Contemporary Issues in Toxicology
Risk assessment of coccidostatics during feed cross-contamination: Animal and
human health aspects
J.L.C.M. Dorne
, M.L. Fernández-Cruz
, U. Bertelsen
, D.W. Renshaw
, K. Peltonen
, A. Anadon
, A. Feil
P. Sanders
, P. Wester
, J. Fink-Gremmels
a
European Food Safety Authority, Unit on Contaminants in the Food Chain, Parma, Italy
b
Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Madrid, Spain
c
Food Standards Agency, London, UK
d
Finnish Food Safety Authority, EVIRA, Helsinki, Finland
e
Universidad Complutense de Madrid, Facultad de Veterinaria, Madrid, Spain
f
ForschungsinstitutFuttermitteltechnik, Braunschweig, Germany
g
AFSSA, LERMVD, Fougères, France
h
RIVM, Food and Consumer Safety, Bilthoven, Netherlands
i
Utrecht University, Veterinary Medicine, Utrecht, Netherlands
a b s t r a c t
a r t i c l e i n f o
Article history:
Received 18 October 2010
Revised 28 December 2010
Accepted 29 December 2010
Available online xxxx
Keywords:
Coccidiostatics
Coccidiostats
Feed
Cross-contamination
Non-ionophoric
Ionophoric
Risk assessment
Toxicokinetics
Toxicology
Non-target species
Animal health
Human health
Coccidiosis, an intestinal plasmodium infection, is a major infectious disease in poultry and rabbits. Eleven
different coccidiostats are licensed in the EU for the prevention of coccidiosis in these animal species.
According to their chemical nature and main biological activity, these compounds can be grouped as
ionophoric (monensin, lasalocid sodium, salinomycin, narasin, maduramicin and semduramicin) or non-
ionophoric (robenidine, decoquinate, nicarbazin, diclazuril, and halofuginone) substances. Coccidiostats are
used as feed additives, mixed upon request into the compounded feed. During the technical process of
commercial feed production, cross-contamination of feed batches can result in the exposure of non-target
animals and induce adverse health effects in these animals due to a speci
fic sensitivity of mammalian species
as compared to poultry. Residue formation in edible tissues of non-target species may result in unexpected
human exposure through the consumption of animal products. This review presents recent risk assessments
performed by the Scienti
fic Panel on Contaminants in the Food Chain (CONTAM) of the European Food Safety
Authority (EFSA). The health risk to non-target species that would result from the consumption of cross-
contaminated feed with coccidostats at levels of 2, 5 or 10% was found to be negligible for most animal species
with the exception of salinomycin and monensin in horses because of the particular sensitivity for which
toxicity may occur when cross-contamination exceeds 2% and 5% respectively. Kinetic data and tissue
analyses showed that residues of coccidiostats may occur in the liver and eggs in some cases. However, the
level of residues of each coccidiostat in edible animal tissues remained suf
ficiently low that the aggregate
exposure of consumers would not exceed the established acceptable daily intake (ADI) of each coccidiostat. It
could be concluded that technical cross-contamination of animal feeds would not be expected to adversely
affect the health of consumers.
© 2011 Elsevier Inc. All rights reserved.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
De
finitions and regulatory framework for coccidiostats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Prerequisites for licensing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Target and non-target animal species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Obligations of feed producers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Stepwise approach to the assessment of the risk to human and animal health associated with the cross contamination of feed for non-target
animal species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Toxicology and Applied Pharmacology xxx (2011) xxx
⁎ Corresponding author.
E-mail address:
(J.L.C.M. Dorne).
YTAAP-12003; No. of pages: 13; 4C:
0041-008X/$
– see front matter © 2011 Elsevier Inc. All rights reserved.
doi:
Contents lists available at
Toxicology and Applied Pharmacology
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y ta a p
Please cite this article as: Dorne, J.L.C.M., et al., Risk assessment of coccidostatics during feed cross-contamination: Animal and human health
aspects, Toxicol. Appl. Pharmacol. (2011), doi:
Hazard identi
fication and characterisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Toxicology of coccidiostats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Toxicology in laboratory animals and health-based guidance values for humans . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Toxicological effects in non-target species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Exposure assessment: analytical techniques, toxicokinetics and human dietary exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Analytical techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Pharmacokinetics of coccidiostats in animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Residue levels in animal tissues, eggs and milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Residues in animal tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Residues in eggs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Excretion with milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Human exposure and risk assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Ionophoric coccidiostats. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Non-ionophoric coccidiostats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Conclusions and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0
Introduction
Coccidiosis is a common protozoan infection in farm animals,
affecting predominantly young animals, whereas older animals
develop immunity. Currently, herd health management cannot
exclude coccidian infections in large poultry and rabbit units and
the use of coccidiostatic agents (coccidiostats) is considered
necessary to maintain animal health and welfare, and to avoid
substantial losses due to acute and often lethal coccidiosis. Of the
40.7 million tonnes of feed produced annually for chickens for
fattening, turkeys and rabbits, approximately 18.3 million tonnes is
manufactured with the addition of a coccidiostat (
2008a, 2008b, 2008c, 2008d, 2008e, 2008f, 2008g, 2008h, 2008i,
2008j
). In the European Union, 11 coccidiostatic substances are
authorised as feed additives for the prevention of coccidiosis in one
or more animal species (mainly chicken, turkeys, and rabbits).
According to their chemical nature and main biological activity, these
compounds can be allocated to two groups: the group of ionophoric
carbocyclic polyethers (monensin, lasalocid, salinomycin, narasin,
maduramicin and semduramicin) and the non-ionophoric com-
pounds, covering structurally diverse substances: robenidine, deco-
quinate, nicarbazin, diclazuril, and halofuginone. An overview over
these products and the corresponding maximum limits in feed (MRL)
are given in
Coccidiostats for poultry and rabbits are exclusively used as feed
additives, mixed with compounded feeds in the producing feed mills
upon request. For the mandatory pre-marketing licensing procedure,
a sound database including ef
ficacy testing, technical properties and
toxicological testing needs to be provided by the applicant. The data
package includes studies on kinetics in the target animal species and
the deposition (residue formation) of the drug and/or its metabolites
in animal tissues. For feed additive use of coccidiostats, these data on
the coccidiostat-containing feed additive product are submitted to the
European Food Safety Authority (EFSA) and more speci
fic to the Panel
dealing with Additives and Products or Substances used in Animal
Feeds (FEEDAP) for assessment. The FEEDAP established, on the basis
of the toxicological data, acceptable daily intakes (ADI) for human
consumers and compared the ADIs and other toxicological data with
residue depletion data to establish maximum residue limits for food
products of animal origin intended for human consumption. The MRL
for a foodstuff gives a legally-enforceable limit to the amount of a
marker residue (either the coccidiostat or a metabolite of it) that is
without a health risk for consumers.
Practical experience indicates that during the technical production
process, residual amounts of a feed batch remain into the production
line of the feed mill, thereby contaminating the following feed
batches. This type of cross-contamination of subsequent feed batches
can result in an exposure of non-target animals. This situation is not
addressed during the licensing procedure by the FEEDAP Panel.
Therefore the Panel on Contaminants in the Food Chain (CONTAM) of
EFSA was given the task to assess the health risks for humans and
animals associated with the currently technically unavoidable cross-
contamination of feed batches. In this approach, three scenarios were
considered, i.e. a level of cross contamination of 2%, 5% and 10%,
respectively as these rates re
flect potential managerial options to
prescribe the maximum rate of cross-contamination in feed mills. This
review presents the considerations and outcome of the recent risk
assessments on coccidiostats performed by the (CONTAM) of the
(EFSA) given the task to evaluate the potential risk for animals and
consumers at this level of cross contamination.
De
finitions and regulatory framework for coccidiostats
Prerequisites for licensing
Currently, coccidiostats are authorised for use as feed additives
according to the provisions of Council Directive 70/524/EEC and
Council Regulation No (EC) 1831/2003 that repeal Directive 70/524/
Table 1a
Coccidiostats authorised in the EU as feed additives according to Council Directive 70/
524/EEC (list of authorised additives in feedingstuffs (2004/C 50/01)) and Regulation
(EC) No 1455/2004 with amendments. This table presents the commercial products and
their target species, including the statutory maximum levels in feed and the withdrawal
periods for the group of ionophoric carbocyclic polyethers.
Coccidiostat
Species
Trade
name
Concentration in
feed
(mg/kg)
WP
(days)
Lasalocid A
sodium
Chickens for fattening
Avatec
125
5
Chickens reared for
laying (max 16 weeks)
Avatec
Turkeys (max. 12 weeks)
Avatec
Maduramicin
ammonium
Chickens for fattening
Cygro
5
5
Turkeys (max. 16 weeks)
Cygro
5
5
Monensin
sodium
Chickens for fattening
Coxidin
Elancoban
125
1
Chickens reared for
laying (max. 16 weeks)
Elancoban
120
1
Turkeys (max. 16 weeks)
Coxidin
Elancoban
100
1
Narasin
Chickens for fattening
Monteban
70
1
Salinomycin
sodium
Chickens for fattening
Salinomax
70
1
Sacox
1
Kokcisan
3
Chickens reared for
laying (max. 12 weeks)
Sacox
50
–
Rabbits for fattening
Sacox
25
5
Semduramicin
sodium
Chickens for fattening
Aviax
25
5
a
The maximum level authorised in complete feed (mg/kg) is given.
b
WP: Withdrawal period.
