The CiToxLAB Group offers a comprehensive range of preclinical services and specialty safety evaluation services to meet the needs of pharmaceutical, biotechnology and chemical companies worldwide. Our four CiToxLAB international facilities in France, Canada, Denmark and Hungary carry out studies in general and reproductive toxicology, carcinogenicity, bioanalysis, immunology and safety pharmacology. The group has special expertise in areas such as inhalation or intra-nasal toxicology, radiation safety (ARS), NHPs and minipigs. Environmental studies are a further specialty including ecotoxicology and those related to REACH regulations. Together with partners such as Atlanbio (St Nazaire, France) Stemina (Madison, USA) and Biomodels (Boston, USA), CiToxLAB also provides services such as clinical bioanalysis, embryonic stem cell biomarker discovery and customized preclinical efficacy models. CiToxLAB now offers flexibility, direct contact to scientists, easy access to management and local, smart-sized facilities. Aggressive scheduling, increased size and capacity, turnkey solutions of global packages supported by project managers and broader geographic proximity are core values of CITOXLAB. Contact our team of experts: www.citoxlab.com

1. Toxicology services
General toxicology:
- Rodents
- Non-rodents: dogs, NHPs and minipigs
Infusion
Global expertise, Local response
Inhalation
Dermal
Ocular
Immunotoxicology
Reproductive toxicology including minipigs and NHPs
CiToxLAB Group companies Also represented by Carcinogenicity studies also in rasH2 and p53+/- mice
CiToxlab France Media Services Ltd Japan Genetic toxicology: ICH compliant package
Phone +33 (0)2 32 29 26 26 Phone +81 3 3666 9915
In vitro toxicology : BCOP, MUSST, DPRA, Photo 3T3, Episkin™
Email contact.france@citoxlab.com Email citoxlab@mediaservices-jp.com Agrochemical / Chemical / REACH
B.P. 563, 27005 Evreux cedex - France Fuji 16 Bldg 7F QSAR
1-11-2 Nihonbashi Kayabacho, Chuo-ku, Physical chemistry
CiToxlab North America Tokyo 103-0025 - Japan
Ecotoxicology: wide range of test species
Phone +1 888 353 2240
Email contact.northamerica@citoxlab.com Croen Research Inc.
Phone +82 31 888 9390
Safety pharmacology
445, Armand-Frappier Blvd,
Laval, Quebec H7V 4B3 - Canada Email ycpark@croen.co.kr CV telemetry / ECG / BP
Advanced Institutes of Convergence Jacketed External Telemetry (JET) / ECG / BP
CiToxlab Hungary Technology - B-6th Fl., 864-1,
Respiratory / plethysmography / JET telemetry
lui-dong, Yeongtong-gu,
Phone +36 88 545-300
Email contact.hungary@citoxlab.com
Suwon-si - Gyeonggi-do, 443-270, Korea CNS / EEG
Veszprém, Szabadságpuszta, 8200 - Hungary
Early safety pharmacology
Partner company DMPK and biomarkers
CiToxlab Scantox
Phone +45 56 86 15 00 Stemina Radiolabelled DMPK: in all species
Email contact.scantox@citoxlab.com
Phone +1 608 204 0104 Bioanalysis LC-MS/MS, GC-MS/MS, LC-ICP/MS, ELISA, RIA
Hestehavevej 36A, Ejby E-mail info@stemina.com Toxicogenomics, miRNA: Affymetrix™ / Accredited service
DK-4623 Lille Skensved - Denmark Website www.stemina.com
provider
504 South Rosa Road, Suite 150
atlanbio Madison, Wisconsin 53719 Immunology: 10-color flow cytometer, Luminex, Mesoscale
Phone +33 (0)2 51 10 01 00
Email atlanbio@atlanbio.com Specialized expertises
Website www.atlanbio.com
Juvenile studies including minipigs
- June 2012
1 Rue Graham Bell - Z.I de Brais B.P 40309,
44605 Saint Nazaire Cedex - France
Fertility studies in rodents and NHPs
Radiation safety and efficacy studies
Tissue Cross Reactivity: human and animal tissue banks
Gene therapy vector biodistribution via qPCR
ES cell testing: devTOX™ and cardioTOX™ (with Stemina)
Lead optimization and predictive toxicology services:
Leadscreen™
www.citoxlab.com

2. CiToxlab Scantox
CiToxlab France
atlanbio
CiToxlab Hungary
CiToxlab North America Croen Research Inc.
Stemina Media Services Ltd Japan

