Discover our citoxlab nonclinical services

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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

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Discover our citoxlab nonclinical services

  1. 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 NHPsCiToxLAB Group companies Also represented by Carcinogenicity studies also in rasH2 and p53+/- miceCiToxlab 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 chemistryCiToxlab 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 / BPCiToxlab 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 biomarkersCiToxlab 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 150atlanbio 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. 2. CiToxlab Scantox CiToxlab France atlanbio CiToxlab HungaryCiToxlab North America Croen Research Inc. Stemina Media Services Ltd Japan
  3. 3. CiToxLAB, our newly established group, created through the merger of CiT and LAB Research, providesa 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 000non-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. 2Our broad range of GPL and non GLP nonclinical services combined with our 40 years of experienceare at the service of our customers to meet the demands of today’s complex global marketplace. Wecan 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 marketingauthorization 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 particularattention is accorded to housing conditions, social interaction and enrichment of their environment.CiToxLABs ethics committees have established and rigorously enforce our ethics charter for LaboratoryAnimals. All employees must continuously demonstrate their commitment to animal welfare and arerequired 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 AmericanAssociation of Laboratory Animal Care (AAALAC).As a highly qualified service provider, we also strive to be flexible, accomodating and respond asquickly as possible to each of your individual needs.Our objective can be summarized by our claim: CiToxLAB: Global expertise, Local response. 1
  4. 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. 5. General Toxicology (Acute to Chronic)With over 40 years of experience, the toxicity testing capabilities of CiToxLABcomprise a vast array of designs, ranging from acute single dose studiesto carcinogenicity studies, including specialty dose routes such as inhalation andinfusion. All studies are fully GLP compliant in accordance with current guidelines orcustom-designed for particular needs.CiToxLAB’s four facilities are located in France, North America, Denmark andHungary. We offer close to 60,  000  2 of vivarium and supporting laboratories mfor the conduct of general and specific toxicology studies on: pharmaceuticals,biotechnology products and medical devices. Our clients include an impressive listof 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. 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 specialists4
  7. 7. Dog ToxicologyThe dog is the most common non-rodent species used for the safety testing ofmedicinal products and chemicals. Such studies are routinely performed at allfour CiToxLAB facilities. The animals are housed and handled in accordance withthe 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 OStaff and intravitreal)  IntrathecalOver 800 staff, including:  Intraarticular  Project managers  Study directors  Immunologists  Veterinary surgeons  Pathologists  Toxicologists  Animal technicians  nalytical and bioanalytical A experts  Regulatory specialists 5
  8. 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 specialists6
  9. 9. Minipig ToxicologyThe minipig is a good laboratory animal model for many aspects of humanphysiology and metabolism. For this reason, it is becoming increasingly popularas an alternative to the dog or non-human primate for non-rodent safety testing.The CiToxLAB facility in Denmark has routinely performed studies in minipigssince they pioneered the use of this species in the 1980s. Minipig studies are alsoavailable 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 respiratoryInfrastructure 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 FDARoutes 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. 10. Our services Study Types Routes of Administration and Know-How Reach Mechanistic Toxicology Bioanalysis and Pharmacokinetics8
  11. 11. 9
  12. 12. Efficacy ModelsStudy 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. 13. Genetic ToxicologyStudy 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. 14. In vitro ToxicologyOur tests comply with latest versions of the guidelines issued by the ICH and OECD and are performed in accordancewith the current OECD Good Laboratory Practice regulations to ensure their acceptability to regulatory authoritiesworldwide.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. 15. Safety PharmacologyStudy 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. 16. Juvenile ToxicologyStudy 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. 17. DART: Developmental And Reproductive ToxicologyAn integrated evaluation of potential risks to reproduction and development is an essential component of marketingauthorization 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 anddevelopmental toxicity studies in accordance with current international guidelines (ICH, OECD, US EPA, etc) forpharmaceutical, biopharmaceutical, veterinary, chemical, agrochemical, food and consumer products.CiToxLAB has comprehensive historical control databases (rat and rabbit fetuses as well as fetal abnormalities inminipigs). This extensive experience allows our staff to conduct standard studies as well as highly specific customprojects.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. 18. CarcinogenicityStudy 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. 19. Biocompatibility of medical devicesStudy 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. 20. HistopathologyStudy 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. 21. Histopathology (CNTD)Specific expertiseTissue Cross Reactivity: Tissue collection for RNA Bone and joint research:CiToxLAB offers high quality in vitro or DNA extraction: CiToxLAB provides a complete set ofTissue Cross Reactivity (TCR) for the CiToxLAB provides a complete set of services (in vivo and ex vivo) for theimmunohistochemistry screening of services in molecular pathology and evaluation of the effects of productstherapeutic 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. 22. Immunology ServicesRoutes 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. 23. Dermal StudiesRoutes 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. 24. Inhalation Toxicology ServicesCiToxLAB 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 equipmentNose-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 PAerosol 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 rodentsSpecies  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 testExperience 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. 25. Continuous Intravenous InfusionRoutes 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
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