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Acute oral toxicity ofp‐aminopropiophenone to stoats(Mustela erminea)Penny M. Fisher a , Cheryl E. O'Connor a & Elaine C. Murphy ba Landcare Research , P.O. Box 69, Lincoln, 8152, New Zealandb Department of Conservation , Private Bag 4715, Christchurch,New ZealandPublished online: 30 Mar 2010.

To cite this article: Penny M. Fisher , Cheryl E. O'Connor & Elaine C. Murphy (2005) Acute oraltoxicity of p‐aminopropiophenone to stoats (Mustela erminea), New Zealand Journal of Zoology,32:3, 163-169, DOI: 10.1080/03014223.2005.9518409

To link to this article: http://dx.doi.org/10.1080/03014223.2005.9518409

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New Zealand Journal of Zoology, 2005, Vol. 32Fisheretal.—AcuteoraltoxicityofPAPPtostoats: 163 -1690301–4223/05/3203-0163 © The Royal Society of New Zealand 2005

163

Acute oral toxicity of p-aminopropiophenone to stoats(Mustela erminea)

PENNY M. FISHER

CHERYL E. O'CONNORLandcare ResearchP.O. Box 69Lincoln 8152, New Zealand

ELAINE C. MURPHYDepartment of ConservationPrivate Bag 4715Christchurch, New Zealand

Abstract No toxic baits are currently registered inNew Zealand for stoat (Mustela erminea) control.PAPP (p-aminopropiophenone) has potential ap-plication as a vertebrate pesticide for stoat controlin New Zealand, and in the hydrochloride formwas highly toxic (LD509.3 mg/kg) to stoats in pentrials. The first visible signs of toxicosis, cyanosisand salivation, generally appeared within 20 min ofgavage administration of PAPP. These signs weregenerally followed by rapid respiration, lack of co-ordination and lethargy. Death generally followedwithin an hour of receiving a lethal dose. Stoatsremained at least partly conscious until just priorto death, or may have had periods of intermittentconsciousness in the later stages. PAPP toxicosisin stoats appeared relatively rapid (in comparisonwith other vertebrate pesticides in mustelids) and onpreliminary assessment appears relatively humane.Further investigation and development of targetedbait delivery of PAPP for stoat control in New Zea-land is recommended. This should be conductedalongside formal assessment of humaneness andthe potential for unwanted effects such as non-targetmortality and environmental contamination.

Keywords control; lethal dose; poisoning; p-ami-nopropiophenone; p-aminopropiophenone hydro-chloride; stoat; time to death; vertebrate pesticide

Z05003; Online publication date 4 August 2005Received 2 February 2005; accepted 28 April 2005

INTRODUCTION

Mustelid control is a critical component of manyNew Zealand strategies for local conservation ofnative birds. Potential control techniques for stoats(Mustela erminea) include trapping, tracking withdogs and baiting, although no toxic bait formulationsare currently registered for stoat control. Sodiumfluoroacetate (1080) in whole egg baits has beeninvestigated experimentally for stoat control (Dilks& Lawrence 2000; Spurr 2000); and while they ap-peared to be effective, this bait type was not easilyapplied in the field, and 1080 is not target specific.The availability of an effective and humane toxicant,combined with a targeted delivery system for stoats,would improve future protection of native wildlifefrom stoat predation. Given the increasing publicawareness of the risks of pesticide use, and increas-ing regulatory scrutiny of hazardous substancesapplied to the environment, any new toxic bait for-mulations will need to demonstrate field efficacy,target specificity, acceptable environmental risk, andrelative humaneness.

Oral administration of p-aminopropiophenone(PAPP) can significantly elevate methaemoglobin(MetHb), because ap-hydroxy metabolite of PAPPis thought to be responsible for the direct formationof MetHb (Marrs et al. 1991). The metabolite p-hy-droxyaminopropiophenone, produced by N-hydrox-ylation of PAPP in vivo, is a potent MetHb-formingcompound (Graffe et al. 1964). Methaemoglobinreduces the capacity of blood to carry oxygen totissues (Friedell 1954; Salerna & Friedell 1954). El-evation of MetHb can cause anaemia (Smith 1969).Sufficiently high concentrations of MetHb in bloodproduce anoxic effects (Marrs & Bright 1987). Thetoxicity of PAPP is assumed to be largely due to thismode of action (Goldstein & Doull 1973). ControlledMetHb formation is one potential strategy to coun-ter cyanide toxicity, and PAPP has been previouslystudied in this context (e.g., Marrs & Bright 1987;Rockwood 1999).

The potential for PAPP to be used as a vertebratepesticide has also been investigated (Savarie et al.

