tolylfluanid should not result in accumulation of parent even with weekly applications, although the DMST metabolite may accumulate up to 4.5 mg/L in the best case and continually increase in the worst case.  Chronic toxicity data only for rainbow trout were submitted which indicate no risk (EEC<NOEC) in the best case.  As the worst case EEC continues to increase, the hazard appears unacceptable and requires clarification of the number of repeated applications and application interval to better define the EEC.

In the more likely exposure of water bodies by spray drift or run-off, a 10% drift would still result in unacceptable risk for fish and invertebrates, but acceptable for algae.  A further refinement of drift (according to computer modelling) from a low boom ground sprayer with a buffer zone of 9.5 m would give a drift of 0.54% necessary to reduce the risk to fish and invertebrates to an acceptable level.  Therefore Environment Australia suggested, and the company agreed to, a buffer zone of 10 m downwind of all strawberry fields to be treated with Euparen Multi 500 WG Fungicide.  New information from the company suggests that applications are likely to be made approximately every 2 weeks in rotation with other fungicides.  Therefore the worst case half-life of DMST of 3.8 mg/L is less than the NOEC for trout of 9.2 mg/L and the hazard is acceptable.  As DMST partitions preferentially to water, contamination of water bodies by surface run-off may be expected but this hazard would be lower than above which is based on the worst case of repeated oversprays.

Efficacy and Crop Safety Aspects

Data presented by Bayer Australia Ltd supported claims that Euparen Multi 500 WG fungicide controls black spot and grey mould and suppresses powdery mildew on strawberries.  The active ingredient is tolylfluanid a polyvalent fungicide with a protective mode of action.  Tolylfluanid is closely related to dichlorfluanid, the active ingredient in registered fungicide Euparen.  The activity of tolylfluanid is at least equivalent to, and in most cases better than dichlorfluanid.

Scientifically sound experiments were used to provide data.  Adequate controls, replicates and treatments were used in all experiments.

Disease pressure for the four different experiments varied but was adequate to support efficacy work.  Disease pressure is dependent on weather conditions which varied but sufficient disease development occurred to allow measurement of fungicide efficacy.  Euparen Multi 500 WG fungicide provided at least equivalent control of black spot and grey mould in all experiments when compared with controls.  For example, Euparen Multi 500 WG fungicide decreased the proportion of fruit affected by black spot and grey mould from 51% to <4% and 24% to 5% respectively.  The fungicide also suppressed the development of powdery mildew.  For example, Powdery mildew levels were decreased from 21% to <2%.  Experiments for efficacy were conducted in Queensland and Victoria.

All data was statistically analysed using standard techniques and was correctly interpreted.

Crop safety

Three experiments were done, in Western Australia and Queensland, to determine the phytotoxicity of Euparen Multi 500 WG fungicide.  Results from these experiments and the four efficacy experiments reported no observations of phytotoxicity.  Even at extremely high rates of active ingredient only slight burning of leaves was observed under warm conditions.

Introduction

This publication provides a summary of the data reviewed and an outline of the regulatory considerations for the proposed registration of Euparen Multi 500 WG Fungicide, which contains the new active constituent tolylfluanid.

Responses to this public release summary will be considered prior to registration of the product. They will be taken into account by the APVMA in deciding whether the product should be registered and in determining appropriate conditions of registration and product labeling

Written comments are invited and should be submitted by 4 July 2000, addressed  to:

Colin Byrnes

AgVet Chemicals Evaluation Section

National Registration Authority

PO Box E240

KINGSTON ACT 2604

Phone 02 6722 4850

Fax   02 6272 3218 

Applicant:

Bayer Australia Limited

Product details

Euparen Multi 500  WG Fungicide is a water dispersible granule formulation containing 500g/kg tolylfluanid.  Tolylfluanid is a polyvalent sulfamide fungicide with a protective mode of action.  Tolylfluanid is closely related to dichlofluanid, the active ingredient in the registered product Euparen Fungicide Spray.  The activity of tolylfluanid is at least equivalent to, and in most cases better than dichlofluanid.  The biochemical mode of action has not been fully elucidated although it is assumed that tolylfluanid, like dichlofluanid, interferes with several enzymes by reaction with -SH bonds.

The active constituent is manufactured by Bayer AG in Germany and the product will be formulated by that company, also in Germany.

The product is proposed to be registered for control of black spot and grey mould and suppression of powdery mildew on strawberries in all States.

Water dispersible granule or wettable powder concentrate formulations of tolylfluanid are registered in 24 countries under a variety of tradenames.  The products are registered for use on strawberries in 17 of those countries.

Chemistry and Manufacture

The product proposed for registration in Australia is a water dispersible granule formulation under the trade name Euparen Multi 500 WG Fungicide.

The formulation storage stability and the physical and chemical properties of the formulated product and active constituent have been evaluated by the APVMA and are considered acceptable.

The source of Technical Grade Active Constituent to be used in the product has been approved by the APVMA (Approval No 51029).

Active constituent

The chemical active constituent in Euparen Multi is tolylfluanid which has the following properties:

Common name (ISO): tolylfluanid
Chemical name:

N-(dichlorofluoromethylthio)-N',N'-dimethyl-N-p-tolylsulfamide (IUPAC)

CAS Registry Number: 731-27-1
Empirical formula:   C10H13Cl2FN2O2S2
Molecular weight:  347.3
Physical form: Crystal solid
Melting point for E/Z mixture (1:1): 93°C
Colour: White
Odour:   Aromatic
Octanol/water partition coefficient (Kow): 3.90 at 20°C
Vapour pressure at 25C: 4x10-4 Pa (extrapolated)
Structural formula:

Structural formula

Formulated product

Product name:   EUPAREN MULTI 500 WG FUNGICIDE

Active content:  500g/kg tolylfluanid

Formulation type: Water dispersible granule

Density: 0.65g/mL

Toxicological Assessment

EVALUATION OF TOXICITY

The toxicological database for tolylfluanid which consists primarily of toxicity tests conducted using animals, is quite extensive. In interpreting the data, it should be noted that toxicity tests generally use doses that are high compared with 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 the 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

Tolylfluanid has a low acute oral toxicity in rats (LD50 > 5000 mg/kg) when formulated as a water based suspension but low to moderate toxicity (LD50 > 1000 mg/kg) when formulated as a solution in an acetone/oil mixture. For the acetone/oil solvent, oral LD50 values in other species were > 1000 mg/kg in mice and 250 to 500 mg/kg in guinea pigs. The acute dermal toxicity of tolylfluanid in rats was also low with an LD50 > 5000 mg/kg for the aqueous suspension and > 400 mg/kg for an acetone/oil formulation, in both cases there were no deaths and no visible signs of toxicity. The inhalation LC50 was 265 mg/m3 in rats following 4 h exposure, indicating a moderate toxicity rating for tolylfluanid by this route. Tolylfluanid produces a slowly reversible moderate to severe skin and eye irritation in rabbits and is a skin sensitiser in guinea pigs.

Euparen Multi 500 WG Fungicide is a moderate skin irritant and slight eye irritant in rabbits and a skin sensitiser in guinea pigs.