3. CiToxLAB, our newly established group, created through the merger of CiT and LAB Research, provides
a comprehensive range of preclinical and specialty services from our facilities in France, Canada,
Denmark and Hungary. With a combined capacity in excess of 800 employees, 27 000 rodents, 5 000
non-rodents, including 1 200 non-human primates on-site, and purpose built facilities of 60, 000 m2
(645, 000 ft ), the new group is a major global player in the preclinical outsourcing arena.
2
Our broad range of GPL and non GLP nonclinical services combined with our 40 years of experience
are at the service of our customers to meet the demands of today’s complex global marketplace. We
can provide you with accelerated product development, expansion into new markets, risk mitigation,
reduced regulatory delays and improved quality.
Reports from our four facilities have been successfully used by our clients in support of marketing
authorization and new product approval submissions around the world, including to the European
(EMA, ECHA), US (FDA and EPA) and Japanese (MHLW and MAFF) regulatory authorities.
CiToxLAB is committed to the humane treatment of the research animals entrusted to our care.
We guarantee they will be treated with the highest standards of respect and compassion, and particular
attention is accorded to housing conditions, social interaction and enrichment of their environment.
CiToxLAB's ethics committees have established and rigorously enforce our ethics charter for Laboratory
Animals. All employees must continuously demonstrate their commitment to animal welfare and are
required to sign our ethics charter as a condition of initial and continuing employment.
Since 2004, our high ethical standards have been recognized by accreditation from the American
Association of Laboratory Animal Care (AAALAC).
As a highly qualified service provider, we also strive to be flexible, accomodating and respond as
quickly as possible to each of your individual needs.
Our objective can be summarized by our claim:
CiToxLAB: Global expertise, Local response.
1

4. Our commitment to animal welfare
CiToxLAB is committed to the humane treatment of the research animals entrusted to our care. We
guarantee that animals will be treated with the highest standards of respect and compassion, and
particular attention is accorded to housing conditions, social interaction and enrichment of their
environment.
AAALAC recognition has been obtained for most of our sites.
Ethical commitment Housing and enrichment Staff
CiToxLAB’s ethics committees have CiToxLAB always complies with the CiToxLAB employs highly qualified and
established and rigorously enforce our highest standards of animal care trained staff, who receives continuous
ethics charter for laboratory animals. and use. training in order to reinforce their skills
All employees are encouraged CiToxLAB has a well defined housing and provide updates on the latest
to continually demonstrate their policy which was designed to ensure techniques for animal well-being
commitment to animal welfare and animal well-being in accordance with optimization.
are asked to sign our ethics charter regulations and current scientific
as a condition of initial and continuing knowledge. Animals are group housed CiToxLAB employs trained
employment. and kept under appropriate conditions veterinarians with relevant experience
CiToxLAB employs independent to facilitate the expression of species in laboratory animals, and who
attending veterinarians, dedicated to behavior. are committed to monitoring and
animal care. CiToxLAB is particularly improving the animal care and use
committed to the 3Rs to minimize program.
animal use, to enhance their well-
being and to use alternative methods Our ethics committees include
whenever possible. Laboratory animals veterinarians and laypersons. They
are not exposed to unnecessary review all study protocols to ensure
distress or pain. Endpoints for the that CiToxLAB complies with its ethical
removal of animals from a study are commitments.
defined for all studies.
2

5. General Toxicology (Acute to Chronic)
With over 40 years of experience, the toxicity testing capabilities of CiToxLAB
comprise a vast array of designs, ranging from acute single dose studies
to carcinogenicity studies, including specialty dose routes such as inhalation and
infusion. All studies are fully GLP compliant in accordance with current guidelines or
custom-designed for particular needs.
CiToxLAB’s four facilities are located in France, North America, Denmark and
Hungary. We offer close to 60, 000 2 of vivarium and supporting laboratories
m
for the conduct of general and specific toxicology studies on: pharmaceuticals,
biotechnology products and medical devices. Our clients include an impressive list
of major pharmaceutical and biotech companies.
Study types Species Routes of administration
 Acute toxicology  Rat  Oral
 Subchronic toxicology  M
ouse (including  I
nhalation (including
 Chronic toxicology genetically modified mice intratracheal and intranasal)
 Cyto- and genotoxicity for carcinogenicity and  Intravenous
 Immunotoxicity immunological investigations)  Continuous intravenous infusion
 Carcinogenicity  Rabbit  Subcutaneous
 Reproductive toxicology  Guinea Pig  Dermal
 Genomics  Hamster  Intradermal
 In vitro toxicology  Dog  Intramuscular
 Tissue Cross Reactivity  Minipig  Intraperitoneal
 ADME and Pharmacokinetics  Domestic pig  Intravaginal and Intraurethral
 Lead optimization  on-human primate
N  Intrarectal
 Wound Healing (Cynomolgus  Intravesicular
and Rhesus NHP)  cular (including subretinal
O
and intravitreal)
 Intrathecal
 Intraarticular
3

6. Rodent Toxicology
Rodents are the species of choice for the safety testing of chemicals, foods and many pharmaceuticals.
All four CiToxLAB facilities offer a wide variety of rodent protocols, from single dose to carcinogenicity
studies. CiToxLAB works with all major suppliers to obtain a range of conventional and genetically
modified strains. Our study directors and pathologists have extensive experience in the interpretation
of in vivo and post-life data from rats, mice and other rodent species.
Study types Infrastructure Routes of administration
 Acute toxicology  H
ousing capacity for 27 000  Oral gavage
 Short-term immunotoxicity rodents  Dietary
 Subchronic  Intravenous
 Chronic Species  I
nhalation (including intranasal,
 S
kin sensitization and  Rat nose-only exposure system)
photoirritation  M
ouse (including genetically  Continuous intravenous infusion
 Repeat dose  Subcutaneous
modified mice)
 Carcinogenicity  Dermal
 Guinea pig
 Intradermal
 Hamster
Staff  Intramuscular
 Intraperitoneal
Over 800 staff, including:
 cular (including subretinal
O
 Project managers
 Study directors
and intravitreal)
 Endoscope-assisted
 Immunologists
 Veterinary surgeons
administration
 Pathologists
 Toxicologists
 Animal technicians
 nalytical and bioanalytical
A
experts
 Regulatory specialists
4