2
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–xxx
Please cite this article as: Dorne, J.L.C.M., et al., Risk assessment of coccidostatics during feed cross-contamination: Animal and human health
aspects, Toxicol. Appl. Pharmacol. (2011), doi:
EEC and for which authorisation and prerequisites for their use are
de
fined for individual products (brands) following review by the
European Food Safety Authority (EFSA) Panel on Additives and
Products or Substances used in Animal Feed (FEEDAP Panel) of data
provided by the applicant. Previously, ADIs have been derived by four
international committees and public health agencies: the Scienti
fic
Committee for Animal Nutrition (SCAN), and its successor, the Panel
on Additives and Products or Substances used in Animal Feed
(FEEDAP) of the European Food Safety Authority (EFSA); the
Committee on Medicinal Products for Veterinary Use (CVMP) of the
European Medicines Agency (EMA), and the Joint FAO/WHO Expert
Committee on Food Additives (JECFA).
Target and non-target animal species
Authorisation for coccidiostats can be given for more than one
target animal species provided species-speci
fic data are presented to
EFSA's FEEDAP Panel. Typical target species are poultry chickens,
turkey and rabbits and within a given species, use can be con
fined to a
particular animal category or age group. The most prominent example
is the situation in poultry chickens. Most coccidiostats are licensed for
chickens for fattening and chickens for rearing, for which the use of
in-feed coccidiostats is indispensable in many cases. In-feed concen-
trations and appropriate withdrawal times are prescribed during pre-
marketing assessment. In contrast, coccidiostats are not authorised for
use in laying hens as there is a considerable risk that coccidiostats are
excreted in eggs resulting in an undesirable level of exposure of the
human consumer. Therefore, the term target species covers in most
cases fattening chickens, chickens reared for laying or turkeys until
the age of 12 or 16 weeks (as de
fined in the authorisation of the
speci
fic product) and sometimes rabbits. It needs to be emphasized
that a chicken or turkey after this de
fined period turns into a non-
target animal species.
Obligations of feed producers
Regulation No (EC) 183/2005 of the European Parliament and of the
Council of 12 January 2005 lays down the requirements for feed hygiene
that has been applied since 1st January 2006 onwards replacing Council
Directive No (EC) 95/69. Article 10 of Regulation No (EC) 183/2005
provides that feed business operators shall ensure that establishments
under their control are approved by the competent authority in case
these establishments are manufacturing and/or placing on the market
coccidiostats and histomonostats or premixtures containing coccidio-
stats and histomonostats. Cross-contamination, i.e. the transfer of
residual amounts of feed in the technical installation to the following
feed batch, has been evaluated by various expert groups (
). Systematic investigations have been carried out for
some coccidiostats, including Lasalocid and Nicarbazin (
) and showed the persistence of these
compounds in various feed batches produced after the intentional
incorporation of an ionophoric coccidiostat into feed. Technical
improvement can reduce this cross-contamination considerably and
hence limits of cross-contamination can be de
fined per product to
exclude any health risk for human and non-target animal species. These
considerations formed the basis for the selection of the three scenarios
i.e. a rate of cross-contamination of 2, 5 or 10%, respectively.
Stepwise approach to the assessment of the risk to human and
animal health associated with the cross contamination of feed for
non-target animal species
As most of the licensed coccidiostats have never been authorised
for use in the non-target animals, the available database for the
assessment of adverse health effects is very limited and often con
fined
to anecdotal reports of intoxications of farm animals in the literature
and a few tolerance studies, often without a full description of the
experimental design and the rate of exposure. Regarding the risk
associated with human health, maximum tissue levels have been
established for target animal species, and need to be derived from the
available data for other foodstuffs such as milk and eggs, which are not
included in the evaluation during the authorisation process of
coccidiostats for target animal species.
Hazard identi
fication and characterisation
Each coccidiostat has an individual toxicological pro
file, which is
based on closely related molecular mechanisms of action in the case of
the different ionophoric carbocyclic polyethers that affect transmem-
brane ion transport. In contrast to this rather homogenous group, the
non-ionophoric compounds represent a very heterogeneous group of
compounds which have a long history as coccidiostats, but for which
the mechanisms of action are incompletely known.
For the human health hazard identi
fication, the toxicological and
pharmacological effects in laboratory animals (rat, mouse, dog and
rabbit) are assessed during the licensing procedure and health-based
guidance values i.e. acceptable daily intakes (ADI) are derived on the
basis of the no-observable-adverse-effect levels (NOAEL), applying an
appropriate uncertainty factor.
For non-target animals, there were rarely suf
ficient data to allow
the identi
fication of NOAELs, so LOAELs (lowest observable effect
level) estimated from the available clinical data have been used to
characterise the risk to each non-target animal.
Toxicology of coccidiostats
Ionophoric carbocyclic polyethers. The group of carbocyclic polyether
ionophores, is comprised of natural antibiotic compounds produced by
Streptomyces spp. that also exhibit antiprotozoan activity and some are
used as coccidiostats. In general, ionophores are de
fined as lipophilic
chelating agents that transport cations across cell membranes, including
the plasma cell membrane and subcellular structures. True ionophoric
compounds are highly selective for speci
fic cations and can be either
monovalent (monensin, narasin, salinomycin, maduramicin and
semduramicin) or bivalent (lasalocid). For example, the monovalent
monensin forms monovalent complexes with Na
+
outside the cell
which are carried into the cell, thereby producing high intracellular
Table 1b
Coccidiostats authorised in the EU as feed additives according to Council Directive 70/
524/EEC (list of authorised additives in feedingstuffs (2004/C 50/01)) and Regulation
(EC) No 1455/2004 with amendments. Presented are the commercial products and
their target species, including the statutory maximum levels in feed and the withdrawal
periods of the non-ionophoric coccidiostats.
Coccidiostat
Species
Trade
name
Concentration
in feed
(mg/kg)
(days)
Decoquinate
Chickens for fattening
Deccox
40
3
Diclazuril
Turkeys
Clinacox
1
–
Rabbits for fattening
Clinacox
1
–
Turkeys for fattening
(max. 12 weeks)
Clinacox
1
–
Rabbits for fattening
Clinacox
1
1
Halofuginone
hydrobromide
Chickens for fattening
Stenorol
3
5
Chickens reared
for laying
(max 16 weeks)
Stenorol
3
–
Turkeys (max 12 weeks)
Stenorol
3
5
Nicarbazin
(combined
with narasin)
Chickens for fattening
Maxiban 50
5
Robenidine
hydrochloride
Chickens for fattening
Robenz
36
5
Turkeys
Robenz
36
5
Rabbits for fattening
Cycostat
66
5
a
The maximum level authorised in complete feed (mg/kg) is given.
b
WP: Withdrawal period; CODEX (Codex Alimentarius of JECFA).
3
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–xxx
Please cite this article as: Dorne, J.L.C.M., et al., Risk assessment of coccidostatics during feed cross-contamination: Animal and human health
aspects, Toxicol. Appl. Pharmacol. (2011), doi:
sodium concentrations, which cannot be rapidly counteracted by the
much slower K
+
ef
flux. Na
+
in
flux is balanced by an initial H
+
ef
flux
resulting in cellular alkalosis. High intracellular Na
+
concentrations give
rise in turn to intracellular Ca
++
levels due to an ATPase-driven
exchange, resulting in energy depletion and persistent high intracellular
Ca
++
levels. Salinomycin and narasin preferentially complex with K
+
ions. Lasalocid belongs to the group of bivalent ionophores that directly
translocate Ca
++
ions. As a consequence of high intracellular Ca
++
concentrations, mitochondrial uptake increases, but the elevated
cytoplasmatic Ca
++
levels will ultimately result in cellular necrosis,
which occurs primarily in cardiac and peripheral muscle cells, and
impairs conductance on peripheral nerves (
).
Subsequently, acute rhabdomyolysis with muscle weakness and
myocard insuf
ficiency are major clinical signs in acute intoxications
with monensin and other ionophoric compounds. These symptoms
have been observed not only in animals, but also in humans following
accidental ingestion of high doses of monensin (
). For example, clinical intoxications were
observed in India after the consumption of 1 g/kg b.w. per day (1 million
times the ADI) from a pudding mixed with contaminated vegetable oil.
Within 4 h all victims developed vomiting, limb and truncal muscle
weakness; two patients died within two days and symptoms included
rhabdomyolysis, hyperkalaemia, metabolic acidosis and hypocalcaemia,
respiratory failure and polyneuropathy together with markedly
elevated creatinine phosphokinase MM isoenzyme. At 8 days after
exposure, clinical examination of the surviving patients revealed toxic
polyneuropathy with varying degrees of rhabdomyolysis, and poly-
radiculopathy of nerves. Electrocardiographic and echocardiographic
results were normal and cardiomyopathy was not detected. Acute renal
failure (following myoglobinurea) developed at 8
–10 days after
exposure in 4 of the 5 survivors (
). Comparable
signs with muscle weakness and extremely high CPK values were also
reported following the ingestion of a ruminant formula of monensin by a
young man (
) as well as following accidental
inhalation/ingestion of salinomycin by a farm worker (
).
Other publications refer to the risk of pharmacological effects on
the cardiovascular system (e.g. inotropy) following exposure to
ionophoric substances. Such effects were provoked in anaesthetised
dogs following parenteral administration of monensin, resulting in an
increase in coronary blood
flow and cardiac contractility with a NOEL
of 0.0345 mg/kg b.w. (
). For narasin, a pharmacological
NOEL of 1.53 mg/kg b.w./day was identi
fied for effects on cardiovas-
cular function (inotropy) in dogs (
). For other
ionophoric coccidiostats, NOELs for cardiovascular effects were not
identi
fied. A specific finding for maduramicin and semduramicin was
macrocytic hypochromic anaemia in avian species. The mechanism
behind this observation still remains to be characterised.