Short-Term Studies

Applications of tolylfluanid to the skin of rabbits at up to 500 mg/kg bw/day for 14 days in 2 studies caused no observable systemic effects. In one study slight surface skin effects were noted which included erythema and scaly skin changes, an increase in the skin thickness and signs of inflammation which appeared to reverse within 2 weeks of the discontinuation of tolylfluanid treatment.

In a study in rats treated with tolylfluanid at up to 225 mg/kg bw/day, given in their food, for 3 months the only effects of treatment related to lower body weight gains.

In rats fed food containing tolylfluanid at up to 9000 mg/kg of food, for 13 weeks (approximately equivalent to a dose of 450 mg/kg bw/day), the effects were limited to a slight disturbance of thyroid function and a slight disturbance in the level of liver enzymes in the blood. A slight reduction in weight gains and food efficiency were observed in groups treated at the highest level and water intake was increased in males at 9000 mg/kg of food, and in females at 1650 and 9000 mg/kg of food. In males at the highest treatment level a slight increase in liver weights was observed at the end of the 13-week treatment period. All treatment related effects either resolved completely over the 4 weeks following the treatment period or faded in intensity and approached the values observed for untreated animals.

In dogs fed for 13 weeks on food containing 0, 330, 1000 or 3000 mg/kg of tolylfluanid, treatment related effects were limited to those treated at 3000 mg/kg of food. These animals had an unkempt and emaciated appearance with lower activity levels, they ate less and gained less weight, had a progressive increase in alkaline phosphatase blood levels which appeared to reflect an absence of the normal age-related reduction in ALP values, and the liver weights were increased.

Long-Term Studies

Long term studies have been conducted in mice, rats and dogs at doses of up to approximately 750, 400 and 62.5 mg/kg bw/day respectively. No evidence of carcinogenicity was observed. In mice and rats the animals ate less and gained less weight at the highest doses used. In all three species evidence of liver and / or kidney damage was found which included; increased alkaline phosphatase levels (mice and dogs), increased liver and kidney weights (rats), increased liver enzyme levels in the blood of dogs (alanine amino transferase), and kidney function abnormalities (increases in blood urea and creatinine levels, urinary glucose levels - dogs). No structural changes were observed in the liver or kidneys of mice or rats but in dogs microscopic structural changes in the kidney were found which consisted of; dilatation, epithelial flattening and desquamation. In rats a hardening of the skull bones in male and female rats and a lengthening of the front teeth (incisors) in the males of the highest dose group were seen together with bone thickening on the internal surface of the skull and on the sternebrae. The NOEL from the dog study, 12.5 mg/kg bw/day, was the lowest of all studies evaluated and therefore sets the overall NOEL for tolylfluanid.

Reproduction and Developmental Studies

In two studies in rats to examine the effects of tolylfluanid on the development of the rat foetus the mothers were given oral doses of up to 1000 mg/kg bw/day during the period of foetal organ formation. No evidence of malformation was observed

Similarly in a rabbit study where the mothers were given tolylfluanid at oral doses of up to 70 mg/kg bw/day during the period of foetal organ formation there was again no evidence of malformation. Foetal loss increased at the highest dose however, but no effects were observed at doses of 25 mg/kg bw/day or less.

Genotoxicity

A total of 8 in vitro and 8 in vivo genotoxicity studies were carried out using tolylfluanid.

In 6 of the 8 in vitro studies (including studies on reverse mutations in S. typhimurium and Saccharomyces cerevisiae strains, enhancement of forward mutations in Chinese hamster ovary cells (HGPRT locus), and induction of DNA repair in primary cultures of rat hepatocytes) tolylfluanid showed no evidence of genotoxic activity. In the remaining 2 studies (mouse lymphoma TK +/- forward mutation assay and chromosome aberrations in human lymphocytes) positive findings for genotoxic activity were obtained. In both of these tests the positive results were found in both the absence and in the presence of metabolic activation but required the use of tolylfluanid concentrations which were toxic to the target cells.

To test whether the chromosome damage seen in vitro was likely to occur in a living animal four of the eight in vivo tests assessed, looked at this end point (chromosomal aberrations in Chinese hamster bone marrow cells or in Chinese hamster and rat spermatogonia) but found no evidence of genotoxicity. Tolylfluanid's ability to induce genotoxicity was also assessed in a mouse coat-spot test, a sister chromatid exchange study in mouse bone-marrow cells, a micronucleus test in mouse bone marrow cells and in a dominant lethal test in mice. Tolylfluanid gave no indications of genotoxic activity in any of the in vivo tests.

Neurotoxicity Studies

Other Studies

Acute toxicity studies with the major plant and animal metabolites of tolylfluanid demonstrated that these were similarly or less toxic than tolylfluanid itself. Studies on plant specific metabolites of tolylfluanid showed that none of these compounds produced genotoxic actions in Ames tests and the oral LD50 values for all four compounds in rats was > 5000 mg/kg (the highest dose used).

The acute oral toxicities of triadimefon (LD50 = 1045 mg/kg) and tolylfluanid (LD50 > 5000 mg/kg) were determined in rats, and then the LD50 values for mixtures of triadimefon (523 or 1045 mg/kg) plus tolylfluanid (2500 and 5000 mg/kg) were assessed. None of the combinations produced a greater than 50% death rate in the experimental groups. Thus, there was no synergism in the toxicity of the individual constituents of these mixtures.

Thiazolidin thiocarbonic acid (TTCA), an animal and plant metabolite of tolylfluanid, was tested for its ability to interact with thyroid enzymes. In these tests TTCA was found to have similar actions on the thyroid enzymes as that of some antithyroid drugs.

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 tolylfluanid be placed in Schedule 6 of the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP). There are provisions for appropriate warning statements and first-aid directions on the product label.

NOEL/ADI

The most sensitive species tested was the dog with a NOEL of 12.5 mg/kg bw/day in a 1 year dietary study. 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 0.1 mg/kg bw/day was established for tolylfluanid.

Metabolism and Toxicokinetics Assessment

Toxicokinetics and Metabolism

Tolylfluanid is rapidly and extensively absorbed following its oral administration and is then quickly excreted, predominantly in the urine but with a small proportion excreted in the bile and subsequently the faeces, resulting in > 90% of the dose excreted within 48 hours. Bioaccumulation of tolylfluanid or its metabolites was not observed. Low and moderate doses of tolylfluanid (2 or 20 mg/kg p.o.) and repeated low doses (2 mg/kg/day over 14 days) were handled in essentially the same manner. After a high dose (100 mg/kg p.o.) however, some evidence of limited absorption was observed. In the rat, tolylfluanid is rapidly metabolised, losing its fluorodichloromethylsulfenyl side-chain before under going further changes. Experiments in hens, goats and plants (apples, strawberries and grapes) suggested that similar routes of tolylfluanid metabolism were present in all three species.

Metabolism

Following oral administration to rats tolylfluanid was rapidly absorbed and excreted, mainly in the urine as 4-(dimethylaminosulfonylamino)benzoic acid.  After 48 hours the amount of tolylfluanid equivalents in the body (excluding GIT) was less than 0.05% of the administered dose (2 mg/kg bw) or less than 0.2% of the administered dose (100 mg/kg bw).  Elimination was nearly complete irrespective of dose level, sex or pretreatment.