7. Dog Toxicology
The dog is the most common non-rodent species used for the safety testing of
medicinal products and chemicals. Such studies are routinely performed at all
four CiToxLAB facilities. The animals are housed and handled in accordance with
the latest international regulations, and animals are socialized whenever possible.
Dogs are available from a variety of approved suppliers.
Study types Infrastructure Specialties
 Acute toxicology  O
ver 130 rooms designed for  P
ermanent dog colonies
 Short-term immunotoxicity dog housing for telemetry and
 Subchronic  ousing capacity for 1 600+
H pharmacokinetics
 Chronic dogs  odel development services
M
 Safety pharmacology  Intraperitoneal
 Pharmacokinetics  Intravaginal and intraurethral
and Toxicokinetics  Intrarectal
 Efficacy  Intravesicular
 cular (including subretinal
O
Staff and intravitreal)
 Intrathecal
Over 800 staff, including:
 Intraarticular
 Project managers
 Study directors
 Immunologists
 Veterinary surgeons
 Pathologists
 Toxicologists
 Animal technicians
 nalytical and bioanalytical
A
experts
 Regulatory specialists
5

8. Non-human primate Toxicology
Non-human primate (NHP) studies are required for the safety testing of medicinal agents (including
biotechnology products) that cannot be evaluated in other non-rodent species due to species-
specific differences in pharmacology or metabolism. The CiToxLAB facilities in France and North
America offer studies in Cynomolgus and Rhesus NHP. Only purpose-bred NHP are used, and these
are obtained from approved breeders in four different countries. The on-site pathologists are familiar
with the spontaneous lesions that can occur in the animals from each source. An extensive panel of
biomarkers has been validated for use in toxicology studies.
Study types Infrastructure Routes of administration
 Acute toxicology  O
ver 100 rooms designed for  Oral (gavage, capsules, pills)
 Short-term immunotoxicity non-human primate housing  I
ntravenous (bolus or
 Subchronic  ousing capacity for 1 800
H continuous
 Chronic non-human primates infusion ; also available with
 Safety pharmacology  ultiple state-of-the-art surgical
M vascular access port “ cath-in-
 Pharmacokinetics suites cath ”)
Toxicokinetics  Subcutaneous
 Efficacy Strains  Dermal
 C
ynomolgus (Mauritius, China,  Intradermal
Staff Vietnam, Philippines)  Intramuscular
 Rhesus (China)  Intraperitoneal
Over 800 staff, including:
 Intranasal
 Project managers
 Intravaginal and intraurethral
 Study directors
 Intrarectal
 Immunologists
 cular (including subretinal
O
 Veterinary surgeons
 Pathologists
and intravitreal)
 Endoscope-assisted
 Toxicologists
 Animal technicians
administration
 nalytical and bioanalytical
A (e.g. directly into the
experts duodenum)
 Regulatory specialists
6

9. Minipig Toxicology
The minipig is a good laboratory animal model for many aspects of human
physiology and metabolism. For this reason, it is becoming increasingly popular
as an alternative to the dog or non-human primate for non-rodent safety testing.
The CiToxLAB facility in Denmark has routinely performed studies in minipigs
since they pioneered the use of this species in the 1980s. Minipig studies are also
available at our CiToxLAB France, North America and Hungary facilities.
Study types Specialty studies Safety pharmacology
 Acute toxicology  ermal
D and wound healing studies
 Subchronic The skin structure and the  Implanted telemetry for
 Chronic physiology of the epidermis in cardiovascular monitoring
 R
eproductive and embryofetal the minipig resembles that of (DSI system)
 Local tolerance humans more closely than in  Jacketed External Telemetry
 Implantation any other species. Sparse hair (JET) for monitoring
covering makes the minipig cardiovascular and respiratory
Infrastructure very suitable for dermal functions (Ponemah, DSI systems)
 3
3 rooms designed for administration of test articles.  Functional Observational
minipig housing Battery (FOB)
 Juvenile
 ousing capacity for 800+
H
minipigs Juvenile studies are required
for pediatric indications by
Regulatory Authorities. The FDA
Routes of administration now offers patent extensions
 Oral for products for which the
- Gavage indications are expanded to
- Capsule include children.
- Dietary admixture
 Intravenous C
ontinuous infusion
- Bolus and intravenous
- Continuous infusion Minipigs are very amenable
 Intraocular to intravenous procedures,
 Subcutaneous both short- and long-term.
 Intramuscular We perform both continuous
 ll other standard routes
A infusion and vascular access port
studies in minipigs.
7

10. Our services
Study Types
Routes of
Administration
and Know-How
Reach
Mechanistic
Toxicology
Bioanalysis and
Pharmacokinetics
8