Non-ionophoric compounds. In comparison with ionophoric coccidio-
stats, the toxicology of non-ionophoric coccidiostats varies consider-
ably, as these belong to entirely different chemical classes. Many of
the compounds have been derived from parasitological screening
experiments, and their mechanisms of toxicity have not to date been
characterised. This applies to robenidine, decoquinate and nicarbazin,
a chemically synthesized product, representing an equimolar complex
of 4,4
′-dinitrocarbanilide (DNC
) and 2-hydroxy-4,6-dimethylpyri-
midine (HDP). Diclazuril belongs to the group of benzene acetonitrile
compounds that also includes toltrazuril a coccidiocidal agent used in
veterinary therapy. The mechanisms of toxicity of diclazuril has not
been fully elucidated. However, it was noted that both diclazuril as
well as halofuginone reduced testicular size in male dogs.
Toxicology in laboratory animals and health-based guidance values for
humans
Previously, ADIs have been derived by four international committees
and public health agencies: the Scienti
fic Committee for Animal
Nutrition (SCAN), and its successor, the Panel on Additives and Products
or Substances used in Animal Feed (FEEDAP) of the European Food
Safety Authority (EFSA); the Committee on Medicinal Products for
Veterinary Use (CVMP) of the European Medicines Agency (EMA), and
the Joint FAO/WHO Expert Committee on Food Additives (JECFA). A
brief appraisal on the derivation of ADIs for ionophoric and non-
ionophoric coccidiostat is given in
. This table summarises the
hazard identi
fication and characterisation details of the ionophoric and
non-ionophoric coccidiostats performed by the CONTAM panel of EFSA
referring to the pivotal toxicological, test animal species, and uncer-
tainty factors applied in the derivation of the ADI.
Ionophoric polyether coccidiostats. For monensin, an ADI of 0.003 mg/
kg b.w. per day was derived by applying the 100-fold safety factor to
NOAEL values of 0.345 and 0.3 mg/kg b.w. per day based on a one-year
study in dogs on two different preparations using cardiovascular
changes measured as an increase in blood
flow through the coronary
artery and developmental toxicity in rabbits respectively (
).
For lasalocid, a two-year dietary study in rats using doses of 0, 0.5,
1.8 and 6.2 mg/kg b.w. per day and 0, 0.6, 2.2 and 8.1 mg/kg b.w. per
day in males and females respectively has been used to set the ADI.
Increases in liver weight in both sexes treated at the mid and high
doses group, and an increase in adrenal gland weight in females at the
mid and high dose groups were observed with respective NOEL values
of 0.5 and 0.6 mg/kg b.w per day for males and females respectively. In
1
DNC is also known as N,N
′-bis(4-nitrophenyl)urea.
Table 2
Summary of critical toxicological endpoints used for the derivation of acceptable daily
intake level for coccidiostats by the European Food Safety Authority.
Coccidiostat
NOEL/NOAEL
Species/
study length
UF
ADI
mg/kg b.w per day
mg/kg
b.w per
day
Lasalocid
0.5: Increased liver and adrenal
weights
Rat/2 years
100 0.005
Maduramicin
0.16: Decrease body weight gain
Rat/2 years
100 0.001
Monensin
0.345: Increased blood
flow
(coronary artery)
Dog/acute
100 0.003
Narasin
0.5: Axonal degeneration of
peripheral nerves and focal
degeneration of skeletal muscles
Dog/1 year
100 0.005
Salinomycin
0.5: Neurotoxic effects (myelin
loss and axonal degeneration)
Dog/1 year
100 0.005
Semduramicin 0.125: Decreases in serum
concentrations of protein and
sodium
Rat/2 year
100 0.00125
Decoquinate
15: Subdued behaviour, reduced
activity and emesis
Dog/
12 weeks
200 0.075
Diclazuril
2.9 Swelling of centrilobular
hepatocytes and of sinusoidal
cells. Decreases in serum
concentrations of protein and
sodium
Mice/2 years
100 0.029
(0.030)
Halofuginone
0.03: Maternal toxicity (reduced
bodyweight gain) in a
developmental toxicity study
Rabbit/
reprotoxicity
100 0.00003
Nicarbazin
200: Maternal toxicity (increased
mortality) and foetotoxicity
(delayed ossi
fication and reduced
foetal weight)
Rat/
reprotoxicity
500 0.2 (0.4)
DNC (marker
residue for
nicarbazin)
154: elevation of serum alanine
aminotransferase
Dog/2 years
200 0.77
Robenidine
7.5: Liver enlargement
Dog/90 days
200 0.0375
a
Data provided by JECFA and/or the CVMP.
b
ADI for nicarbazin derived for the metabolite 4,4
′-dinitrocarbanilide in 2010.
4
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aspects, Toxicol. Appl. Pharmacol. (2011), doi:
comparison, dogs were less sensitive than rats, and a NOEL of 1 mg/kg
b.w. per day was derived for both sexes based on an increase in serum
alkaline phosphatase activity. Hence, the NOEL of 0.5 mg/kg b.w per
day for changes in liver weight in rats was used to derive an ADI of
5
μg/kg b.w. (0.005 mg/kg b.w.) using a 100-fold uncertainty factor
). In a developmental toxicity study with New Zealand
white rabbits, lasalocid was given to groups of 12 pregnant rabbits at
dose levels of 0, 0.5, 1 and 2 mg/kg b.w./day (by gavage) and the NOEL
for maternal and foetal toxicity was also 0.5 mg lasalocid/kg b.w. per
day. Skeletal deformations were observed at high concentrations. As
the quality of these experiments did not meet recent standards and
only limited data regarding the potential neurotoxicity were
presented, different uncertainty factors have been discussed, varying
between 100 (
) and 200 (
).
Applying the latter uncertainty factor, an ADI of 0.0025 mg/kg b.w.
was derived.
Two salinomycin-based products were assessed by EFSA. A one-year
oral study in dogs showed a NOAEL of 0.5 mg/kg b.w. per day.
Toxicological endpoints for the NOAEL included neurotoxic effects
characterised by myelin loss, primary axonal degeneration and
Wallerian-like degeneration. The ADI was then derived by applying a
100-fold uncertainty factor to give a provisional ADI of 5
μg/kg b.w.
(0.005 mg/kg b.w.) (
EFSA, 2004b, 2004d, 2005a, 2008a
).
The ADI for maduramicin of 1
μg/kg b.w. (0.001 mg/kg b.w) was
derived on the basis of a two-year oral toxicity study in rats to which
an uncertainty factor of 100 fold was applied to the NOEL of 0.16 mg/
kg b.w. per day applying and rounding down to one-signi
ficant figure
for maduramicin (
For semduramicin an ADI of 0.00125 mg/kg b.w. was derived using
the most sensitive NOAEL of 0.125 mg/kg b.w. per day from a 2-year
dietary study in rats and an uncertainty factor of 100 (
). The
toxicological endpoints re
flected changes in blood biochemistry para-
meters (decreased serum protein and sodium levels) with a LOAEL
0.25 mg/kg b.w. per day in this study. In dogs (1, 6 and 12-month
studies), retinal changes (degeneration of rods and cones) were
observed at 1 mg/kg b.w. per day (LOAEL) with a NOAEL of 0.3 mg/kg
b.w. day (
For narasin, the critical toxicological study to set the ADI was a
one-year oral study in dogs using doses of 0, 0.5, 1.0, 2.0 mg/kg b.w.
per day. Focal degeneration of skeletal muscles, including the
diaphragm, and axonal degeneration of peripheral nerves were
observed at 1 and 2 mg/kg b.w per day in both males and females
with a NOAEL of 0.5 mg/kg b.w. per day. An ADI of 0.005 mg/kg b.w.
was calculated by applying a 100-fold uncertainty factor to the NOAEL
(
Non-Ionophoric coccidiostats. For robenidine an ADI of 0.0375 mg/kg
b.w. was established by applying an uncertainty factor of 200 to a NOEL
of 7.5 mg/kg b.w. per day, based on liver enlargement in a 90 day dog
study. The uncertainty factor of 200 was selected in account of the
limited quality of the available studies. At higher doses (32.5 mg/kg b.w.
per day) diffuse cytoplasmic vacuoles were observed in hepatocytes.