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164 New Zealand Journal of Zoology, 2005, Vol. 32

1983; Marks et al. 2004). Published LD50 values forPAPP in mammals and birds indicate a wide rangein oral toxicity, although mammalian carnivoresappear to be generally more susceptible than eitherrodents or birds (see Discussion), suggesting thatstoats may be quite susceptible to PAPP. Females ofsome species may be intrinsically more susceptibleto PAPP toxicosis. Female beagles produced moremethaemoglobin for a given dose of PAPP thanmales (Bright et al. 1987), and female rats had ap-proximately twice the susceptibility of males to oraldoses of PAPP (Scawin et al. 1984). Given the lackof information regarding the susceptibility of stoatsto PAPP, documentation of acute toxicity was con-sidered a necessary first step in evaluating whetherthis compound might be suitable for further develop-ment as a stoat control tool in New Zealand.

MATERIALS AND METHODS

Wild-caught stoats were housed in outdoor cages (60x 150 × 90 cm) at the Landcare Research AnimalFacility, Lincoln. Each stoat was provided with anest box (40 × 33 × 15 cm) containing shreddedpaper as nesting material. Stoats were fed a dailyrotation of dead day-old chicks, chicken pet minceand mutton/beef pet mince and had free access towater. They were acclimatised to captivity for atleast 8 weeks before being used in trials.

Pilot trialApilot trial was conducted to determine whether thesusceptibility of stoats to PAPP was within the rangeof high acute toxicity that would be required foran effective vertebrate pesticide. A standard indexof toxicity following ingestion of a pesticide is theLD50, which is the amount of compound required to

kill 50% of a sample of animals. Oral LD50 values inbirds and mammals are often expressed as milligramof pesticide per kilogram of animal bodyweight (mg/kg), equivalent to parts per million (ppm). An LD50

of PAPP in stoats of less than 25 mg/kg was con-sidered a sufficient level of toxicity to proceed withtrials to refine an estimate of acute oral toxicity.

Although PAPP is nominally water soluble (Merck1989), stable PAPP solutions of suitable concentra-tion for gavage delivery to stoats were most easilyachieved by the formulation of the hydrochloridesalt. Dosing solutions were prepared to final PAPPconcentrations of 10—50 mg/ml, depending on thetreatment group. An appropriate quantity of crystal-line PAPP (Merck Ltd, New Zealand) was groundin a mortar and pestle, and equal parts water andmonopropyleneglycol (MPG) added. This mix washomogenised in an ultrasonic bath, then 35% hy-drochloric acid was added (at a 1:0.7 ratio w/w) andfurther homogenised. This mixture was warmed untilsolution was complete, then made up to appropriatevolume with MPG and water. The maximum dosevolume of PAPP hydrochloride solution admin-istered to stoats was 2.5 ml/kg, and control stoatsreceived 1 ml MPG only.

For the pilot trial, light anaesthesia with fluothanewas necessary to minimise handling time and stressto the wild-caught stoats. From previous experi-ence, stoats were expected to recover from fluothaneanaesthesia within 5 min, so that the onset of signsof PAPP toxicosis were not expected to be maskedby the effects of anaesthesia beyond this time. Onseparate days, a group of stoats (n = 6) was dosedwith 50 and 25 mg/kg PAPP respectively, alongsidecorresponding groups of control stoats (Table 1). Allstoats were monitored by direct observation for 1 hfollowing dosage, with the control animals providinga reference for normal behaviour during recovery

Table 1 Treatment groups of stoats used to estimate toxicity of PAPP. BW = body weight (mean ± SE).

Date dosed

Pilot trial22 Feb 200012 Apr 2001

Acute toxicity trial17 Dec 20014 Feb 200222 Mar 20021Jul2002

No. and sexdosed

4 M , 2 F6M

6M6M6M6M

Mean weightdose group (g)

308.2 ± 24.8296.0 ± 12.5

311.7 ± 24.0357.0 ± 15.2344.3 ± 15.7329.7 ± 21.1

Dose(mg/kg)

5025

12.518.7515.639.38

No. and sexof controls

2M, 1F6M

233*

Mean weightcontrol group (g)

323.7 ± 30.5309.7 ± 23.2

362.0±11.0363.0 ± 8.5330.3 ± 21.6

-

*Control animals were unavailable for the final dose group. However, substantial experience with gavage dosing andobservations of normal recovery from anaethesia was available by this time.

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Fisher et al.—Acute oral toxicity of PAPP to stoats 165

from anaesthesia and gavage. All procedures werecarried out in a room with a temperature between18°and23°C.