11. 9

12. Efficacy Models
Study types
CiToxLAB offers a wide range of efficacy models in support of drug discovery. Development of new
models is undertaken by a team of experts, including veterinary surgeons, immunologists, physiologists,
pharmacologists, toxicologists and animal health technologists. Proof-of-principle and screening studies
are individually designed and conducted according to strict norms of quality, while providing the
flexibility required according to the stage of development.
CiToxLAB has access to a large network of industry-recognized experts to enhance the range of
efficacy models that we offer by providing expertise in dermatology, electrocardiology, radio-oncology,
ophthalmology, pharmacophysiology and many other fields of preclinical research.
Imaging technologies are a cornerstone of our efficacy models, with ultrasonography, CT-scan, magnetic
resonance imaging, fluoroscopy and digital radiography ; all available for the optimal assessment of
scientific endpoints.
Available efficacy models Infrastructure
Rodents Rabbits  Multiple surgical suites
 Sepsis  Arterial restenosis  S
eparate areas for pre- and
post‑operative care
 kin burn
S  Heptanol induced corneal ulcer
 Hypoxemic (in mice)  Hemostasis Equipment
 Vascular permeability (in mice) Multi-Species  X-ray
 Tumor  Dialysis in pigs and dogs  Fluoroscopy
Non-human primates  ndoscopy (gastroscopy,
E  Ultrasound
 Anemia duodenoscopy and colonoscopy)  Micro-isolator caging
in dogs, minipigs, pigs and non-human  Laminar hoods
 one marrow flow cytometry analysis
B primates
 elemetry and cytokine profiling
T  Microsurgery
 ndotoxemic shock with core body
E
temperature measurements using  DEXA
Dogs
telemetry cytokine profiling
 Anesthetized hypoxemic
 astric emptying time in dogs,
G
 Cardiac pacing
non-human primates and rats
 Atrial effective refractory period
 lomerular filtration rate using
G
CT‑Scan in dogs and pigs
— June 2012
 ntravesical (urinary bladder)
I
in rats, dogs, minipigs and non-human
primates
 ound healing in mice, rats, rabbits,
W
pigs and minipigs
 hole body irradiation in dogs,
W
non‑human primates and rats
 Biomedical devices
www.citoxlab.com

13. Genetic Toxicology
Study types
CiToxLAB group provides over 25 years of experience and expertise in the performance of standard
genotoxicity studies in our modern facility, along with testing of pharmaceuticals, biopharmaceuticals,
cosmetics, industrial chemicals, agrochemicals, feed and food additives, as well as other types of test
item including medical devices. We can make the appropriate recommendations on how to proceed on
a case-by-case basis and how to test even the most unusual products.
Our tests comply with the latest versions of the guidelines issued by the ICH and OECD and are performed
in accordance with the current OECD Good Laboratory Practice regulations to ensure their acceptability
to regulatory authorities worldwide.
Study types
GLP Genotoxicity: Screening Genotoxicity:
 acterial reverse mutation test
B We offer screening versions of the
(the Ames test) - OECD 471 genotoxicity tests, which are useful
 ammalian chromosome aberration
M during the early development of new
(cytogenetic) in vitro test using products. These can be designed to
cultured human lymphocytes meet the specific requirements of each
OECD 473 Sponsor.
 ammalian cell gene mutation in vitro
M  Mini-Ames
test using mouse lymphoma  BlueScreen™
L5178Y tk +/- cells - OECD 476  Mini-micronucleus
 ammalian erythrocyte micronucleus
M
in vivo test in mice and rats - OECD 474
— June 2012
www.citoxlab.com

14. In vitro Toxicology
Our tests comply with latest versions of the guidelines issued by the ICH and OECD and are performed in accordance
with the current OECD Good Laboratory Practice regulations to ensure their acceptability to regulatory authorities
worldwide.
Study types Reporting
Cytotoxicity Cutaneous penetration All in vitro toxicology reports are
- Acute toxicology - utomized process using dynamic
A optimized to be available within 2
Frantz cells weeks after the end of the experimental
- echanistic toxicology (e.g.
M phases.
oxidative stress)
 Immunotoxicology
- ADCC
Skin or eye irritation and corrosion - Chemotaxis
- BCOP - Lymphocyte proliferation
- 3D models - NK assay
Skin sensitization
- Peptide reactivity
- MUSST assay
Phototoxicity
- 3T3NRU
- 3D skin models