A lactating goat study showed that tolylfluanid was readily eliminated in the urine with very little tissue retention.  The goat in the study was administered [phenyl-UL-14C]tolylfluanid at 10 mg/kg bw on 3 consecutive days and sacrificed 2 hours after the last dose.  Up to sacrifice the excretion totaled 59.7% of the totally administered dose with elimination in urine accounting for 49.4% of the total dose.  At sacrifice the total residue in edible tissues and organs was 2.8% of the total dose.  The major metabolite in all organs, tissues, milk and urine was found to be N-[4-(dimethylaminosulfonylamido)-benzoyl]-glycine which is the hippuric acid conjugate of N-4-(dimethylaminosulfonylamido)-benzoic acid (previously identified as a metabolite in rats).

In hens administered radiolabelled tolylfluanid orally in a single dose of 5 mg/kg bw or 3 consecutive daily doses of 5 mg/kg the excretion up until sacrifice amounted on average to 83.9% of the totally administered radioactivity.  Only 0.01% of the total dose was determined in the eggs.  At sacrifice the total residue in the edible tissues and organs was found to be 0.18% of the total dose. T he parent compound was not found in any of the biological materials tested.  In muscle eggs and liver the major metabolite was 4-(dimethylaminosulfonylamido)-benzoic acid.  In fat the major metabolite was dimethylaminosulfo-toluidid (DMST).

Metabolism studies in strawberries showed that the parent compound and DMST accounted for over 80% of the total residue. A significant portion of the tolylfluanid residue was found on the surface of the fruit. A further study in strawberries showed that the dichlorofluoromethylthio side chain of tolylfluanid is metabolised mainly to thiazolidine-2-thione-4-carboxylic acid (TTCA) and some carbon dioxide. Because the postulated intermediate thiophosgene is volatile it is difficult to draw conclusions about the likely presence of TTCA under field conditions.

Experiments with radiolabelled tolylfluanid in apples showed that unchanged parent compound accounted for up to 89% of the recovered radioactivity. DMST was identified as a minor metabolite along with two benzoic acid derivatives.

Metabolism of tolylfluanid in grapes was found to be more extensive than that previously identified in strawberries and apples. Unchanged parent compound and DMST were observed however the major metabolites were found to be glycoside conjugates of DMST.

Residues Assessment

Data concerning residues of tolylfluanid in strawberries, metabolism in plants and animals, environmental fate and chemistry were considered as part of the residue evaluation of the application.

Analytical methods

A validated analytical method was used to determine tolylfluanid residues in the Australian residue trials. The methodology involves solvent extraction of the fruit followed by clean-up on solid phase extraction cartridges and quantitation by gas chromatography. Recovery data was provided for determination of both tolylfluanid and DMST in apples, strawberries, raspberries, lettuce, tomatoes, grapes, grape juice and wine. The average tolylfluanid recovery in strawberry samples was of the order of 88-96% at fortification levels of 0.05-5.0 ppm. Under actual conditions of use the analytical Limit of Detection was set at 0.05 mg/kg. The methodology is considered adequate for determination of tolylfluanid and DMST residues in or on strawberries.

Storage stability

Storage stability studies of tolylfluanid and DMST residues in apples and strawberries were presented in the application. It was found that tolylfluanid and DMST residues were stable for up to 168 days in apples stored at -18°C and 811 days in strawberries stored at -20°C.

Residue definition

The plant metabolism studies support a residue definition of "tolylfluanid" as being appropriate. Such a definition is adequate for the purposes of monitoring Good Agricultural Practice.

Residue trials

Four Australian residue trials were presented. In most cases the trials were conducted at 1x and 2x the maximum application rate. The maximum application rate is expressed as either 1 kg ai/ha or 100 g ai/100L and trials were conducted at both of these rates. Plants were sprayed to the point of run-off in the trials conducted at the 100 g ai/100L application rate. The total number of applications varied between 4 and 7. The time between spray applications ranged from 6-15 days but was usually around 7 days. Samples of fruit were collected at 0-8 days after the final treatment and analysed to determine the tolylfluanid residue level. In all cases finite residues of tolylfluanid were observed in or on strawberries up to 8 days after the final treatment.

The results of the Australian residue trials conducted at the maximum application rate are summarised in the table below.

Trial No. Application rate No. of applications Tolylfluanid residue (mg/kg)
Days after last application
0 1 3 5 7
DJR 70/95 1 kg ai/ha 5 2.6 0.65 0.99 0.33 0.43
RAV 010/97 1 kg ai/ha 5 1.53 0.73 0.7 0.39 0.12
RTL 509/98 1 kg ai/ha 4 0.65 0.96 0.57 0.2 0.11 1
RTL 407/96 100 g ai/100L 7 1.07 1.92 0.65 - 0.36
RTL 509/98 100 g ai/100L 4 1.3 1.53 1.38 0.93 0.42 1

1. Sample was collected 8 days after final treatment rather than 7.

Tolylfluanid appears to be non-persistent and the number of applications does not significantly affect the residues observed at sampling.  Overall the highest residue at the proposed withholding period (1 day) was 1.92 mg/kg.  The Australian residue data submitted with the application support a MRL of 3 mg/kg and a withholding period of 1 day when Euparen Multi 500 WG Fungicide is used according to proposed Australian GAP.

Processing studies

A British study investigating the fate of tolylfluanid and DMST residues after washing, jam making and preserve making was submitted with the application.  Tolylfluanid residues in or on strawberry fruit were found to reduced by approximately 50% by washing the fruit in water. Both tolylfluanid and DMST residues were found to be depleted rather than concentrated during processing of strawberries.

Animal feed commodity MRLs and animal commodity MRLs

No feed commodities in which tolylfluanid residues are expected are fed to animals in commercial situations.  It is considered unlikely that detectable residues of tolylfluanid would occur in animals as a result of the use of Euparen Multi 500 WG Fungicide on strawberries and consequently no recommendations on animal feed commodity MRLs or animal commodity MRLs are being made at this time.

Estimated dietary intakes

The theoretical maximum daily intake of tolylfluanid from the proposed use pattern is approximately 0.1% of the ADI of 0.1 mg/kg body wt/day.

Bioaccumulation potential

The log octanol/water partition coefficient (log Pow) of tolylfluanid was found to be 3.9. The FAO manual# designates compounds as fat soluble if they have log Pow values greater than 4. Compounds with log Pow less than 3 are not designated fat soluble. A log Pow value of 3.9 indicates that tolylfluanid is on the borderline of the fat soluble designation. In the metabolism study of tolylfluanid in a lactating goat no parent compound was observed in any tissue. The major residue observed in the fat was DMST although only 2.8% of the total dose remained in the edible organs and tissues at sacrifice. Metabolite concentrations were highest in the kidney and liver rather than body fat. In general tolylfluanid was extensively metabolised and excreted. DMST is considerably more hydrophilic (log Pow=1.6) than tolylfluanid so excretion is enhanced following hydrolysis.

Due to the rapid breakdown and immobility in soil and rapid metabolism and excretion in animals, the use of tolylfluanid does not pose a significant risk of bioaccumulation in animals. In the current application food producing animals are unlikely to be exposed to tolylfluanid as strawberries are not used commercially as a stock feed commodity.