Other toxicological studies that were considered in the assessment were
90-day feeding studies in mice and rats, an 84-week feeding study in
rats, a two-generation reproduction study in rats (incorporating an
investigation of developmental toxicity), and a developmental toxicity
study in rabbits. Mutagenicity tests (a bacterial reverse mutation test, an
in vitro test for chromosomal aberrations in mammalian cells and a
mouse bone marrow micronucleus test) gave uniformly negative
results. No carcinogenicity study was provided, but limited histopath-
ological examinations of tissues from the 84-week rat study showed no
evidence of any treatment-related neoplasms (
For decoquinate an ADI of 0.075 mg/kg b.w. was calculated by
applying an uncertainty factor of 200 to the lowest toxicological
NOAEL, namely 15 mg/kg b.w. per day, for subdued behaviour,
reduced activity and emesis in dogs in a 12-week oral toxicity
study. The 200-fold uncertainty factor was applied rather than the
standard 100-fold factor to take into account the uncertainty in the
determination of the NOAEL because the critical dog study (and other
studies such as a rabbit developmental toxicity study) was not
conducted according to current standards (
For nicarbazin, a NOEL of 200 mg/kg b.w. per day of the 3:1 mixture
(i.e. 150 mg DNC: 50 mg HDP/kg b.w.) was found in a two generation
reproduction toxicity study, in which rats were treated with 0, 50, 150
or 300 mg DNC/kg b.w. per day and 0, 17, 50, or 100 mg HDP/kg b.w.
per day continuously through the production of two litters per
generation for three successive generations. There were isolated
occurrences of slightly reduced litter size at birth or depressed body
weight gain during lactation at the highest dose level. These effects
were not observed in the majority of litters and showed no
progression with the duration of the study. Teratogenic effects were
not observed. While the JECFA concluded in 1999 (
)
that the results of this study show that nicarbazin had no signi
ficant
effects on reproduction in rats and proposed a NOEL of 400 mg/kg b.w.
day, the FEEDAP Panel used the more conservative approach and
selected 200 mg/kg b.w. as provisional no-effect level among others in
consideration of a second study with high doses of nicarbazin (up to
600 mg/kg b.w.) in which maternal toxicity and fetotoxicity (delayed
ossi
fication) were observed. In addition, the FEEDAP Panel expressed
its concerns about the equivocal results in a bacterial reverse
mutation test, which would need further clari
fication. A negative
result was obtained with in vivo assays such as in a micronucleus test
in bone marrow erythrocytes, but no other mutagenicity or
genotoxicity assays were available. Only recently the FEEDAP panel
set an ADI of 0.77 mg/kg b.w. for the metabolite of nicarbazin, DNC on
the basis that new mutagenicity tests, and in consideration of the
finding that nicarbazin is rapidly metabolised to DNC and hence it is
unlikely that consumers are exposed to nicarbazin. A NOAEL of
154 mg/kg.b.w per day was derived based on a two-year dog study
and the elevation of serum alanine aminotransferase activity and
applying a safety factor of 200 (
For diclazuril and ADI of 0.029 mg/kg b.w. was derived by applying
a 100-fold uncertainty factor to the lowest no observed effect level
(NOEL) of 2.9 mg/kg b.w. per day, established from a two-year oral
toxicity/carcinogenicity study in male mice using non-speci
fic
changes in the liver (swelling of centrilobular hepatocytes and of
sinusoidal cells) and, histiocytosis and the presence of pigmented
macrophages in the mesenteric lymph nodes as toxicological end-
points. Diclazuril had very low acute toxicity and was not mutagenic,
genotoxic, carcinogenic, embryotoxic, fetotoxic or teratogenic (
). Other evaluations of
and the JECFA
(FAO/WHO, 1999???) derived an ADI of 30
μg/kg b.w. based on the
same data and apparently by rounding the ADI to one signi
ficant figure.
For halofuginone hydrobromide, the FEEDAP Panel could not
establish an ADI based on the data presented in the course of an
application for use in poultry. The available data suggest obvious
species differences in metabolism, and non-identi
fied metabolites in
avian species. Hence it was concluded that further investigations need
to elucidate the chemical composition and toxicity of the various
metabolites, particularly as there was one positive result in a bone
marrow mutagenicity assay with halofuginone hydrobromide in avian
species. Halofuginone lactate is used as a therapeutic agent in calves.
For this derivative the CVMP established an ADI of 0.3
μg/kg b.w. This
ADI was used to establish the MRL values of 10, 25, 30 and 30
μg/kg for
muscle, fat, liver and kidney tissue, respectively. The MRLs apply to
bovines not producing milk for human consumption. The CVMP based
their conclusion among others on the fact that the indication for use of
halofuginone in non-ruminating calves of 4 to 15 days of age implies
that treated animals will not be sent for slaughter during or
immediately after treatment and thus would not enter the food
chain (
5
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Please cite this article as: Dorne, J.L.C.M., et al., Risk assessment of coccidostatics during feed cross-contamination: Animal and human health
aspects, Toxicol. Appl. Pharmacol. (2011), doi:
Toxicological effects in non-target species
Toxicological investigations in laboratory animals as well as target
animal species indicated the signi
ficant differences in the sensitivity of
animals, particularly with respect to the ionophoric compounds. In non-
target species, hazard identi
fication and characterisation has to rely
upon basic mechanisms of toxicity and clinical cases of intoxications to
identify critical concentrations for the individual coccidiostats. Toxic
syndromes in non-target animal species are related to: (1) incidental
consumption of forti
fied feeds (in most cases intended for chickens) by
other animal species; (2) feed-mixing errors or ingestion of premix
concentrates with unsafe amounts of ionophores; (3) off-label use,
either accidental or intentional, have resulted in adverse reactions in
adult poultry (laying hens), ostriches, ornamental and game birds,
rabbits, camels, deer, water buffaloes, and humans; and (4) drug
interaction with other veterinary medicinal products (target and non-
target animal species).
Common textbooks in Veterinary Toxicology refer to the high
sensitivity of horses to monensin and unexpected cases of ionophore
intoxications in companion animals (
). The current review aimed particularly at the identi
fication of
animal species that might experience adverse health effects following
exposure to feed contaminated with the low concentration that may
result from cross-contamination of feed batches during the produc-
tion process.
Identi
fication of animal species sensitive to ionophoric coccidiostats. The
general underlying pharmacological and toxicological properties of
ionophoric coccidiostats relate to their structure as carboxylic iono-
phoric compounds, modifying the permeability of biological mem-
branes by forming lipid soluble, dynamically reversible cation
complexes thus facilitating a unidirectional transport of cations into a
cell which in turn results in an accumulation of intracellular calcium.
Each ionophoric coccidiostat species has its own molecular polarity,
inorganic ion selectivity pattern and toxicity. The most common signs
clinical signs of intoxication include cardiovascular effects (inotropy and
raised blood pressure), necrosis of striated muscles (rhabdomyolysis)
and damage to nerves (peripheral neuropathy). Other signs of
intoxication include anorexia, diarrhoea, depression, dyspnoea (prob-
ably as consequence of the cardiac effects) as well as growth retardation.
Horses. Horses have been considered as one of the most sensitive
animal species to ionophoric compounds. This assumption was based
on the sensitivity of horses to monensin (
).
Clinical reports refer to the consumption of cattle feed (33 mg/kg
monensin) causing transient anorexia in horses. The consumption of
feed containing 121 mg/kg monensin (intended for chickens for
fattening) causes clinical signs of toxicity ultimately resulting in death
(
). Typical
findings were partial anorexia, colic,
tachycardia, progressive ataxia and recumbence, profuse sweating
and at later stage polyuria. Post mortem investigations revealed
haemorrhage and pale areas in the heart (in contrast to pigs and dogs
in which the lesions are most prominent in skeletal muscle tissue),
and in some cases pulmonary oedema, hydrothorax, ascites and
in
flammatory reactions in the stomach and the intestines (
). In a controlled exposure study an LD50 of 1.38 mg/kg
b.w. was estimated (
). One of the likely reasons of
the high susceptibility of horses to monensin is their relative
de
ficiency in CYP450 demethylating enzyme capacity and hence the
slow clearance of monensin. In vitro experiments with liver micro-
somes from various animal species, including horses, pigs, broiler
chickens, cattle and rats, showed that horses has the lowest catalytic
ef
ficiency to demethylate (and hence detoxify) monensin (
).
The second toxic ionophore for horses is salinomycin. Clinical signs
of intoxication such as paralysis of the hind limbs occurred at doses as
low as 0.12
–0.25 mg/kg b.w. At 0.6 mg/kg b.w per day, symptoms of
intoxication were immobility, increase in heart and respiratory rates,
cardiac insuf
ficiency with development of stasis-induced hyperaemia
and pulmonary oedema together with fat accumulations in the liver
and myocardium with subsequent scar formation and destruction of
the musculature (
). In contrast, semduramicin at
doses of 0.25 mg/kg b.w. per day (25 mg/kg feed) induced no
signi
ficant alterations in body weights, haematology and clinical
chemistry values, and clinical signs of intoxication were not observed
(
Narasin toxicity in horses was observed at gavage doses of 1.6 mg/
kg b.w. and included anorexia, uneasiness, ataxia, sweating, increased
and laboured respiration, weakness and recumbence with myocardial
degeneration at necropsy and irritation of the gastric mucosa (
).
Lasalocid was reported to be lethal in horses at 15 mg/kg b.w.
through toxic myocarditis of lesser intensity than that produced by
monensin (
Kronfeld, 2002; Nicpon et al. 1997
No clinical case reports could be found involving maduramicin or
semduramicin.
These data indicate that intoxications caused by ionophoric
compounds are a critical differential diagnosis in horses exhibiting
signs of muscle weakness, laboured respiration and cardiac symp-
toms. Moreover intoxications have been observed following the
ingestions of poultry feed forti
fied with monensin. As salinomycin is
licensed in a concentration of 50
–70 mg/kg feed for fattening
chickens, the ingestion of less than 1.5 kg of this feed by a horse
would present a serious health risk. On the basis of the rather
incomplete dose
–response assessment of ionophoric coccidiostats for
horses, the CONTAM Panel concluded that salinomycin at a level of 2%
cross-contamination (from chicken feed) and monensin probably
only at a level of 5% cross-contamination are able to induce adverse
health effects in horses. For other ionophoric coccidiostats, the risk is
lower and clinical cases of intoxications are not expected even at the
level of 10% cross-contamination.