Acute oral toxicity trialAdult male stoats only were used in this trial becausethey were likely to be less susceptible than femalesto PAPP. Having a larger average body weight thanfemales, males also represented the upper limit forcalculating effective toxic loadings for PAPP deliv-ery in baits. On the mornings of four different days,four groups (n = 6) of stoats were administered dif-ferent doses of PAPP using the procedures alreadydescribed, alongside corresponding control groups(Table 1). Following dosing, stoats were placed backinto clean nestboxes and monitored constantly bydirect observation for the following 2 h. Their behav-iour, any signs of toxicosis, and time to death wererecorded. Death was confirmed by lack of heartbeatand corneal reflex. Dosed stoats that appeared torecover fully, i.e., were displaying normal alert be-haviour 6 h after dosing, and the control stoats, werereturned to outdoor housing. The behaviour of thesestoats was recorded for a further 2 h, i.e., until 8 hafter dosing, and they were then monitored at leastdaily for 2 weeks thereafter, including observationsof food intake, general health, and behaviour.

One stoat in the first group dosed in the pilot trial(50 mg/kg) and another dosed in the acute toxicitytrial (18.75 mg/kg group) died within 8 min of gav-age dosing. Necropsy indicated that some of thedose had entered the lungs, and these stoats werediscounted from statistical analysis. Mortality dataof all remaining stoats dosed with PAPP were usedin both logistic and probit regression models (Gen-stat) to approximate lethal dose (LD50, LD95, and

LD99) values and corresponding 95% confidenceintervals.

RESULTS

All control stoats survived, and always recoveredfrom anaesthesia within 3 min. Within this time, araised head was generally observed within the firstminute, rapid but uncoordinated movement aboutthe box within the following 2 min, and apparentlynormal behaviour thereafter, e.g., lying in a curledposition but alert and responsive to stimuli.

Stoats dosed with PAPP showed recovery fromanaesthesia consistent with that of control stoats.However, after this there was a generally consistentprogression of signs of PAPP poisoning, in mostinstances leading to death. Within approximately20 min of recovery from anaesthesia, movements ofPAPP-dosed stoats appeared slower and less coor-dinated, and cyanosis (a bluish discoloration of theskin resulting from inadequate oxygenation of theblood) began to affect the lips and nose (Table 2). By30 min after recovery from anaesthesia, stoats wereless responsive to disturbance, e.g., noise or touch,often lying curled with head down and displayingrapid, shallow respiration. After this, in comparisonwith control stoats, the behaviour of PAPP-dosedstoats was visibly affected. They showed little activ-ity, often lying in a curled position, with cyanosisevident in exposed skin. Some stoats first displayedexcessive salivation at this stage, with respirationremaining rapid and increasingly laboured. Anymovement attempted appeared very uncoordinated,often with legs splayed sideways and an inabilityto raise their heads. Excessive salivation was ob-

Table 2 Mortality and time to death and to first observation of cyanosis, as adistinctive symptom of poisoning, in groups of stoats gavage-dosed with PAPP(mean ± SE).

PAPP dose(mg/kg)

Pilot trial5025

Acute toxicity trial18.7515.6312.59.38

Mortality(no. dead/no. tested)

5/56/6

5/56/63/62/6

Time to death(min)

40.6 ± 2.636.7 ± 3.6

35.6±1.942.0 ± 3.139.3 ± 1.468.5 ± 20.5

Time to first obs.cyanosis (min)

Not recordedNot recorded

18.2 ± 3.524.0 ± 4.420.8 ± 2.513.8 ± 4.0

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166 New Zealand Journal of Zoology, 2005, Vol. 32

served in 10 of 24 PAPP-dosed stoats, and vomitingor retching observed in two of 24 stoats. Retchingwas observed once in one stoat, which survived, inthe lowest dose group (9.38 mg/kg), and retchingwith resultant vomitus in one stoat, which died, inthe 15.63 mg/kg group. Mean times to death wereconsistently around 40 min after dosing, exceptfor the lowest-dose group (9.38 mg/kg) where themean time to death (n = 4) was just over 1 h afterdosing (Table 2). Stoats that died appeared to lose

Table 3stoats.

Lethal dose values calculated for PAPP in

Lethal dose value(mg/kg)

LD50 = 9.3LD50 = 9.3LD90=15.1LD95= 17.3LD99=22.4

95% CI

0.4-11.80.01-11.811.9-16713.5-90216.0-20 500

Genstat analysis

ProbitLogitProbitProbitProbit

consciousness just prior to death (unresponsive tonoise or touch), with breathing slow, irregular, and"gasping". Just prior to death, some stoats showedwrithing or paddling movements, which appearedinvoluntary.