Recommended amendments to the MRL Standard:

Table 1

Compound Food MRL (mg/kg)
ADD:    
Tolylfluanid FB 0275   Strawberry 3
Table 3
Compound Residue
ADD:  
Tolylfluanid Tolylfluanid

The MRL recommendations indicated above will be conveyed to the Australia and New Zealand Food Authority (ANZFA) for consideration for incorporation into Standard A14 of the Food Standards Code and consequent adoption into the State/Territory food legislation.

Withholding periods:

The following withholding period statement is recommended in conjunction with the above MRL:

STRAWBERRIES: DO NOT HARVEST FOR 1 DAY AFTER APPLICATION

Assessment of Overseas Trade Aspects of Residues in Food

Overseas registration status

The overseas registration status (as at 30th January 2000) of tolylfluanid formulations is summarised in the table below:

Country Tradename AI content (g/kg) / formulation type Registered on Strawberries
Belgium Euparen M 500 WP Yes
Belgium Euparen M WG 500 WG Yes
Brazil Euparen M 500 PM 500 WP No
Croatia Euparen Multi 500 WP Yes
Czech. Republic Euparen Multi 500 WP Yes
Hattrick 500 WP No
Demark Euparen Multi 500 WG No
Ecuador Euparen M 50 PM 500 WP No
El Salvador Euparen Multi 50 WP 500 WP Yes
Finland Euparen M 500 WG Yes
France Methyleuparene 500 WP No
Germany Euparen M WG 500 WG Yes
Great Britain Elvaron M 500 WG Yes
Guatemala Euparen Multi 50 WP 500 WP Yes
Ireland Elvaron WG 500 WG Yes
Kenya Euparen M 50 WP 500 WP No
Netherlands Eupareen-M 500 WP Yes
Euparen-Spuitkorrels 500 WG Yes
Nicaragua Euparen Multi 50 WP 500 WP Yes
Norway Euparen M 500 WG Yes
Peru Euparen M 50 PM 500 WP No
Poland Euparen Multi 50 WP 500 WP Yes
Slovakei Euparen Multi 500 WP Yes
Hattrick 500 WP No
South Korea Baycor+Euparen-M 27 FW 27 FW Yes
Euparen-M 50 WP 500 WP No
Spain Euparen M 50 PM 500 WP Yes
Sweden Euparen M 50 WG 500 WG Yes
Zambia Euparen Multi 50 WG 500 WG No

Overseas MRLs

The following overseas MRLs for tolylfluanid in strawberries have been established.

Country Commodity name MRL (mg/kg)
Spain Strawberries 3
Netherlands 1 Strawberry 10
Germany Strawberries 5
Belgium Strawberry 2
Austria Strawberries 5
Finland 2

Berries

10
Denmark Berries and small fruit 5
EEC (proposed) Strawberries (field) 3
South Korea Strawberry 3
Sweden Fruits 3

1   Sum of tolylfluanid and DMST, expressed as DMST

2   Sum of dichlofluanid and tolylfluanid

CODEX Alimentarius Commission MRL

The current CODEX MRL for tolylfluanid in strawberries is 3 mg/kg.  The residue definition is the parent compound ie. "tolylfluanid".  The magnitude of the MRL and the residue definition are identical to the proposed Australian situation.

Export of strawberries from Australia

Total export of strawberries in 1996 was valued at $A11 million with major importers being Hong Kong ($A7.5 million), Singapore ($A1.3 million) and UK ($A0.7 million).  The volumes of strawberries exported to various countries are summarised below.

Country of destination Quantity (tonnes)
Hong Kong 3047
Singapore 661
UK 122
Netherlands 27
Indonesia 95
Belgium 20
UAEM 46
Germany 14
New Zealand 20
Switzerland 12
Italy 8
Saudi Arabia 23
Malaysia 29
New Caledonia 28
Other 42
Total 4194

Potential risk to Australian export trade

In assessing the potential risk to Australian export trade the volume of strawberry exports, the existence of a CODEX MRL and the Australian residue trials were all considered.

Although the quantities of strawberries exported are not insignificant they can be considered a minor export commodity in relation to Australia's overall export of horticultural commodities. The residue trials submitted with the application demonstrate that residues of tolylfluanid are unlikely to exceed the proposed Australian MRL when the product is used according to GAP.

In addition, the proposed Australian MRL and residue definition are the same as those recommended by CODEX.  Under the GATT agreement an MRL in place under CODEX should be adopted by importing countries even when there is a local MRL lower than the CODEX MRL.  It is noted that some of the potential importers of Australian strawberries do not have national MRLs in place. It should be the Australian exporter's responsibility to determine whether the CODEX MRL is acceptable in such situations.

The risk to Australian trade posed by the use of Euparen Multi 500 WG Fungicide on strawberries is considered to be small and consequently, from a trade perspective, registration of the product is supported.

Occupational Health and Safety Assessment

Tolylfluanid is not currently listed in the NOHSC List of Designated Hazardous Substances.  Bayer Australia Limited classified tolylfluanid as a hazardous substance according to NOHSC Approved Criteria for Classifying Hazardous Substances.  This classification is based on its acute inhalational toxicity, irritant and sensitising effects.

The following risk phrases are allocated to tolylfluanid:

R23   Toxic by inhalation

R38   Irritating to skin

R36   Irritating to eyes

R43   May cause sensitisation by skin contact

Substances containing tolylfluanid at concentrations greater than or equal to 1% are considered hazardous.

Tolylfluanid is composed of solid colourless crystals with a weak aromatic odour.  It is of low acute and dermal toxicity in rats (oral LD50 >5000 mg/kg, 1/10 deaths; dermal LD50 >5000 mg/kg, no deaths), and moderate inhalational toxicity in rats (4 hr LC50 265 mg/m3).  Tolylfluanid was determined to be a severe eye and skin irritant in rabbits and causes skin sensitisation in guinea pigs. Tolylfluanid has the potential to affect the thyroid function (decreased thyroxine and high thyroid stimulating hormone levels) and to induce pathological changes in the gland.

Euparen Multi 500 WG Fungicide is classified by Bayer Australia Limited as a hazardous substance based on its skin sensitising effects.

Euparen Multi 500 WG Fungicide is formulated as wettable granules.  There were no studies available on the acute toxicity of the product.  Euparen Multi 500 WP Fungicide is a moderate skin and slight eye irritant in rabbits, and causes skin sensitisation in guinea pigs.

The product will be imported fully formulated in 400 g polybags.

Transport, storage and retailing

Considering that the product will be imported formulated, transport workers, store persons and retailers will only handle the packaged product; therefore, they could only become contaminated if the packaging were breached.

Advice on safe handling of the product during routine use is provided in the Material Safety Data Sheet (MSDS) for Euparen Multi 500 WG Fungicide.

End use

Euparen Multi 500 WG Fungicide is to be applied to strawberries at the rate of 200-1333 g/100 L water.  The maximum application rate is 2 kg/ha.  The water volumes will vary between 150 L/ha for low volume application and 2000 L/ha for high volume application.  The maximum concentration of tolylfluanid in spray is 6.67 g/L (1.3% product).  Spraying is to commence from flowering until the end of harvest at 7 to 10 day intervals.  No re-entry period is specified on the draft label.  A one-day withholding period for harvesting strawberries is proposed.