Companion animals (dogs and cats). Dogs and cats are less likely to
be exposed to ionophoric compounds, as their feed is produced in
most cases separately from the large feed mills that produce feed for
farm animals. However, dogs are very sensitive to ionophoric
compounds, as indicated by the controlled experiments in dogs,
which were conducted as part of the overall toxicological assessment
of these compounds. NOAEL levels varied between 0.3 mg/kg b.w. for
monensin, 0.5 mg/kg b.w. for salinomycin and lasalocid and 1 mg/kg
b.w. for the other ionophoric coccidiostats. In dogs, signs of
intoxication included neurological de
ficits (at 5 mg/kg b.w. per day)
with quadriparesis, hypore
flexia together with systemic signs,
including dyspnoea, a high body temperature, tongue laxity, hyper-
aesthesia and anisocoria. Activities of creatine kinase, lactate
dehydrogenase and aspartate aminotransferase were also increased
in the blood serum (
). Salinomycin induced signs of
neurotoxicity as well in experimental studies, with a NOAEL of
0.5 mg/kg b.w. (signi
ficantly higher than the tolerable level for
horses) as well as skeletal muscle degeneration (
). Skeletal muscle damage was also the most prominent symptom
of exposure to semduramicin. In addition, semduramicin induces retinal
changes in dogs that have not been shown in other species yet.
In cats an outbreak of acute paralysis occurred in the Netherlands
and in Switzerland related to two brands of dry cat feed from one
manufacturer containing salinomycin (from cross contamination of raw
materials in the feed mill) at levels of 16
–21 mg/kg feed (approx. 16% of
the maximal licensed feed concentration), indicating that the cat is more
sensitive to salinomycin than dogs. The intoxicated cats developed
paresis and paralysis of hind limbs and lameness. Post-mortem
examination revealed distal polyneuropathy including sensory and
motor neurones. Peripheral nerve injury of the axons, (myelin sheath,
collapsed axonal sheaths
filled with foamy macrophages and swollen
Schwann cells) was more severe than the central nerve injury in affected
cats (
van der Linde-Sipman et al., 1999
).
6
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Farm animal species. Pigs: Pigs are generally considered to be less
sensitive to ionophoric compounds. Studies with monensin, for
example, showed that a single oral gavage dose of 5 mg/kg b.w. was
well tolerated (NOAEL), whereas at 10 mg/kg b.w. clinical signs of
intoxications were noted. A dose of 30 mg/kg b.w. was lethal (
). In barrows, gilts and in pregnant sows, the NOAEL for
salinomycin was equal to or greater than 5 mg/kg b.w. per day
(corresponding to approximately 60 mg/feed). Salinomycin toxicosis
was also induced experimentally in weanling pigs resulting in severe
ataxia and recumbence attributable to acute skeletal muscle necrosis at
a concentration of 441 mg/kg in coarse feed (
). This
concentration is about 4 times higher than the maximum authorised
feed concentration for poultry and 10 times higher that the previously
authorised dose in pigs indicating an appreciable margin of safety in
porcine species. Narasin caused clinical signs of toxicity in growing and
fattening pigs were observed at concentrations of 75 and 125 mg/kg
feed (licensed concentration for poultry 70 mg/kg feed), with symp-
toms of anorexia, dyspnoea, depression, leg weakness, ataxia, and
lateral recumbence (
). These
findings did not identify a
speci
fic risk for porcine species associated with cross-contamination of
feeds during the production process.
Cattle: In various countries monensin is licensed for use in fattening
cattle to improve rumen function up to a concentration of 50 mg/kg
feed, and is one of the most frequently used feed additives in the USA.
No signs of toxicity (detectable by haematology, blood biochemistry
and necropsy) were observed at dietary concentrations of up to
110 mg/kg feed for beef cattle and 120 mg/kg for calves (
). In contrast, clinical signs of intoxication (with lethargy,
diarrhoea and reduced milk production) occurred following a mixing
error resulting in a feed concentration of 500 mg monensin per kg
concentrate, of which dairy cows consumed approximately 23 kg per
day (approx. 17 mg/kg b.w.) (
). In comparison to
cattle, buffaloes have a lower tolerance to monensin pointing again to
the fact that species differences are of importance in the evaluation of
non-target animal toxicity (
).
Clinical intoxications attributable to lasalocid included watery
diarrhoea, muscle tremors, and greater cardiac and respiratory rates
followed by or concurrent with anorexia (
).
In steers, treated with lasalocid at doses of 1, 10, 50 or 100 mg/kg b.w,
clinical symptoms (muscle tremors, tachycardia and rumen atonia)
including death were observed at 50 mg/kg b.w. In contrast, in young
(pre-ruminating) calves (
b7 days old), lethal effects were observed
already at doses from 5 to 8 mg/kg b.w (
). An
even higher sensitivity of pre-ruminant calves fed milk powder
contaminated with salinomycin. The lethal dose was approximately
1.5 mg/kg b.w. Associated symptoms were vascular degeneration and
of the heart myo
fibrils and widespread tubulonephrosis (
). Salinomycin caused adverse and lethal effects in young
steers (cardiovascular disturbances, tremor and food refusal) at 8 and
10 mg/kg b.w., respectively. Adult (ruminating) cattle showed
comparable signs of intoxication, with myocardial lesions and
multifocal muscle hypertrophy at 90 mg/kg feed concentrate con-
taminated with salinomycin.
Studies with narasin in Hereford heifers showed no clinical signs of
toxicity were up to 0.5 mg/kg b.w. per day (equivalent to 25 mg
narasin/kg feed) but doses of 4 and 8 mg/kg b.w. per day were lethal
after 5 and 6 days respectively. Pathology revealed marked congestion
and oedema of the lungs and focal haemorrhages in the heart. The
NOAEL for maduramicin was 4 mg/kg feed (0.06 mg/kg b.w. per day)
in mid-lactating cows, and 0.15 mg/kg b.w. per day in steers. These data
allow the conclusion that cattle, might be at risk following the accidental
consumption of feed intended for poultry, but the risk for adverse
health effects following feed levels resulting from cross-contamination is
low. Apparent exception is the pre-ruminating calf, which is very
sensitive to salinomycin, with a dose of 1.5 mg/kg b.w. being lethal,
suggesting that these animals are even more sensitive than dogs.
Small ruminants: In sheep, clinical signs of monensin intoxication
included CNS depression, anorexia, diarrhoea, and stiffness. Serum
creatine phosphokinase and aspartate aminotransferase activities were
increased. At necropsy skeletal muscle haemorrhages, pale myocardium,
and pulmonary oedema were seen. Intoxications were observed at
concentrations of 40
–50 mg/kg of feed, demonstrating that sheep are
more sensitive that cattle. In male lambs for fattening, a LOAEL of 5 mg/
kg b.w. was estimated and an LD50 of 12 mg/kg b.w. (
). In sheep the signs of a lasalocid intoxication
comprised cardiac dilatation, congestive heart failure following cardio-
myopathy and severe skeletal muscle lesions in the hindquarters
(
Poultry, turkeys and rabbits: target animals or species at risk?
Poultry chickens are the major target animals for the use of
coccidiostats. However, the margin of safety is rather small and a
reduction of feed intake and growth rates has been reported at the
maximum authorised dietary concentration in some cases. Clinical
reports indicated also that turkey pullets are even more sensitive to
certain coccidiostats, which cannot be used in these species as the
effective dose causes serious side effects. A comparison of the
available data is presented in
. Signs of intoxication caused
by ionophoric compounds in avian species include locomotor
disorders, severe dyspnoea, and moderate diarrhoea. At post-mortem,
muscle
fibre damage [Zenker's (hyalinic) degeneration] and necrosis
were noted. In addition, catarrhal enteritis, renal degeneration and
pulmonary congestion were described as typical post-mortem
findings (
).
Rabbits: Rabbits are one of the target animal species for coccidio-
stats. The selection of the compounds licensed for rabbits had to take
into account the sensitivity of these animals to certain compounds,
such as lasalocid with a NOEL for maternal and foetal toxicity of
0.5 mg/kg b.w. (
). In male rabbits, symptoms of
toxicity due to narasin were observed at doses of 30 mg/kg feed or
higher and included decreased locomotor activity, weakness in the
extremities, ataxia, relaxation of the abdominal muscle, ptosis and
decreased respiration (
). For maduramicin a LOAEL
of 0.075 mg/kg b.w. per day de
fined the rabbit as most sensitive
species.
Identi
fication of animal species sensitive to non-ionophoric coccidiostats.
In contrast to the ionophoric compounds, the non-ionophoric
coccidiostats are diverse in their chemical structure, and no general
Table 3
Comparison of the toxicity of coccidiostats in poultry chicks and turkeys.
Max. licensed
(mg/kg feed)
Chicken
(mg/kg feed)
T/NT
Turkey
T/NT
Ionophoric coccidiostats
Monensin
100
–125
LOAEL 250
T
LOAEL 150
T
Lasalocid
125
NOAEL 150
T
NOAEL 375
T
LOAEL 345
Salinomycin
50
–70
LOAEL 50
T
LOAEL 13
NT
Narasin
70
LOAEL 100
T
LOAEL 43
NT
Maduramicin
5
LOAEL 5
T
LOAEL 10
T
Semduramicin
25
LOAEL 30
T
NOAEL 25
NT
Non-ionophoric coccidiostats
Robenidine
36
LOAEL 300
T
LOAEL 750
T
Decoquinate
40
LOAEL 320
T
ND
NT
Nicarbazin
50
LOAEL 400
T
ND
NT
Diclazuril
1
NOAEL 25
T
NOAEL 25
T
Halofuginone
3
LOAEL
T
LOAEL 6
T
T
— target animal species, NT non target animal species.
a
Reduction of feed intake was the only adverse sign.
b
At a concentration of 13
–18 mg/kg feed mortality reached 16%.
c
At a concentration of 43 mg/kg mg/kg feed, mortality exceeded 30%.