Those stoats that survived dosing all reached thestage where they were visibly affected, as describedabove. They remained in curled or prostrate posi-tions for at least 1 h and up to 3 h after dosing, duringwhich time it was difficult to ascertain whether theywere conscious. Recovery was usually precededby a raised head and shaky movements, followedgradually by increasing coordination of head andleg movement. Stoats that survived dosing in themorning all ate food presented to them that nightand, from daily checks, appeared to be eating andbehaving normally over the following 2 weeks.

Using either probit or logit analysis, the LD50

for PAPP in stoats was calculated at 9.3 mg/kg(upper 95% CL 11.8 mg/kg). Other LD valueswere also calculated with 95% confidence intervals(Table 3).

Table 4 Reported oral lethal dose (LD50) values for PAPP in various species. Where available thesex, species, and strain of the animals tested are given. In the absence of these in some references,"mouse" was assumed to be laboratory (Mus musculus) and "rat", laboratory (Rattus norvegicus).

Species

Dog (Canis familiaris)Coyote (Canis latrans)Kit fox (Vulpes velox)Cat (Felis libyca domestica)Bobcat (Lynx rufus)North American badger (Taxidea taxus)Raccoon (Procyon lotor)Striped skunk (Mephitis mephitis)Guinea pig (female) (Cavellio porcinus)Mouse (albino)Mouse (female)Mouse (male) (Swiss Webster strain)Rat (female) (Porton Wistar strain)Rat (male)RatRat (male) (Sprague-Dawley)Golden eagle (Aquila chrysaetos)Coturnix quail (Coturnix coturnix)Starling (Sturnus vulgaris)Red-winged blackbird (Agelaius phoenicus)Black-billed magpie (Pica pica)Common crow (Corvus brachyrhynchos)

LD50 (mg/kg)

7.55.6

14.15.6

10c. 100

142>4001020223

>5000168223.7475177221>50

>316>316

133178178

Reference

Colemanetal. (1960)Savarieetal. (1983)Savarieetal. (1983)Savarieetal. (1983)Savarieetal. (1983)Savarieetal. (1983)Savarieetal. (1983)Savarieetal. (1983)Scawinetal. (1984)Savarieetal. (1983)Scawinetal. (1984)Pan et al. (1983)Scawinetal. (1984)Scawinetal. (1984)Savarieetal. (1983)Pan et al. (1983)Savarieetal. (1983)Savarieetal. (1983)Savarieetal. (1983)Savarieetal. (1983)Savarieetal. (1983)Savarieetal. (1983)

1Dosing route not specified, assumed to be oral.

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Fisher et al.—Acute oral toxicity of PAPP to stoats 167

DISCUSSION

On the basis of an oral LD50 of 9.3 mg/kg, PAPPappears to be sufficiently toxic to stoats for furtherdevelopment as a pesticide for this species. Upperconfidence limits calculated for the PAPP toxicityvalues in stoats reflected the shape of the probitfunction, so that as the mortality rate approached 1,a large change in dose was required to gain a smallincrease in mortality. The lower confidence limitsfor the toxicity values estimated for PAPP in stoatswere less robust, and depended on the analysis used(Table 3), because the data only just extended intogroups showing 50% mortality. 1080 is more toxicto stoats than PAPP, with oral LD50 for 1080 instoats estimated as 0.49 mg/kg (0.29-0.70 95% CI),and LD90 at 0.70 mg/kg (0.47-0.87 95% CI) (Spurr2000). In comparison, relatively broad confidenceintervals for toxicity estimates of PAPP in stoats arereported here, suggesting that future bait formula-tions will need to contain sufficient PAPP to accountfor potentially wide variation in susceptibility withinfield populations of stoats. Gavage dosing with PAPPhydrochloride in solution probably resulted in higherbioavailability than would be expected after theingestion of PAPP in food. Further trials with PAPPdelivered in baits, rather than by oral gavage, arerequired to confirm an effective toxic concentra-tion and bait formulation that can achieve high killefficacy in stoats. Encapsulated formulations ofPAPP may overcome this practical limitation, andare currently being developed and pen-tested forefficacy when delivered in food to stoats (Murphyet al. 2005).