For end users, the main route of exposure is dermal and inhalational.  Tolylfluanid is of moderate acute inhalational toxicity and low volatility.  Given that the product is to be applied in field grown strawberries, inhalation exposure to product vapour/mist is not expected to be significant.  However, workers can be exposed to dust generated during handling of the granules.  The applicant indicated that the product is not likely to be dusty.  The undiluted product is a moderate skin and slight eye irritant and causes skin sensitisation.  Given the dilution of the product (1.3 % w/v), the prepared spray is expected to present irritant and sensitising effects.

No worker exposure data were available for tolylfluanid or Euparen Multi 500 WG Fungicide.  The risk assessment was based on exposure estimates from the UK Predictive Operator Exposure Model and a German model submitted by the applicant.  The risk assessment conducted using data from these models indicated that the risk was not acceptable for workers performing combined tasks without gloves.

The risk assessment indicated that cotton overalls buttoned to the neck and wrist and a washable hat and elbow length PVC gloves are recommended when opening the container, preparing spray and using the prepared spray.

Entry into treated areas or handling treated crops

Workers re-entering treated crops may come into contact with product residues.  Workers are not likely to re-enter treated crops immediately after spray application. Considering that Euparen Multi is a moderate skin and slight eye irritant and is a dermal sensitiser, and that tolylfluanid is of moderate inhalational toxicity, the following re-entry statement is recommended: 'Do not allow entry into treated areas until the spray has dried.  When prior entry is necessary, wear cotton overalls buttoned to the neck and wrist and a washable hat and chemical resistant gloves'.

Recommendations for safe use

Workers involved in transport, storage, and retailing should be protected by safe work practices and training.  End users should follow the instructions and Safety Directions on the product labels.  Safety Directions include the use of cotton overalls buttoned to the neck and wrist and a washable hat and elbow-length PVC gloves when opening the container, preparing spray and using the prepared spray.

The personal protective equipment recommended should meet the relevant Standards Australia standards specified below:

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

AS 3765-1990 Clothing for Protection Against Hazardous Chemicals

Manufacturers and importers should produce a MSDS for hazardous products containing tolylfluanid.  These should contain 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.

Conclusions

Euparen Multi 500 WG Fungicide can be used safely if handled in accordance with the instructions on the product label.  Additional information is available on the MSDS for Euparen Multi 500 WG Fungicide.

Environmental Assessment

Environmental Exposure

Euparen Multi 500 WG Fungicide, containing the technical grade active constituent (TGAC) tolylfluanid at 500 g a.i./kg, is proposed as a protectant spray against black spot and grey mould in strawberries.  The label advises users to start spraying at the commencement of flowering and to continue at 7-10 d intervals until the end of harvest.  When applied on a schedule, Euparen Multi 500 WG Fungicide will suppress powdery mildew.  The application rate of 2 kg EUP/ha is equivalent to 1 kg a.i./ha and should not be applied in volumes less than 500 L/ha.  An alternate application rate of 200 g EUP/100 L (equivalent to 1 kg a.i./ha) should be used where the spray volume exceeds 1,000 L/ha.

The company clarified that the number of applications will be the same as for dichlofluanid (Euparen), which tolylfluanid is replacing.  The Queensland fungicide program consists of 15-20 applications, generally consisting of 6-8 dichlofluanid sprays.  The Victorian program is 20-30 applications, with the maximum number of Euparen sprays of approximately 10-14. 

Environmental Chemistry and Fate

. Abiotic transformation

Tolylfluanid hydrolyses rapidly at alkaline pH with a half-life of <<10 min at pH 9 and 22°C with the main product dimethylaminosulfotoluidide (DMST).  At neutral pH 7, the half-life is 29.1 h while at pH 4 the hydrolysis half-life slows to 11.7 d.  Direct photolysis is not considered to be a major route of transformation as tolylfluanid in aqueous solution does not absorb light at wavelengths >290 nm though half-lives (probably indirect) of 5.5-8.2 h were reported.

. Biotic transformation

In an aerobic loamy sand, degradation of tolylfluanid was initially rapid with a DT50 of 1.4 d in the first 9 d of sampling, but 0.24% of the originally applied amount was still detectable at 65 DAT.  Parent compound degraded linearly in a second loamy sand with a half-life of 9.3 d.  In another experiment using four soils, degradation was again initially rapid in three soils with DT50 of <1 d (12 d in the fourth) and a significant lag phase with parent still detectable 99 DAT at <1% of the originally applied amount (7.7% in the fourth).  In two unidentified soils, the same pattern of rapid degradation followed by a lag phase in one soil, and a moderate half-life of 4.5 d in another, was evident.  The metabolite DMST also follows a rapid initial degradation with DT50 of 1.9-7.4 d followed by a lag phase.  Degradation of parent compound in two natural sediment/water systems was rapid with undetectable concentrations by 14 DAT.  However, DMST partitioned preferentially to the water phase with 14 DAT peaks of 69.1-71.3% with half-lives in the whole water-sediment system of 42.1-76.4 d.

. Mobility

No studies were submitted on the adsorption/desorption of tolylfluanid in soil but Environment Australia estimated the KOC as 4,625 which is slightly mobile.  This was confirmed by leaching studies where no parent or DMST were detected in tests conducted according to German BBA guidelines.  After 12 and 40 d ageing of parent compound in soil, only 6.6 and 4.9%, respectively, of the originally applied radioactivity leached through 27 cm of soil with undetectable parent compound and 0.2% as DMST.  However, only 9.8% remained in the soil as DMST after 40 d while 75.1% was bound in the top 9 cm of soil (68.5% was unextractable).

. Field dissipation

Based on old and poorly described studies, the half-life of tolylfluanid in the top 10 cm of a sandy loam was 4.5 d with both parent and DMST nondetectable at 59 DAT.  In a sand soil, dissipation was highly variable and nonlinear with an estimated DT50 of 14 d.  Other soils had DT50 values of 8.2-10.6 d with nondetectable concentrations by 59-60 DAT.

 Accumulation

Environment Australia modeled the accumulation of tolylfluanid in soil given an application rate of 1 kg a.i./ha, repeat sprayings at 7-10 d intervals and an aerobic soil DT50 of <1-12 d.  In the best case DT50 of 1 d, there would be no accumulation given weekly applications.  However, a worst case DT50 of 12 d would result in peak soil concentrations of about 2.5 mg a.i./kg soil after 10 weekly applications.  If directly applied to a 15 cm water body, the hydrolysis half-life at neutral pH 7 of 29.1 h would result in no accumulation from weekly sprays.  However, the concentration of the metabolite DMST could continue to increase in the unlikely worst case direct overspray for 25 consecutive weeks and half-life of 76.4 d.

Environmental Toxicology

. Birds

An unacceptable study reported a single dose acute oral LD50 of >5,000 mg/kg bodyweight to Japanese quail while an acceptable study found the 5-d dietary LC50 to be >5,000 mg a.i./kg food which is practically nontoxic to quail.  For bobwhite quail, the single oral dose LD50 was >2,000 mg a.i./kg bodyweight indicating tolylfluanid was practically nontoxic.  The NOEC and LOEC to bobwhite quail in a one generation dietary toxicity study were 888 and 2,800 mg a.i./kg food, respectively, based on 75% mortality at the upper dose.