7
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comparisons can be made. Hence the available information will be
presented per substance. A comparison of the susceptibility of avian
species is included in
.
Decoquinate. Decoquinate has a low acute oral toxicity in a range of
avian and mammalian species with LD50 values often exceeding
5000 mg decoquinate/kg body weight. It is licensed at a concentration
of 20
–40 mg/kg feed. The most sensitive animal species is the horse,
with a of NOAEL 6 mg/kg b.w per day in ponies and horses
(approximately 0.13 mg/kg feed, which is much lower that the feed
concentration generally applied in poultry, and hence the given
NOAEL does not exclude adverse effects following the accidental
ingestion of poultry feed). In dogs, experimental studies (12-week
oral toxicity study) indicated a NOAEL of 15 mg/kg b.w. per day for
subdued behaviour, reduced activity and emesis (
). In
farm animals the NOAEL varies between 80 mg/kg feed (pigs and
large ruminants) and 250 mg/kg in lambs, for which it is approved for
therapeutic purposes (coccidiosis) at a level of 50 mg/kg feed. A
NOAEL of 60 mg/kg b.w. was identi
fied for the rabbit with a slight
reduction in the number of implantation sites and a reduction in the
number of live foetuses at higher doses.
Nicarbazin. Nicarbazin, which rapidly splits into 4,4-acetonitrile
(DCN) and 2-hydroxy-4,6-dimethylpyrimidine following ingestion, is
authorized at a concentration of 50 mg/kg feed. LD50 values of
2400 mg/kg b.w. in chickens and a NOAEL of 200 mg/kg feed, indicate
a therapeutic index of
N10. No data could be identified concerning
intoxications in companion or farm animals (
).
Diclazuril. Diclazuril is licensed as coccidiostat at a concentration of
1 mg/kg feed, the lowest concentration among all coccidiostats. A
limited study in two horses showed no adverse effects at 1 or 20 mg/
kg b.w., as it is poorly absorbed with a bioavailability of 9.5% when
given with feed (
). In contrast, in a dog study a
NOEL could not be identi
fied, as signs of reduced male fertility were
observed at the lowest tested dose (2.5 mg/kg feed, 0.0067 mg/kg b.
w). No adverse effects were seen in calves (5 mg/kg b.w), sheep
(60 mg/kg b.w), goats (80 mg/kg b.w) or piglets (10 mg/kg b.w).
Rabbits showed feed refusal at 3 mg/kg feed. In avian species, signs of
intolerance to diclazuril, starting with feed refusal, were observed in
guinea fowls (3 mg/kg for 24 h,), partridge (from 1 mg/kg), quail
(3 mg/kg), Muscovy ducks (3 mg/kg) and geese (3 mg/kg) (
).
Halofuginone. Halofuginone is licensed at a concentration of 3 mg/
kg feed. No intoxications have been reported from horses, and in dogs
toxicological studies with diets containing 2.5 and 5 mg/kg feed
(equivalent to 0.0067 and 0.134 mg/kg b.w. per day), for 68 weeks,
revealed a signi
ficant decrease in testicular size and in fertility in all
animals, comparable to the results obtained with diclazuril. Pre-
ruminant calves are target animals for the therapeutic administration
halofuginone (recommended therapeutic regimen 0.1 mg/kg b.w. per
day for 7 days). Increased mortality was already observed at 0.2 mg,
indicating a therapeutic margin of
b2. Clinical features of intoxication
were anorexia, diarrhoea, in
flammation and congestion of the
gastrointestinal tract, adrenal hypertrophy, hypoproteinaemia, hyper-
uraemia and high urinary creatinine levels were observed (
). It is also known that avian species, other than
chickens, such as partridge, guinea fowl, Muscovy ducks and geese are
more sensitive than chickens showing feed refusal at concentrations
of 1
–1.5 mg/kg feed or greater (
In conclusion, despite the limited safety margin of some of these
non-ionophoric compounds, the adverse effect on feed intake protect
most animal species from intoxications, which are rarely reported in
the literature.
Toxicological risks evolving from interactions with other veterinary
drugs. Monensin, and lasalocid show interactions with therapeutic
antimicrobials commonly used in veterinary medicine, such as
tiamulin, sulphonamides, chloramphenicol, macrolides (erythromy-
cin and oleandomycin) and furazolidine, which increase their toxicity
(
Frigg et al., 1983; Broz and Frigg, 1987; Anadón and Martinez-
Anadón and Reeve-Johnson, 1999
The most prominent example for an interaction with direct clinical
adverse effects is the co-administration of tiamulin (a pleuromutilin
widely used in veterinary medicine for the treatment of Mycoplasma
spp infections) with monensin. Even if both drugs are given at the
recommended doses, fatal intoxications occurred in chickens, turkeys
and pigs (
Miller et al., 1986; Drake, 1981
). Tiamulin was shown to
inhibit the mixed function oxidase system in chickens as re
flected by
the disposition of antipyrine (
). Recent studies
have demonstrated that tiamulin inhibits the oxidative drug metab-
olism (CYP 3A) via the formation of a cytochrome P450 metabolic
intermediate complex (
) as do macrolides
(
Larrey et al., 1983; Watkins et al., 1986
). This inhibition results in a
slower demethylation (inactivation) of monensin (
), and the animals experience a relative overdose of monensin
and exhibit clinical signs of intoxication.
Exposure assessment: analytical techniques, toxicokinetics and
human dietary exposure
Analytical techniques
Analytical procedures to control the concentrations of licensed
coccidiostats in animal feeds as well as the measurement of residues
in animal tissues are part of the pre-marketing assessment of these
compounds. However, in most cases these methods have not been
validated for other mixed feeds (that might give entirely different
matrix effects) and at the low levels expected in feed as a consequence
of cross-contamination. Moreover, certain animal products such as
milk and eggs, had previously only incompletely been addressed and
in the absence of health-based guidance levels for human consumers,
the lowest detection levels, and validation parameters have only been
de
fined recently following the results of the EFSA reviews. A detailed
description of the individual methods is presented in the EFSA
Opinions for all individual coccidiostats. Recent developments in feed
analysis allowing the simultaneous determination of all relevant
coccidiostats at low (cross-contamination) levels in feeds are
presented by
. Multi-residue analyses are also
described for eggs (
) and tissues (chicken liver) by
.
Pharmacokinetics of coccidiostats in animals
For target animal species, toxicokinetic parameters, particularly the
elimination half-life (t
1/2ß
) and/or the Mean Residence Time (MRT)
were used to determine withdrawal periods, i.e. the time between drug
application and slaughter (and hence consumption). The reader is
referred to the individual EFSA opinions presenting the toxicokinetics
for each coccidiostat in both target and in non-target species where
available. These data indicate that coccidiostats are only partly absorbed
(1
–30%), with the exception of salinomycin and halofuginone having
bio-availabilities of 73 and 81%, respectively. All compounds are well
distributed to all the tissues, including the skin. The highest residues of
coccidiostats were found in liver (and eggs) followed by skin/fat and
muscle. Ionophoric coccidiostats are extensively metabolised and some
show a complex pattern of different metabolites (i.e. for semduramicin
19 metabolites have been identi
fied); this in contrast to the non-
ionophoric substances, which are mainly excreted unchanged. Most
coccidiostats are excreted mainly in faeces (
N90%) and only to a minor
extent with urine (
b5%). However, renal excretion is the main route
(
N90%) of elimination for halofuginone and HDP nicarbazin. Ionophoric
coccidiostats are rapidly eliminated from plasma with half-lives (t
1/2ß
),
ranging from 0.2 to 12 h, whereas the eliminations (t
1/2ß
) of non-
ionophoric coccidiostats varies between 1 and 4 days. The elimination
8
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–xxx
Please cite this article as: Dorne, J.L.C.M., et al., Risk assessment of coccidostatics during feed cross-contamination: Animal and human health
aspects, Toxicol. Appl. Pharmacol. (2011), doi:
from tissues is slower with residue levels measurable until 7 days post
application in most cases. The elimination time into eggs follows a
similar pattern.
Residue levels in animal tissues, eggs and milk
Residues in animal tissues
Muscle and liver from different food-producing animal species are
analysed for residues of coccidiostats by the Member States according
to requirements in Directive No (EC) 96/23. However, the results are
very different in terms of detection limits and the de
finition of
compliant and non-compliant samples. The levels at which a result is
de
fined as non-compliant are not harmonized within the Member
States, but several countries used 10
μg/kg tissue as their non-
compliant limit. UK has monitored residues of coccidiostats in a large
number of foods (animal tissues and eggs) over several years (
) and data are reported in more detailed quantitative
results. The results from coccidiostats survey within Member States,
UK annual survey, or others are summarized in
. No data on
milk samples are available from the survey programs.
Data show that the highest residue levels occur in liver and eggs
(see below), whereas the residue levels in fat/skin, kidney and muscle
tissues are lower. The incidence of positive samples (
N10 μg/kg) in
tissues is low (
b2%) except for nicarbazin and robenidine were found
in 12% and 7% of chicken livers and rabbit muscle, respectively. Tissue
levels estimated from kinetic data are in general higher than the
highest residues reported from the surveys. The high values found in
some occasions (lasalocid, salinomycin, and nicarbazin) from the
survey data seem to be related to non-compliance with the maximum
authorised dose regimens and/or the withdrawal periods, rather than
re
flecting levels that could result from the ingestion of cross-
contaminated feed batches.