15. Safety Pharmacology
Study types
CiToxLAB is an industry leader in GLP-compliant safety pharmacology, offering fully-validated test
systems to support international regulatory requirements (e.g. ICH S7A ICH S7B). A large, dedicated
team of experienced veterinary scientists and surgeons is involved in all aspects of validation and
study conduct and is supported by a network of recognized experts in cardiovascular, respiratory and
central nervous system physiology and pharmacology. CiToxLAB offers a variety of large and small
animal models, using state-of-the-art technologies, to complete the safety pharmacology core battery
of studies. Supplementary or follow-up studies are offered using tailored solutions for comprehensive
pharmacodynamic investigations.
Our colonies of pre-instrumented telemetered dogs, minipigs and non-human primates allow us to
provide optimal timelines using well-established conscious animal models. Validated computerized ECG analysis
combined with expert review by board certified veterinary cardiologists ensure that electrocardiographic and
hemodynamic data are thoroughly and expertly evaluated. Our team benefits from over twenty-five years of
experience using various models for in-depth cardiovascular investigations.
In-house data, obtained with various positive control drugs, is also available to better assess pharmacodynamic
responsiveness, sensitivity and reproducibility of the cardiovascular, respiratory and neurological safety
pharmacology models.
Safety pharmacology core battery Early safety pharmacology Supplemental safety
 C
ardiovascular system in conscious  hERG pharmacology studies
dogs, NHP and minipigs  nesthetized guinea pig or rabbit:
A  G
astrointestinal safety pharmacology
 espiratory system in conscious
R ECG, ABP, LVP and QA in rats, dogs and non-human primates
rats (head-out or whole body  enal function models in rats, dogs
R
plethysmography), dogs, NHP and Follow-up studies and non-human primates
minipigs  F
ully instrumented cardiovascular
 entral nervous system (Modified Irwin
C models in anesthetized dogs, Equipment and infrastructure
Screen or Functional Observational non‑human primates and minipigs  D
ata Science International telemetry
Battery (FOB) in rats, mice, dogs and  ulmonary arterial pressure in dogs
P system (Ponemah)
NHP) and non-human primates  MKA Technologies Notocord
E
 omplete respiratory mechanics in
C  ndustry’s largest telemetry system
I
Safety pharmacology endpoints
anesthetized dogs and non-human
integrated in toxicology studies  ans Rudolph Scireq respiratory
H
primates system
 E
xtensive expertise with
 lood gases and blood pH in all
B
— June 2012
biotechnology-derived drug  edicated rooms for safety
D
species pharmacology
candidates and cancer drugs
 lectroencephalography (EEG) by
E  Multiple surgical suites
 Jacketed External Telemetry (JET): telemetry in dogs and non-human
primates  Imaging (X-ray and fluoroscopy)
- espiratory system in conscious
R
rats (head-out or whole body  lectroretinography (ERG) in rabbits,
E
plethysmography), dogs, NHP and dogs and non-human primates
minipigs
- OB in rodents, dogs, NHP and
F
minipigs
www.citoxlab.com

16. Juvenile Toxicology
Study types
A Pediatric Investigation Plan (PIP) is now an essential component of marketing authorization
applications for all new drugs in Europe and North America, whether or not the medicine is intended
for use in children. Where drugs are intended to be administered to children, the PIP should include
appropriate studies in animals at a stage of development that is relevant to the human population who
will be exposed.
CiToxLAB has extensive experience of conducting juvenile toxicity studies in accordance with the
requirements of the FDA and EMA.
CiToxLAB Scantox (Denmark)
is the global leader in juvenile
minipig studies
Available species Available techniques in rodents Available techniques
 Rat  B
ehavioral tests: 3-T, Morris and  I
mplanted vascular access ports for
 Mouse Cincinnati mazes intravenous administration from 7 days
 mmune assessments:
I of age
 Rabbit
lymphocyte subsets, cytokine  phthalmoscopy from 3-4 weeks old
O
 Minipig
determinations, functional tests  ECG from 7 days old
 Dog
 etailed histopathology of CNS
D  Clinical pathology from 7 days old
 Non-human primate and immune system
 wice-daily toxicokinetic sampling
T
 Bone densitometry (in vivo) from 7 days old and 5 times-daily from
All species can be dosed from 4 to 7
days of age by the oral or subcutaneous 21 days of age
routes. In rats, the intravenous route is  ests for learning and memory are
T
feasible from about 10 days of age. being developed
Please enquire for details.
— June 2012
www.citoxlab.com