. Fish

Technical and formulated (as Euparen M WG 50, but similar to the proposed formulation) tolylfluanid were very highly toxic to juvenile rainbow trout with 96-h LC50 <0.055 and 0.016<LC50<0.048 mg a.i./L, respectively.  For juvenile golden orfe, technical tolylfluanid was also very highly toxic (96-h EC50 = 0.059 (0.048, 0.077) mg a.i./L) as were two formulations (Euparen M WG 50 and Euparen M WP with 0.0610<96-h LC50<0.0948).  The DMST metabolite was apparently slightly toxic to golden orfe (96-h EC50>10.0 mg/L) but this result must be treated with extreme caution because so few organisms were used and no replicates were run.

In chronic 21-d exposures, technical tolylfluanid was highly toxic to juvenile rainbow trout with the NOEC and LOEC of 0.0031 and 0.0098 mg a.i./L, respectively, even though parent compound had hydrolysed completely to DMST by 21 DAT.  As in acute exposures, formulated tolylfluanid (Euparen M WG 50) was very highly toxic to trout with the 21-d NOEC and LOEC of 0.00432 and 0.00931 mg a.i./L, respectively.  DMST was only very slightly toxic to juvenile trout with the NOEC and LOEC of 9.2 and 58 mg/L, respectively.

. Aquatic invertebrates

Technical tolylfluanid was highly toxic to daphnids with a 48-h LC50 of 0.71 (0.62, 0.80) mg a.i./L, while when formulated as Euparen M (50 WP, expected to behave similarly as the proposed EUP), the apparent 48-h LC50 of 0.036 (0.014, 0.071) mg a.i./L would indicate very high toxicity.  The DMST metabolite was only slightly toxic with a 48-h LC50 of 30.8 (25.9, 36.6) mg/L.  When exposures are increased to 21-d, the NOEC and LOEC of technical tolylfluanid of 0.01 and 0.032 mg a.i./L, respectively, is moderately to highly toxic.  This is further reduced to moderate toxicity when daphnids were exposed to formulated Euparen M WG 50 and 21-d NOEC and LOEC values of 0.061 and 0.12 mg a.i./L resulted.  DMST was very slightly toxic in a static renewal test with the 21-d NOEC and LOEC values of 5.6 and 10.0 mg/L, respectively.

. Aquatic plants

The mean 72-h EC50 values of 4.2, 6.6 and >10 mg a.i./L (no 95% confidence interval given) of tolylfluanid (89.3%) to Scenedesmus subspicatus indicate moderate to slight toxicity.  In another study, the highest concentration used of 0.90 mg a.i./L caused no adverse effect to S. subspicatus after 72 h.  When formulated as Euparen M WG 50, the 94-h EbC50 and ErC50 values of 3.22 and 8.03 mg a.i./L also show moderate toxicity to this alga.  The metabolite DMST was slightly toxic to Pseudokirchneriella subcapitata with 96-h EbC50 and ErC50 values of 34.4 and 71.2 mg/L (no confidence limits given), respectively.

. Terrestrial invertebrates

Both technical and formulated (as the proposed EUP) tolylfluanid were very slightly toxic to earthworms with 14-d LC50 values >1,000 mg a.i./kg soil.  When formulated tolylfluanid and tebuconazole (as Euparen M 40 and Folicur 10 WP, respectively) were tested on earthworms at a ratio of 4:1, the LC50 was >399/99 mg/kg dw soil tolylfluanid/tebuconazole.  Ten summaries on toxicity testing with honey bees were submitted, but were lacking study details and not used; a supplementary study was acceptable.  Euparen M WG 50 applied at 2.58 kg a.i./ha was harmful to predatory mites causing 100% combined adverse effect.  However, applications of 1.08 and 2.42 kg a.i./ha were harmless (40.7% and 48.5% combined effect, respectively) to predatory heteropteran bugs after up to 25 d.

Euparen M WG 50 was harmful to the parasitic wasp Aphidius rhopalosiphi at 2.53 kg a.i./ha causing 100% mortality after 24 h.  However, Euparen M sprayed on glass plates at 200 g a.i./ha (5X lower than the proposed rate) was moderately harmful to the wasp Trichogramma cacoeciae, while host eggs dipped in a 2.5 g/L solution (unspecified as EUP or a.i.) only showed an 18.3% reduction in parasitisation and was considered harmless.  In a semi-field study, Euparen M WP 50 sprayed on apple trees at 1.12 kg a.i./ha had no significant effect on the parasitisation efficiency of T. dendrolimi.

Euparen M WP was harmless to Staphylinid beetles at 1.12 kg a.i./ha and Euparen M WG 50 caused no adverse effect at 2.48 kg a.i./ha.  Similarly, carabid beetles were unaffected after being sprayed with Euparen M WG 50 at 2.64 kg a.i./ha or Euparen M WP 50 at 1.125 kg a.i./ha.  An overall 44.5% reduction in reproduction efficiency was considered harmless when ladybird beetles were treated with Euparen M WG at 2.56 kg a.i./ha.  The green lacewing was also unaffected at the low application rate of 139-176 g a.i./ha.

In summary, tolylfluanid was harmless to predatory heteropteran bugs, a parasitic wasp, Staphylinid beetles, carabid beetles, ladybird beetles and the green lacewing.  Predatory mites and a different parasitic wasp were harmed (100% adverse effect) at high rates and may still be affected by the proposed application rate.  An unknown rate was moderately harmful to another parasitic wasp.  Growers releasing predatory mites as part of an IPM program should be made aware of the potential hazard of this product.

Soil nitrification and respiration

Two loamy sands treated with Euparen M WP 50 at 1.3 and 13.0 mg a.i./kg dw soil showed no lasting adverse effects on microbial carbon mineralisation as measured by CO2 production by 28 DAT.  The amendment with lucerne also had no effect on mineralisation.  When these soils at both concentrations were amended with ammonium sulphate and glucose, an adverse but tolerable reduction in nitrification was evident with <30% deviations from controls by 56 DAT.  It should be noted that ammonification processes were not measured.

Environmental Hazard

The environmental hazard of tolylfluanid will be highest to organisms living in the vicinity where it will be applied.  Residues would be expected on strawberry plant surfaces including the interrow plant cover and soil.  Surface water, uncultivated land and nearby non-target plants (e.g. trees and grasses) may be contaminated through overspray, spray drift and/or run-off.

. Expected Environmental Concentrations

After a single application of Euparen Multi 500 WG Fungicide at 1 kg a.i./ha, the estimated environmental concentration (EEC) in the top 10 cm of soil would be 0.83 mg a.i.·kg/soil presuming a soil density of 1.2 g/mL.  Given repeat sprayings at 7 d intervals, in the worst case soil dissipation DT50 of 12 d, a peak concentration of 2.5 mg a.i./kg soil would accumulate after the tenth week.  The best case DT50 of <1 d would not lead to any accumulation of parent compound .