Residues in eggs
Laying hens are the most likely of the non-target species to be
exposed to coccidiostats under practical conditions, as residual
amounts of feeds for rearing chickens, for which coccidiostats are
licensed until the age of 14 or 15 weeks, respectively, may remain in
feed silos and subsequently consumed by laying animals. In principle,
the application of coccidiostats to laying hens is from the clinical point
of view not be essential, as at that age animals generally have acquired
immunity. In a worst case scenario, however, residual levels of
coccidiostats in eggs have to be added to possible tissue levels in
target and non-target animal species in human exposure assessment.
For salinomycin, a linear relationship between the concentration in
feed and eggs could be established, i.e. concentration in eggs (
μg/kg)=
3.33 × concentration in feed (mg/kg) (
). Lasalocid
shows a great af
finity to egg yolk; again a linear relationship between
the concentrations of lasalocid in feed and in eggs following the
equation: concentration in eggs (
μg/kg)=63.6×concentration in feed
(mg/kg) could be established. Narasin also shows a higher excretion rate
with egg yolk, with 250
μg/kg in whites and 800 mg/kg in yolk after a
single dose of 70 mg narasin/kg feed (
). The
elimination half-life of narasin with eggs increases with increasing
doses (
). For decoquinate a maximum level of 900
μg
equivalent per kg egg was reported on day 10 of a 19-day exposure
study with repeated doses of 30 mg
14
C decoquinate/kg (
). Comparable long excretion times are also observed for diclazuril
in laying hens; when diclazuril was administered at 1 mg/kg feed during
14 days, the highest residues of 100
μg/kg were measured from days 10
to 18. After cessation of the exposure, 4 days were required to achieve a
residue level below the limit of detection (
Halofuginone is rapidly eliminated from egg with a t
1/2ß
of 1.6 days. The
concentration in yolk is two times higher than in the albumen. A linear
relationship could be established between the concentration of
halofuginone in feed and in eggs: i.e. concentration in eggs (
μg/kg)=
77.2× concentration in feed (mg/kg)
–0.002 (
Regarding nicarbazin, the cleavage product HDP is more rapidly
declining in eggs than DNC. DNC is accumulated in yolk whereas DHP
is excreted with the albumen. Linear relationships were established
for both, DNC and DHP (
):
feed nicarbazin mg
=kg
ð
Þ = 0:230 × egg residue DHP μg=kg
ð
Þ + 0:737
feed nicarbazin mg
=kg
ð
Þ = 0:0195 × egg residue DNC μg=kg
ð
Þ + 0:05
After feeding nicarbazin to geese (100 mg/kg feed), residues of
DNC of 5980
μg DNC/kg could be measured in egg (
). Following a robenidine dose of 36 mg/kg feed during 14 days,
the highest residue measured in eggs was 1.3 mg/kg (
provides a compilation of the available residue data in
eggs, presenting a comparison between the kinetic studies and the
actual concentration measured in market specimen as reported from
surveys and publications. These data show that the prevalence of
residues in eggs is about 4% of all investigated samples, with the
exception of diclazuril found in up to 7% of the analysed eggs.
Excretion with milk
Monensin equivalents were measured in milk (48
μg eq/kg)
following an intraruminal administration of 1125
μg
14
C-monensin/
day for 9 days, representing only 2% of the total radioactivity (
). However, monensin as such was non-detectable in milk when
administered at 240 mg/kg feed during 21 days (
).
Following the administration of 42 mg
14
C-lasalocid/kg feed for
14 days a maximum of 3.2
μg eq lasalocid/kg milk were measured at
a withdrawal period of 0 days. No other data on the excretion with
milk were identi
fied.
Human exposure and risk assessment
Human exposure was calculated using standard food basket
consumption
figures as used for in the assessment of veterinary
Table 4
Residues of coccidiostats found in eggs.
Max. conc.
kinetic
studies
Survey
UK
μg/kg
egg
Highest
values
μg/
kg egg
Prevalence
NC/T
Reference
Ionophoric coccidiostats
Lasalocid
800
μg/kg
b2–3450
137/2855
UK survey MS
Maduramicin
1/1319
MS
Monensin
19
μg/kg
4/510
2.5
μg/kg 6/161
Narasin
15
μg eq/kg
11
μg/kg
35/146
Sweden
Salinomycin
24
μg/kg
141
μg/
kg
19/3502
MS &
Semduramicin
0.8
μg/kg 1/200
MS France
Non-ionophoric coccidiostats
Decoquinate
120
μg/kg
ND
Diclazuril
13
μg/kg
3.1
μg/kg 25/320
Halofuginone
60
μg/kg
1/320
Nicarbacin
1100
μg
DNC/kg
22/97 HR
540 DNC
900
μg/
kg DNC
123/2178
UK survey
Robenidine
238
μg/kg
12
μg/kg
13/320
UK survey
NC/T: non-compliant to total; HC
— highest concentration.
a
Data from quail egg.
9
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–xxx
Please cite this article as: Dorne, J.L.C.M., et al., Risk assessment of coccidostatics during feed cross-contamination: Animal and human health
aspects, Toxicol. Appl. Pharmacol. (2011), doi:
medicinal products, i.e. muscle (300 g), liver (100 g), kidney (50 g
or10g for poultry), fat (50 g or 90 g skin plus fat for poultry) and eggs
(100 g) and comparing these data with the ADI. Human exposure was
estimated for high consumers.
illustrates the risk character-
isation of coccidiostats for human health after consumption of animal
products from non-target species fed cross-contaminated diets at 2%,
5% and 10% of the maximum levels authorized in target species. Only
limited information was available on the amount and frequency of
contamination of food with residues of coccidiostats resulting from
feeding cross-contaminated feedstuffs to food-producing animals.
Information on concentrations of marker residues of coccidiostats that
had been found in meat, offal and eggs was available from the
monitoring system performed under Directive No (EC) 96/23 and
from surveillance studies performed in the UK over several years
(
). These data gave an indication of the amounts
of residues that have been found in the past and represented misuse
as well as cross-contamination. However, it needs to be emphasized
that these monitoring and surveillance data are not representative as
an indicator of the frequency of contamination, as the surveys were
targeted to samples where contamination was expected (
).
Kinetic studies in non-target species gave useful information on
the distribution of the individual coccidiostats to the different edible
tissues in food producing animals and to eggs. For coccidiostats for
which no data were available from the studies in non-target animals,
the results from the target species were used. As the dose levels used
in the kinetic studies were higher than those that would be expected if
the animals were fed cross-contaminated feed, the CONTAM Panel
extrapolated the results linearly to estimate the levels of residues in
foods derived from animals fed diets cross-contaminated at levels of
2%, 5% and 10% of the maximum concentration permitted in feed
intended for the target species. No information was available on the
amount of residues that might occur in milk.
The conclusions for the different coccidiostats are presented
below.
Ionophoric coccidiostats
For lasalocid, kinetic data were available for several non-target
animals: laying hens, quails, pheasants, cattle and sheep. Data from
surveys and the results of kinetic studies indicated that residues of
lasalocid were likely to be highest in eggs, liver and poultry skin, with
lower levels occurring in muscle, fat and kidney. Estimates of
consumer intakes of lasalocid resulting from eating eggs or liver
from animals given feed contaminated at a level of 10% were in the
region of the ADI of 0.005 mg/kg b.w. However, it was recognised that
exposure to such residues would be a rare event and the CONTAM
Panel concluded that consumers are unlikely to experience any
adverse health effects as a result of eating foods derived from animals
given feed cross-contaminated even up to a level of 10% (
For maduramicin, no kinetic data were available from non-target
animals and no usable data were available from the UK surveys or the
EU monitoring. Kinetic data from target species (chickens and
turkeys) indicated that residues of maduramicin were most likely to
be found in liver but could also be present in skin/fat and muscle.
Estimates of consumer exposure indicated that intakes would be
much lower than the upper limit of the ADI (0.001 mg/kg b.w.); even
if consumers ate foods derived from animals given feed cross-
contaminated at 10%. The estimated consumer intake of maduramicin
was 3.7% of the ADI (
Data from EU monitoring and UK surveys showed that monensin
residues have been found in liver and eggs of non-target animals.
However, estimates of consumer exposure indicated that intakes
would be much lower than the upper limit of the ADI (0.003 mg/kg
b.w.); the estimated consumer intakes of monensin were 0.6% of the
ADI from eggs and 7.3% from liver (
Kinetic studies in various animal species showed that narasin does
not accumulate in edible tissues. In non-target animals (laying hens,
turkeys, ducks, cattle, horses, pigs and rabbits were tested) the
highest concentrations of residues occurred in pig liver and chicken
eggs. Estimates of consumer exposure indicated that intakes would be
much lower than the upper limit of the ADI (0.005 mg/kg b.w.); the
estimated consumer intakes of narasin from pig liver and chicken eggs
were 7% and 0.5% of the ADI, respectively. It was noted that the
majority of more than 1000 samples of eggs from several EU countries
had no detectable residues of narasin (limits of detection: 0.1
–2 ppb)
and that the highest residue concentration in any of the eggs was
11
μg/kg. This result indicates that the theoretical estimate based on
kinetic data seems to overestimate the actual level of consumer
exposure to narasin (
The available kinetic data from laying hens, pigs and cattle
indicated that salinomycin residues primarily occur in eggs and liver.