17. DART: Developmental And Reproductive Toxicology
An integrated evaluation of potential risks to reproduction and development is an essential component of marketing
authorization applications for all new drugs. CiToxLAB offers this expertise.
With over 40 years of experience and expertise, CiToxLAB can perform a full range of reproductive and
developmental toxicity studies in accordance with current international guidelines (ICH, OECD, US EPA, etc) for
pharmaceutical, biopharmaceutical, veterinary, chemical, agrochemical, food and consumer products.
CiToxLAB has comprehensive historical control databases (rat and rabbit fetuses as well as fetal abnormalities in
minipigs). This extensive experience allows our staff to conduct standard studies as well as highly specific custom
projects.
Study types Routes of administration  T
oxicokinetics, pharmacokinetics:
• ertility and early embryonic
F  O
ral: gavage, dietary admixture, parental blood samples, fetal tissues,
development to implantation (ICH S5, drinking water fetal blood, amniotic fluid, milk
segment I)  valuation of visceral/soft tissues:
E
 ntravenous: bolus, slow injection,
I
 ffects on embryo-fetal development
E continuous infusion, cycles (vascular fresh visceral dissection or fixed
(ICH S5, segment II) access port) tissues (examination of rat, rabbit and
minipig fetal head)
 ffects on pre- and post‑natal
E  ther parental routes: subcutaneous,
O
 valuation of effects on the skeleton:
E
development, including maternal intradermal, intramuscular,
function (ICH segment III) intraperitoneal single or double staining, X-ray, DXA,
pQCT, microCT, clinical chemistry,
 ultigeneration (OECD)
M  Dermal histomorphometry
 xtended one-generation
E  ther routes: please consult
O  enomics: a large variety of tissues
G
 exually mature non-rodents with
S can be collected and analyzed (PCR,
male or female reproductive function Specialty services Affymetrix micro-chips)
parameters (treatment at a specific We offer a range of possible options
time of the cycle possible) that can be included in routine studies Support services
 terotropic assays (juvenile or
U or in tailored studies, in order to meet  D
edicated customized unit for the
castrated) specific needs. preparation of dosage forms
 ershberger assays (juvenile or
H  eurobehavioral testing
N  nalytical chemistry for formulation
A
castrated) - FOB analysis (results obtained prior to
- earning and memory: our state-
L administration)
Species of-the-art facilities and equipment  tatistical analysis
S
 R
odent (rat and mouse) and include multiple T mazes: 3T or 9T
non‑rodent (rabbit) species required (Cincinnati water maze) and Morris
by international guidelines. Historical water maze (circular pool of water,
data for different strains no T)
 Minipig  S
perm analysis (rodent and non-
 on-human primate
N rodent) including motility, morphology
(Macaca fascicularis): and concentration
available 2012 (ICH S5, segment II) Histopathology
- ale reproductive organs including
M
testicular staging
- emale reproductive organs
F
including estrous cycle staging

18. Carcinogenicity
Study types
For products where prolonged or lifetime exposure may occur in humans, it is always necessary to
consider performing carcinogenicity studies. CiToxLAB has performed more than 100 carcinogenicity
studies. The traditional study designs involve exposure of rodents to the test item for up to two years,
with an extensive pathological examination at the end of the study to detect any tumours that may be
present in the tissues of the animals. CiToxLAB has more than a dozen board certified pathologists.
Discipline Species Specialty services
CiToxLAB routinely performs these The choice of animal strain and diet In ICH guideline S1B, the
studies using all of the standard is very important. CiToxLAB routinely possibility of using alternative models
guidelines, including those of the uses: for carcinogenicity testing is described.
EU (CPMP), ICH, FDA, EPA, JMHW,  Wistar Han rats An extensive evaluation of these models
JMAFF and OECD. The basic design was performed under the auspices of
 CD-1 mice
of the study is similar for all of these the International Life Sciences Institute
guidelines, although for agrochemicals  Sprague-Dawley rats (ILSI) of the Health and Environmental
and industrial chemicals it is possible Sciences Institute (HESI), Washington
to combine one of the carcinogenicity DC. The use of some of the models is
studies with the long-term chronic becoming more common, particularly
toxicity study. for submissions to the US FDA.
CiToxLAB has been very active in the
evaluation of these models as part of
the ILSI program.
CiToxLAB can offer the following
models:
 p53+/- mouse model
 Tg-rasH2 mouse model
— June 2012
www.citoxlab.com

19. Biocompatibility of medical devices
Study types
CiToxLAB offers extensive services in medical device testing, principally safety/compatibility testing
according to ISO 10993 including custom-designed testing programs for each device we are asked to
assess. With over 20 years of experience in designing packages, our experts take into consideration
the various guidelines, the nature and construction of the device, its use, and its mode and duration of
patient contact.
Study types Species
CiToxLAB can perform all standard  T
est for systemic toxicity (acute or  Rabbit
biocompatibility tests. In addition, repeated exposure)
 Guinea pig
customized tests can be designed and  Genotoxicity
 Mouse
validated, as necessary. - Ames test (OECD 471)
 Rat
- Gene mutation test (OECD 476)
 Minipig
Cytotoxicity test (in vitro)
 Hamster
Sensitization test  Implantation test
- Local lymph node assay - uscular or subcutaneous
M
- uinea pig maximization test
G implantation in rabbits
(GPMT)  Hemolysis and coagulation tests
 arcinogenicity and reproductive
C
Irritation toxicity tests
- ingle or cumulative exposure
S
in accordance with the intended
clinical use
- Intracutaneous reactivity
- opical (skin, buccal cavity, vagina,
T
urethra, rectum)
— June 2012
www.citoxlab.com