In a worst-case scenario of a direct overspray of a 15 cm deep body of water with the maximum single application rate of 1 kg a.i./ha of Euparen Multi 500 WG Fungicide, the EEC would be 0.67 mg a.i./L.  If this were repeated weekly, the expected hydrolytic degradation at pH 7 (half-life=29.1 h) is rapid enough that no accumulation of parent tolylfluanid is expected.  However, the metabolite DMST may accumulate in water up to about 4.5 mg/L with a best case half-life of 42.1 d.  In the worst case with a half-life of 76.4 d, the concentration of DMST increases without an apparent limit.  This estimate does not account for dissipation in the water (e.g., flowing water) between treatments.

. Hazard to Terrestrial Organisms

There is no expected hazard to bobwhite quail from short term exposure to tolylfluanid residues in their food resulting from the proposed application.  Even with the worst-case accumulation in soil from repeated spraying at 7 d intervals, the NOEC from chronic dietary studies is 2.8X higher than the EEC.  Coupled with the birds' ability to leave the treated area and feed on noncontaminated items, the hazard to quail is expected to be acceptable.  As toxicity studies on mallard ducks were not submitted, the hazard cannot be assessed.  Earthworms are expected to be adequately protected from both acute and chronic toxicity as are honey bees, predatory heteropteran bugs, the parasitic wasp Trichogramma dendrolimi and staphylinid, carabid and ladybird beetles.  However, the hazard to the predator Phytoseiulus persimillios (used in IPM against the two spotted mite), wasps T. cacoeciae and Aphidius rhopalosiphi, green lacewings and predatory mites at the proposed application rate is unclear. 

Growers intending to use Euparen Multi 500 WG Fungicide in IPM programs (e.g. release of predatory mites) should be made aware of the potential hazard to these organisms.  Carbon mineralisation processes are not expected to be adversely affected even in the worst case soil accumulation, however, an adverse but tolerable reduction in nitrification may occur and the hazard to ammonification processes could not be assessed.

. Hazard to Aquatic Organisms

Water bodies adjacent to strawberry plots may be contaminated by tolylfluanid through direct overspray.  Contamination outside the target area is likely to result from spray drift, particularly where sprayers producing small (vmd < 100 m) droplets are used, and from run-off of material sorbed to soil and organic matter particles.  In the worst-case scenario of a direct overspray of a 15 cm deep body of water with Euparen Multi 500 WG Fungicide, the expected environmental concentration of 0.67 mg a.i./L would result in Q-Values of 14 and 19 for fish and daphnids, indicating unacceptable risk for both. 

The Q-Value of 0.21 for algae indicates a risk that may be mitigated by restricted use but the hazard for macrophytes cannot be assessed due to lack of data.  The rapid hydrolysis of tolylfluanid should not result in accumulation of parent even with weekly applications, although the DMST metabolite may accumulate up to 4.5 mg/L in the best case and continually increase in the worst case. 

Chronic toxicity data only for rainbow trout were submitted which indicate no risk (EEC<NOEC) in the best case.  As the worst case EEC continues to increase, the hazard appears unacceptable and requires clarification of the number of repeated applications and application interval to better define the EEC.

In the more likely exposure of water bodies by spray drift or run-off, a 10% drift would still result in unacceptable risk for fish and invertebrates, but acceptable for algae.  A further refinement of drift (according to computer modelling) from a low boom ground sprayer with a buffer zone of 9.5 m would give a drift of 0.54% necessary to reduce the risk to fish and invertebrates to an acceptable level.  Therefore Environment Australia suggested, and the company agreed to, a buffer zone of 10 m downwind of all strawberry fields to be treated with Euparen Multi 500 WG Fungicide.  New information from the company suggests that applications are likely to be made approximately every 2 weeks in rotation with other fungicides.  Therefore the worst case half-life of DMST of 3.8 mg/L is less than the NOEC for trout of 9.2 mg/L and daphnia of 5.6 mg/L respectively and the hazard is acceptable. 

As DMST partitions preferentially to water, contamination of water bodies by surface run-off may be expected but this hazard would be lower than above which is based on the worst case of repeated oversprays.

Desirable Vegetation

Although no toxicity studies were submitted on the terrestrial plants, the hazard to these organisms is expected to be low as tolylfluanid is used on strawberries, grapes, vegetables and ornamentals in other countries.

Conclusions and Recommendations

Bayer Australia Ltd has applied for the registration of a new product Euparen Multi 500 WG Fungicide containing 500g/kg tolylfluanid.  This product is proposed for the control of black spot and grey mould and the suppression of powdery mildew in strawberries.  With a long growing season and treatment at 7-10 d intervals, in theory up to 44 treatments per year of 1 kg a.i./ha could be applied.  However, the company has clarified that Euparen Multi 500 WG Fungicide is intended to replace Euparen (dichlofluanid) in rotation with other fungicides in a spray schedule and likely have a maximum of 10-14 sprays in a year.  Significant contamination of soil, both on site and off, is likely from spray drift and run-off.  However, the buffer zone of 10 m (agreed to by the company) surrounding all strawberry fields to be treated is expected to provide adequate protection to aquatic organisms from parent tolylfluanid and the DMST metabolite by reducing the amount of drift into nearby water bodies. 

Efficacy and Safety Assessment

Justification for Use

Euparen Multi 500 WG Fungicide contains 500 g/kg tolylfluanid.  The new product has been developed to improve the control of grey mould (Botrytis cinerea) and black spot (Colletotrichum acutatum) and suppression of powdery mildew (Sphaerotheca macularis) on strawberries, which are major limitations on production throughout Australia.  Registration of a new product for control /suppression of these three diseases will allow Australia's strawberry growers to increase the quantity and quality of production.

Euparen Multi 500 WG Fungicide is a logical replacement for Euparen (dichlofluanid) as it is closely related and has many advantages.  Euparen is already registered for control of black spot and grey mould and for the suppression of powdery mildew and Euparen Multi is a suitable replacement.  Registration of this chemical should remove some the resistance problems (grey mould) becoming evident in strawberry growing regions of Australia.

Australian agricultural authorities support registration.

Adequacy of efficacy data

Data presented by Bayer Australia Ltd supported claims that Euparen Multi controls black spot and grey mould and suppresses powdery mildew on strawberries.  The active ingredient is tolylfluanid a polyvalent fungicide with a protective mode of action.  Tolylfluanid is closely related to dichlofluanid, the active ingredient in registered fungicide Euparen.  The activity of tolylfluanid is at least equivalent to, and in most cases better than dichlofluanid.

Scientifically sound experiments were used to provide data.  Adequate controls, replicates and treatments were used in all experiments.

Disease pressure for the four different experiments varied but was adequate to support efficacy work.  Disease pressure is dependent on weather conditions which varied but sufficient disease development occurred to allow measurement of fungicide efficacy. 

Euparen Multi 500 WG Fungicide provided at least equivalent control of black spot and grey mould in all experiments when compared with controls.  For example, Euparen Multi decreased the proportion of fruit affected by black spot and grey mould from 51% to <4% and 24% to 5% respectively.  The fungicide also suppressed the development of powdery mildew.  For example, Powdery mildew levels were decreased from 21% to <2%.  Experiments for efficacy were conducted in Queensland and Victoria.

All data was statistically analysed using standard techniques and was correctly interpreted.

Claims

Euparen Multi 500 WG Fungicide, containing 500 g/kg tolylfluanid, is proposed to be applied at 7-10 day intervals from flowering to harvest.  The proposed application rate is 2 kg/ha (>500 L/ha application) or 200 g/100L (>1000 L/ha application).