It was estimated that, at a level of cross-contamination of 10%,
consumers could be exposed to salinomycin residues from pig liver at
levels of 0.5
μg/kg b.w./day and 0.038 μg/kg b.w./day from chicken
eggs. Such intakes would be well below the upper limit of the ADI of
0.005 mg/kg b.w. (respectively 10% and 0.76% of the ADI) (
For semduramicin, no kinetic data from non-target species were
available, so the results of kinetics studies for chickens for fattening (a
target species) were used to estimate residue levels in edible tissues
and to calculate consumer exposure. The estimated consumer
exposure to residues of semduramicin resulting from the consump-
tion of foods derived from animals that ate feed cross-contaminated at
a level of 10% was well below (5%) the ADI of 0.00125 mg/kg b.w.
(
Non-ionophoric coccidiostats
For decoquinate, consumer exposure was estimated from the
results of kinetic studies in chickens and laying hens. It was calculated
Table 5
Risk characterisation of coccidostats for human health after consumption of animal
products from non-target species fed cross-contaminated diets at 2%, 5% and 10% of the
maximum levels authorized in target species.
Coccidiostat
ADI (
μg/kg
b.w per day)
Animal products
% ADI after
cross-contamination
2%
5%
10%
Ionophoric coccidiostats
Lasalocid
5
Eggs/liver/skin
3
13
27
Maduramicin
1
Liver/skin/fat and
muscle
0.7
1.9
3.7
Monensin
3
Liver and eggs
0.1
0.3
0.6
Narasin
5
Liver and eggs
0.07
0.35
0.17
Salinomycin
5
Liver and eggs
0.2
0.4
0.8
Semduramicin
1.25
Muscle/liver
2
5
10
Non-ionophoric coccidiostats
Decoquinate
75
Eggs/liver/kidney/
muscle/skin/fat
0.14
0.38
0.75
Diclazuril
29
Eggs/liver/kidney/
muscle/skin/fat
0.016
0.04
0.08
Halofuginone
n.a
Eggs/liver/kidney/
muscle/skin/fat
n.a
n.a
n.a
Nicarbazin
Eggs/liver/muscle
0.04
0.09
0.18
Robenidine
37.5
Eggs/liver/kidney/
muscle/skin/fat
0.9
2.2
4.3
a
An ADI of 2 g/kg k.w. had been suggested for Nicarbazin considering the parent
compounds, but awaits con
firmation following the elucidation of the chemical nature of
the residues.
b
Values for daily human food consumption, as de
fined in Directive No (EC) 2001/79
are for birds: 300 g muscle, 100 g liver, 10 g kidney (50 g for mammals), 90 g skin/fat in
natural proportions (50 g for mammals) and 100 g eggs (and 1500 g milk). Values for
mammals are given in parentheses when they differ from bird values.
10
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Please cite this article as: Dorne, J.L.C.M., et al., Risk assessment of coccidostatics during feed cross-contamination: Animal and human health
aspects, Toxicol. Appl. Pharmacol. (2011), doi:
that, when hens were fed a 10% cross-contaminated diet, con-
centrations of decoquinate residues of 12, 51, 63, 30 and 75 ppb would
be present in eggs, liver, kidney, muscle and skin/fat, respectively,
giving an estimated total consumer exposure of 0.0334 mg/person/
day (0.00056 mg/kg b.w./day for a person weighing 60 kg). This
exposure would be well below (0.75%) the ADI of 0.075 mg/kg b.w.
(
).
For diclazuril, no kinetic or occurrence data were available
regarding residues in meat, offal or milk from non-target animal
species. Therefore, consumer exposure was estimated from kinetic
data in rabbits (a target species). Data from laying hens gave an
indication of residues in eggs. It was estimated that consumers could
have an intake of 0.4
μg/kg b.w./day of diclazuril as a result of
aggregate consumption of muscle, skin/fat, liver, kidney and eggs
from animals receiving diet cross-contaminated at a level of 10% with
diet containing the maximum permitted amount of diclazuril. This
amount represents 1.5% of the ADI of 0.029 mg/kg b.w. (
).
No kinetic or occurrence data were available to estimate the
amount of halofuginone residues in foods derived from non-target
animal species. Hence, consumer exposure was estimated using data
from the measurement of residues in eggs and from the kinetic data
from chickens for fattening. The results of kinetic studies were
extrapolated to correspond to feed cross-contaminated with halofu-
ginone at a level of 10% of the maximum level authorised for target
species. The maximum human consumer exposure level was
estimated to be 0.1
μg equivalents/kg b.w./day from eggs and
0.29
μg equivalents/kg b.w./day (for a 60 kg person) from liver,
kidney, muscle and skin/fat. These exposures represented 33% and
97% of the ADI of 0.0003 mg/kg b.w., respectively. However, the
chemical form and toxicity of the residues in avian species was not
known, and the CONTAM Panel could not reach conclusions on the
potential impact for consumers of such exposure (
).
Food survey data showed that concentrations of the dinitrocarba-
nilide (DNC) component of nicarbazin of up to 7200, 900 and 110 ppb
had been detected in chicken liver, chicken eggs and chicken muscle,
respectively. It was estimated that consumers who ate these high
levels of residues would have exposed to up to 0.014 mg/kg b.w./day
of DNC, which is well below (1.8%) the ADI of 0.77 mg/kg b.w. that
was proposed for DNC by the FEEDAP Panel (
) and also well
below (3.5%) the ADI of 0.4 mg/kg b.w. that was set for nicarbazin by
JECFA (WHO, 1999???). Estimates of consumer exposure calculated
from the results of the kinetic studies in chickens showed that, at 10%
cross-contamination, the intake of DNC would be 0.0014 mg/kg
b.w./day (0.18% of the FEEDAP ADI for DNC and 0.35% of the JECFA
ADI for nicarbazin). As a result of the remaining uncertainties in the
toxicological evaluation, the CONTAM Panel did not present conclu-
sions about the consumer safety of nicarbazin (
No kinetic or occurrence data were available to estimate the
amount of robenidine residues in foods derived from non-target
animal species. Hence, consumer exposure was estimated using the
kinetic data from the target species: chickens for fattening. The
results of the kinetic studies were extrapolated to correspond to feed
cross-contaminated with robenidine at a level of 10% of the
maximum level authorised for target species. The human exposure
from eating liver, muscle, skin/fat, kidney and eggs was estimated to
be 1.6
μg/kg b.w. per day. This exposure represented 4.3% of the ADI
of 0.0375 mg/kg b.w. (
). A summary of the results is
presented in
Conclusions and future perspectives
Cross-contamination of feed during production can result in the
exposure of non-target animals to coccidiostatics and subsequently
consumers could be exposed following the consumption of animal-
based products (eggs, muscle, fat, liver, kidney, and milk). No
appreciable risk for consumers could be indenti
fied for lasalocid,
maduramicin, monensin, narasin, nicarbazin,
salinomycin, decoqui-
nate, diclazuril and robenidine following the consumption of meat, offal
or eggs derived from non-target animals. The CONTAM Panel presented
no
final conclusion over the safety of foods derived from non-target
animals given feed cross-contaminated with halofuginone in consider-
ation of the remaining uncertainties over the safety of residues derived
from this coccidiostat. Animal health risks following carry over were
identi
fied only for horses exposed to feed cross-contaminated with
salinomycin and monensin or at 2 and 5% respectively.
Although the substances used as coccidiostatics in animal
production are not currently used in human medicine, such uses
have been suggested and may be feasible in the future. Indeed,
ionophoric polyethers, including the coccidiostatics, experience
increasing interest in oncology, due to their effect as inhibitors of
ATP-Binding Cassette (ABC) ef
flux transporters which may convey
(multi-drug) resistance to cytostatic drugs used in cancer therapy
(
Schrickx and Fink-Gremmels, 2008
). Moreover, their antimicrobial
effects seem to offer successful opportunities in the treatment of
multi-resistant bacteria (
). Halofuginone has been
shown to effectively suppress tumour progression and metastasis in
mice. This effect is likely to be attributed to the inhibition of
angiogenesis, due to an inhibition of collagen synthesis (
). This hypothesis is based on the previous data
showing that halofuginone inhibits the expression of type I collage-
nase and matrix metalloproteinase 2 (MMP-2). Subsequently,
halofuginone has shown successful therapeutic activities in models
of chemically induced bladder cancer, nephroblastoma (Wilms
tumour), pheochromocytoma, prostate cancer and sarcomas (
). More recently, halofuginone has been shown to suppress
the growth of hepatocellular carcinomas in a xenograft model (
). In the
first clinical Phase 1 study, the dose-limiting
toxicity and the maximum tolerated dose as well as the kinetic
characteristics were studies in human patients with advanced solid
tumours (
). Indeed, halofuginone induced nausea,
vomiting and fatigue, but these symptoms were reversed with
common anti-emetics and the current recommended oral dose is
0.5 mg per day. These recent
findings constitute examples for
potential future uses of some of coccidiostatics in human therapies.
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J.L.C.M. Dorne et al. / Toxicology and Applied Pharmacology xxx (2011) xxx
–xxx
Please cite this article as: Dorne, J.L.C.M., et al., Risk assessment of coccidostatics during feed cross-contamination: Animal and human health
aspects, Toxicol. Appl. Pharmacol. (2011), doi:
Document Outline
- Risk assessment of coccidostatics during feed cross-contamination: Animal and human health aspects
- Introduction
- Definitions and regulatory framework for coccidiostats
- Stepwise approach to the assessment of the risk to human and animal health associated with the cross contamination of feed ...
- Hazard identification and characterisation
- Toxicology of coccidiostats
- Toxicology in laboratory animals and health-based guidance values for humans
- Toxicological effects in non-target species
- Hazard identification and characterisation
- Exposure assessment: analytical techniques, toxicokinetics and human dietary exposure
- Human exposure and risk assessment
- Conclusions and future perspectives
- References
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