20. Histopathology
Study types
CiToxLAB histology laboratories can offer all routine procedures, along with special techniques such as
immunohistochemical and fluorescence staining on paraffin, frozen or plastic blocks.
State-of-the-art equipment including GLP-validated software (Provantis, Pathdata, Bone, Cell D) are
dedicated to histology operations.
Our team of certified and experienced veterinarians, pathologists and technical staff has a wealth of
expertise in evaluating the safety of pharmaceutical, veterinary pharmaceutical, biotechnological,
medical device, chemical, agrochemical, food and consumer products, in rodents and non-rodents.
Proficient routine expertise
Necropsy: Histology: Pathology:
 killed prosectors
S  Highly experienced staff  xperienced board certified
E
 hole and upper body perfusion
W  rgan trimming according to RITA-like
O veterinary pathologists (ACVP
in rodent and non-rodent species instructions for rodent species and ECVP)
 rgan trimming according to RITA-like
O  valuation of a wide range of studies
E
 pecial collection procedures for
S
immunohistochemistry, genomics, instructions for non-rodent species in rodents and non-rodents, from
neurotoxicology and electron acute to chronic oral administration,
 onsistent presentation of tissues on
C
microscopy injection/infusion, dermal, inhalation,
slides irradiation and local (incl. wound
 uick and careful tissue collection for
Q  araffin, frozen and methacrylate
P healing) toxicity, developmental
RNA or DNA extraction embedding and reproductive, intravesical and
 one collection for histomorphometry
B  tandardized and special staining
S carcinogenicity studies
 nline data acquisition (organ weights
O procedures  lossary defined according to the
G
and gross observations)  araffin, plastic and cryosectioning
P international recommendations for
terminology
 mmunohistochemical and
I
fluorescence staining of paraffin  istorical control data from rodents
H
embedded or frozen tissues and non-rodents for use with
toxicology and carcinogenicity studies
— June 2012
 outine internal peer review
R
 Immunotoxicology
 esticular and ovarian staging
T
 istomorphometry to quantify tissue
H
changes
 nline data acquisition
O
 igital imaging, high resolution
D
photographs, telepathology
 oard certified pathologists may read
B
or review your slides at your facility
www.citoxlab.com

21. Histopathology (CNTD)
Specific expertise
Tissue Cross Reactivity: Tissue collection for RNA Bone and joint research:
CiToxLAB offers high quality in vitro or DNA extraction: CiToxLAB provides a complete set of
Tissue Cross Reactivity (TCR) for the CiToxLAB provides a complete set of services (in vivo and ex vivo) for the
immunohistochemistry screening of services in molecular pathology and evaluation of the effects of products
therapeutic antibodies. genomics (transcriptomics). on the skeleton (pharmacological and
toxicological effects).
 S
tandard preliminary and definitive  S
pecifically trained team in order to:
protocols, GLP or non-GLP, performed - ollect the tissues in a very short
C  B
one densitometry: standard
according to FDA recommendations time to avoid RNA degradation radiology, DXA, pQCT, micro-CT
 tate-of-the-art equipment: Ventana
S - recise trimming procedures
P  lastic embedding
P
Discovery XT® and DAKO® autostainer to avoid contamination with  tate-of-the-art histomorphometry
S
Link 48 to maximize repeatability adjacent tissues with validated software for
 ull range of frozen normal human
F  xtensive list of tissues in rodent and
E measurement of static and dynamic
tissues available from multiple donors non-rodent species parameters
with patient history  omplete set of blood and urine bone
C
 iToxLAB offers molecular pathology
C
 ull range of frozen normal animal
F services with real-time PCR (rt-PCR) markers in rodent and non-rodent
tissues available from several species and quantitative PCR (Q-PCR) species
including Cynomolgus, Rhesus, dog,
rat, mouse, rabbit, or minipig
Image analysis:
 rozen pathological tissues available
F
as positive controls  H
istomorphometry is performed using
validated computerized image analysis
 igh resolution photographs to
H
software to efficiently quantify the
illustrate the representative staining in
user-defined changes for a wide range
your GLP audited report
of parameters
 emi-quantitative evaluation by a
S
 rained technical staff under the
T
board certified veterinary pathologist
supervision of pathologists
 nternal peer review
I
 LP or non GLP projects
G
 ultiple digital image workstations
M

Comprehensive reports with statistical
analysis if required

22. Immunology Services
Routes of Administration and Know-How
Several facilities in the CiToxLAB group offer immunology services and provide industry‑leading
expertise in the conduct of GLP-compliant immunotoxicology evaluations. Our experts are abreast of
the evolving regulatory requirements and are able to offer guidance in study and program design.
Assessment of autoimmunity Study types Support services
 A
ssays for anti-dsDNA and  E
xtended histopathological  I
mmunogenicity analysis,
anti‑nuclear antibodies examination of lymphoid tissues and including development
 arkers of TH2 activation in rodents
M organs of antidrug antibody and
prone to developing autoimmune  -dependent antibody responses
T neutralizing antibody assays
reactions (KLH)  ioanalytical immunoassays for
B
 creening for other auto-antibodies in
S  mmunophenotyping for quantitation
I toxicokinetic and pharmacodynamic
nonclinical toxicology studies of lymphocyte lineages or biomarker studies
expression  issue cross reactivity studies on a
T
Adverse immunostimulation  ell mediated immunity (NK and CTL
C full panel of frozen human and animal
Our experts can advise on how to Cytotoxicity) tissues in support of monoclonal
proceed in this rapidly evolving area of antibodies and other ligand binding
 mmunohistochemical staining for cell
I
concern therapeutics
lineage and apoptosis markers in fixed
tissues  rug activity assays in support of
D
 Panels of cytokines
toxicology species justification
 nflammation biomarkers (CRP,
I Pseudoallergic reactions  uantitative gene expression for
Q
fibrinogen, etc.)
 Direct histamine release biomarker analysis
Species commonly used  Complement activation  iodistribution and genomic
B
Non-human primate, dog, rat, mouse integration analysis of nucleic acid
Contact hypersensitivity therapeutics
and minipig.
 LLNA  iodistribution and drug activity
B
 Magnusson-Kligman and Buehler assays for enzyme products
 Photo-LLNA  iodistribution of cell-based
B
therapeutics with PCR,
immunohistochemistry and flow
CiToxLAB offers the full range of
cytometry.
immunology-based support services
necessary for the development of
biotechnology-derived therapeutics,
Infrastructure
along with the experience and expertise  BSL2 capable
— June 2012
necessary to conduct any required  M
odern laboratories in Europe and
immunotoxicology studies. North America
Whether developing a protein, nucleic  Dedicated, separate rooms for:
acid or cell-based therapeutic, our
- Tissue culture
staff can provide full support, from
toxicology species justification, through - Molecular biology
assay development, to final report - General immuno-assays
submission.
www.citoxlab.com