At these rates the data submitted indicateds that Euparen Multi 500 WG Fungicide will control black spot and grey mould and suppress powdery mildew.

The claim for use of the product to control grey mould and black spot of strawberries and suppress powdery mildew is supported by the efficacy data.  The wording on the label is consistent with experimental data presented.

Crop safety aspects

Three experiments were carried out in Western Australia and Queensland, to determine the phytotoxicity of Euparen Multi 500 WG Fungicide.  Results from these experiments and the four efficacy experiments reported no observations of phytotoxicity.  Even at extremely high rates of active ingredient only slight burning of leaves was observed under warm conditions.

Labeling Requirements

The label proposed for the product is as follows:

POISON
KEEP OUT OF REACH OF CHILDREN
READ SAFETY DIRECTIONS BEFORE OPENING OR USING
Euparen(r) Multi 500 WG Fungicide
Active Constituent: 500 g/kg TOLYLFLUANID

GROUP X FUNGICIDE

For the control of black spot and grey mould and suppression of powdery mildew on strawberries

400 g Net

25 kg

Directions for use

Crop

Disease Rate Application Critical Comments

Strawberries

Black spot
Grey mould

Powdery mildew (suppression only)

2 kg/ha Use where spray volume is less that 1000 L/ha.  Do not apply volumes less than 500 L/ha

Start spraying at the commencement of flowering and continue until the end of harvest.  Apply at 7 to 10 day intervals.  Use the shorter interval when conditions favour development of the disease or rapid fruit growth.

When applied on a schedule Euparen Multi will suppress powdery mildew.

DO NOT spray Euparen Multi in temperatures above 300C.

200 g

 

/100L

Use where spray volume exceeds 1000 L/ha

NOT TO BE USED FOR ANY PURPOSE, OR IN ANY MANNER, CONTRARY TO THIS LABEL UNLESS AUTHORISED UNDER APPROPRIATE LEGISLATION

WITHHOLDING PERIOD:

STRAWBERRIES:

DO NOT HARVEST FOR 1 DAY AFTER APPLICATION

General Instructions

Mixing

Add the required quantity of Euparen Multi 500 WG Fungicide by slowly sprinkling granules directly to the water in the spray tank while stirring or with agitators in motion.

Compatibility

Euparen Multi is compatible with most commonly used wettable powder formulations of insecticides and fungicides.

Do not mix Euparen Multi with emulsifiable concentrates, or materials of a strongly alkaline nature.  Do not add wetting or sticking agents to Euparen Multi sprays.

The compatibilities given are based on worldwide experience and are considered correct. However, as changes in climatic conditions can alter the sensitivity of plants to mixtures of sprays, we accept no responsibility for the behaviour of such mixtures.

Fungicide Resistance Warning

For fungicide resistance management the product is a group X fungicide.

Some naturally occurring fungal populations resistant to the product and other Group X fungicides may exist through normal genetic variability in any fungal population.  The resistant individuals can eventually dominate the fungal population if these fungicides are used repeatedly.  These resistant fungi will not be controlled by this product or other Group X fungicides, thus resulting in a reduction in efficacy and possible yield loss.

Since the occurrence of resistant fungi is difficult to detect prior to use, Bayer Australia Limited accepts no liability for any losses that result from failure of this product to control resistant fungi.

Re-entry Period

Do not allow entry into treated area until spray has dried.  When prior entry is necessary, wear cotton overalls button to the neck and wrist and a washable hat and chemical resistant gloves.

Protection of Wildlife, Fish, Crustaceans and Environment

This product is very highly toxic to fish and aquatic invertebrates, and moderately toxic to algae.  Do not contaminate streams, rivers or waterways with the chemical or used container. 

DO NOT apply under meteorological conditions or from spraying equipment which could be expected to cause spray to drift onto adjacent crops, crop lands, pastures or waterways.  Do not apply by aircraft.

Storage and Disposal

Store in the closed, original container in a dry well ventilated area, as cool as possible.  Do not store for prolonged periods in direct sunlight.  Single rinse before disposal.  Add rinsings to spray tank.  Do not dispose of undiluted chemicals on-site.  Puncture and bury empty container in a local authority landfill.  If not available bury the containers below 500 mm in a disposal pit specifically marked and set up for this purpose clear of waterways, vegetation and roots.  Empty container and product should not be burnt.

Safety Directions

Poisonous if inhaled.  Will irritate the eyes and skin.  Repeated exposure may cause allergic disorders.  Avoid contact with eyes and skin.  Do not inhale dust.  When opening the container, preparing the spray and using the prepared spray, wear cotton overalls buttoned to the neck and wrist and a washable hat and elbow-length PVC gloves.  If product on skin, immediately wash area with soap and water.  Wash hands after use.  After each day's use, wash gloves and contaminated clothing.

First Aid

If poisoning occurs, contact a doctor or Poisons Information Centre (Phone 131 126).

Further information is available on the Material Safety Data Sheet.

Liability

This product must be used strictly as directed.  Bayer Australia Limited may not be liable for loss or damage arising from failure to follow directions for use.

(r)Trademark of Bayer Germany  APVMA Approval Number: 50627/

(c)Copyright Bayer Australia Limited NM:

   Batch No.:    ***/**

   Date of Manufacture:   **/**/**

IN A TRANSPORT EMERGENCY DIAL

 

000, POLICE OR FIRE BRIGADE

Bayer Australia Limited emergency contact
1800 033 111
Australia wide, 24 hours

bayer image Bayer Australia Limited

 

875 Pacific Highway

Pymble NSW 2073

Telephone (02) 9391 6000

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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.
Desorption Removal of an absorbed material from a surface.
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
Hydrophobic Water repelling
Leaching Removal of a compound by use of a solvent.
Log Pow Log to base 10 of octanol water partitioning co-efficient.
Metabolism The conversion of food into energy
Photodegradation Breakdown of chemicals due to the action of light.
Photolysis Breakdown of chemicals due to the action of light.
Subcutaneous Under the skin
Toxicokinetics The study of the movement of toxins through the body.
Toxicology The study of the nature and effects of poisons.

References

BBA 1990 Effects on the Activity of the Soil Microflora.  Guidelines for the Official Testing of Plant Protection Products, Biologische Bundesanalstalt fűr Land- und Forstwirtschaft, Federal Republic of Germany.

Food and Agriculture Organisation of the United Nations 1997, FAO Manual on the Submission and Evaluation of Pesticide Residues Data, FAO, Rome.

Goring, C.A.I. et al. 1975, 'Principles of pesticide degradation in soil', in Environmental Dynamics of Pesticides, edited by R. Haque and V.H. Freed, Plenum Press, New York, pp 135-72.

Matthews, G.A. 1992, Pesticide Application Methods, 2nd ed., Longman, London.

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

Australian Pesticides and Veterinary Medicines Authority 1997, Ag Requirements Series:  Guidelines for Registering Agricultural Chemicals, APVMA, Canberra.

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, Ag Labeling Code-Code of Practice for Labeling Agricultural Chemical Products, APVMA, Canberra.

# FAO Manual on the Submission and Evaluation of Pesticide Residues Data, Food and Agriculture Organisation of the United Nations, Rome, 1997, p 36.

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