Oral toxicity of PAPP to stoats was within therange reported for some other mammalian carnivores(Table 4). Durie & Doull (1968) and Savarie et al.(1983) noted that the toxicity of PAPP can vary sig-nificantly between species and even between strains,and attributed this to variations in the metabolicpathways responsible for the detoxification andexcretion of the compound. Distinct intraspecificdifferences in the urinary excretion of aromaticamines, including PAPP, were noted by von Jagowet al. (1966), who measured the percentage of PAPPexcreted as N-hydroxy metabolite by dogs at 1%,guinea pigs approximately 15%, and rabbits 30%.The oral toxicity of PAPP in rodents and birds isgenerally lower than in mammalian carnivores. Me-dian LD50 values of 178 and 223 mg/kg for birds androdents, respectively (Table 4) indicate a relativelyreduced susceptibility. In the context of using PAPPfor stoat control, this is a promising indication ofselective toxicity. However, it should be noted that

these evaluations, in birds especially, cover a limitedrange of species and confidence of estimates. Cur-rently available toxicity figures for PAPP do notinclude New Zealand native species, or marsupials,so it is difficult to make assessments of potentialnon-target hazards of PAPP. Further developmentshould focus on stoat-specific delivery of PAPP,and quantification and minimisation of non-targetpoisoning risks.

The clinical consequences of methaemoglobinae-mia are related to the blood concentration of MetHb.In humans, dyspnoea, nausea and tachycardia occurat levels 30%, while lethargy, stupor, and deterio-rating consciousness are induced by MetHb levelsapproaching 55%. Higher levels may cause cardiacarrythmia, circulatory failure and neurological de-pression, while levels of 70% are usually fatal (Cole-man & Coleman 1996). Although MetHb levels inPAPP-dosed stoats were not measured in this trial,it was assumed that an oxygen supply to cells neces-sary for sustaining life would fail at MetHb levelsapproximating 85% (Bodansky 1951). Observationof cyanosis and progressive lethargy until death inPAPP-dosed stoats was consistent with this mode ofaction. Observations indicated that poisoned stoatsremained at least partly conscious until just priorto death, or may have had periods of intermittentconsciousness in the later stages.

Mean times to death were consistently around40 min after dosing with PAPP, except for the low-est-dose group, 9.38 mg/kg, where the mean time todeath (n = 4) was just over 1 h after dosing (Table2). While this difference suggests dose-dependencethere were insufficient data to test this statistically.Spurr (2000) reported that stoats poisoned with 1080died within 12 h. Stoats poisoned by cholecalciferolin pen trials had an average time to death of 6.3 days,and some had lost significant amounts ofbody weight(Spurr et al. 2001). In comparison, the mean times todeath following a lethal dose of PAPP in stoats weremuch shorter, and the maximum time to death in anindividual stoat was 89 min after receiving a dose of9.38 mg/kg PAPP. Even assuming that stoats wereconscious right up to death, this gives a preliminaryindication that PAPP is relatively humane, at leastcompared with other vertebrate pesticides that havebeen considered for stoat control. Further publishedstudies of other pesticide toxicoses in stoats wouldallow a more thorough comparison with PAPP, andfurther evaluations against a recognised humane-ness standard would be required to make a moreformal assessment of the humaneness of PAPP forstoat control. Bait delivery of PAPP to stoats may

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168 New Zealand Journal of Zoology, 2005, Vol. 32

be improved by encapsulated formulations, whichcould facilitate delivery of an acute toxic dose, andalso overcome possible taste aversion to PAPP.

Various effective treatment regimes have beendescribed for methaemoglobinaemia (Coleman &Coleman 1996), so that if PAPP was used as a ver-tebrate pesticide, there is the desirable possibilityof prescribing an effective treatment for accidentalpoisoning. If PAPP is further developed as a toxicbait formulation for stoats, issues of non-target sus-ceptibility (including ecotoxicity) and the potentialfor bioaccumulation and environmental contamina-tion in the New Zealand context, will need to beconsidered.

CONCLUSIONS

The high oral toxicity of PAPP to stoats suggeststhat this compound is very suitable for continueddevelopment in a new toxic bait formulation for stoatcontrol. Advantages of PAPP as a stoat control toolcould include the potential for effective treatmentof accidental poisoning, and a relatively humaneaction compared with existing vertebrate pesticides.Information gaps in the potential non-target and en-vironmental risks of using PAPP as a control tool forstoats in New Zealand remain as future priorities.

ACKNOWLEDGMENTS

All experimental procedures with animals were carried outwith approval from the Landcare Research Animal EthicsCommittee (99/4/1). Thanks to Andrea Airey, Julie Turner,Penny Willcock, Karen Washbourne and Michael Wehnerfor their technical assistance. Thanks also to Ray Websterand Greg Arnold for statistical advice; Charles Eason andChristine Bezar for comments on earlier drafts; and JohnMcIlroy and Peter Savarie for constructive referee reports.Funding was provided by the New Zealand Departmentof Conservation.

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