23. Dermal Studies
Routes of Administration and Know-How
With more than 25 years of experience in the use of minipigs, supported by scientific staff with many
years of experience in the pharmaceutical industry, and specialized in dermal products, CiToxLAB is your
ideal partner for the development of drugs intended for dermal use.
From 2003 to 2011, CiToxLAB performed approximately 300 minipig studies, including 50 by the dermal
route. We have also performed 15 dermal studies in rats.
We offer wound healing studies to investigate the efficacy and safety of dermal drugs, and during the
last 6 years we have performed approximately 35 wound healing studies in minipigs.
In addition to the following studies, CiToxLAB offers a full first-in-man support service, plus a full range
of studies to support Phase II and III clinical trials.
Species Study types Product types
 Minipig (specific to dermal application)  Gels
 Rabbit  Toxicology – acute to chronic  Creams
 Rat  Local tolerance  Ointments
 Mouse  Sensitization  Patches
(local lymph node assay and guinea
 Guinea pig  Transdermal devices
pig maximization)
 Phototoxicity
 harmacokinetic (transdermal
P
absorption and bioavailability)
 Safety pharmacology
 fficacy (including tensile strength
E
measurements)
— June 2012
www.citoxlab.com

24. Inhalation Toxicology Services
CiToxLAB group offers studies by inhalation in Canada and Hungary. These studies may be performed in rodents,
dogs and non-human primates.
Study types Current infrastructure Technology and equipment
Nose-only and oronasal Studies are performed in purpose-built Rodent exposure
 Single dose laboratories with back-up systems
(pumps, ventilation, generators, etc.). Nose-only exposure using a directed
 Subchronic flow (flow-past) system that minimizes
The facilities are also equipped as
 Chronic follows: test item requirements:
 revents re-breathing
P
Aerosol generations of Seven rodent suites (nose-only)
 estraint designed to minimize
R
 ach containing 5 or 6 exposure units
E thermal stress
 Liquids
(accommodates sham control, vehicle
 Powders  aintains homogeneous breathable
M
control and 4 test item dose levels)
 Gases
atmosphere at all levels of the
 Each unit can accommodate up to inhalation tower
80 rodents
Species  ach exposure unit can accommodate
E
 ach unit physically and spatially
E up to 80 animals
 Rodent separated (walk-in ventilated hoods)
 Dog Large animal exposure
Five large animal suites (oronasal)
 Non-human primate Oronasal exposure using a directed flow
 ach containing up to 4 exposure units
E (flow-past) system that minimizes test
Experience and staff  Each unit can accommodate up to item requirements:
8 animals  revents re-breathing
P
 C
iToxLAB has over 25 years of
experience with various animal species  hysical and spatial separation of
P  ach exposure unit can accommodate
E
given single or repeated nose-only control group exposure units to up to 8 animals and can be used with
and oronasal exposure to liquids or prevent cross-contamination various species
powders.  xposure masks available for various
E In addition, the system can
 he inhalation teams at CiToxLAB are
T species (e.g. dog) accommodate various generating
also supported by our experienced equipment depending on test item (e.g.
board certified pathologists and clinical nebulizers and dust generators)
analytical and bioanalytical teams,
who work closely with the inhalation Supporting services
experts.
 A
nalytical and bioanalytical (HPLC and
LC-MS/MS)
 Pathology
 Immunology
 Toxicokinetics
 fficacy animal models (COPD,
E
asthma, nicotine)

25. Continuous Intravenous Infusion
Routes of Administration and Know-How
CiToxLAB offers acute to chronic continuous intravenous infusion in all major laboratory species. Our staff
includes industry-recognized experts with wide experience in the design, conduct and interpretation of
continuous intravenous infusion studies.
This extensive experience of the intravenous infusion of biotechnology-derived and other pharmaceutical
products, allows us to provide our clients with guidance on optimal vehicles, formulation conditions, pH
and osmolality ranges, and maximum and minimum recommended infusion rates and volumes, as well as
providing input on drug compatibility, background pathology and other issues unique to the intravenous
infusion delivery route.
Species
 Minipig
 Rabbit
 Rat
 Mouse
 Guinea pig
— June 2012
www.citoxlab.com