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Discover our citoxlab nonclinical services
 

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 ...

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 Discover our citoxlab nonclinical services Presentation Transcript

    • 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
    • CiToxlab Scantox CiToxlab France atlanbio CiToxlab HungaryCiToxlab North America Croen Research Inc. Stemina Media Services Ltd Japan
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • Our services Study Types Routes of Administration and Know-How Reach Mechanistic Toxicology Bioanalysis and Pharmacokinetics8
    • 9
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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)
    • 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
    • Surgical CapabilitiesRoutes of Administration and Know-How CiToxLAB’s large dedicated team of experienced veterinary surgeons, combined with our custom built and fully equipped surgical suites, allows us to offer routine and customized surgical models, including orthopedic and soft-tissue procedures. Aseptic technique and attention to pre-and post-operative care are essential, and are accomplished using specifically equipped and designated procedure rooms, with a large and qualified staff of animal health technicians. In-house imaging technologies allow us to fine- tune surgical procedures and to conduct non-invasive follow-ups. Through close collaboration with our clients and our extensive network of recognized experts in a variety of disciplines, CiToxLAB has earned a reputation of being an innovator in the development of specialized models and procedures and for its ability to apply these models to GLP studies. Available surgical models  N  on-invasive cerebrospinal fluid  J  ejunal catheters in dogs, non-human sampling catheter primates and rats Rabbit  ntraarticular injection and synovial I   ortal vein catheters in dogs, P  Arterial restenosis fluid collection non-human primates and rats  Hemostasis  Kidney transplantation   urgical (incisional and excisional) S  Heptanol induced corneal ulcer  Vascular access port (VAP) wound healing models in mice, rats, rabbits, pigs and minipigs Rat   ubcutaneous and intramuscular S   elemetry in dogs, minipigs, T  Bile duct catheter implantations non-human primates, rats and mice  Continuous lymph collection Multi-species   ascular access port (VAP) in rats, V  Kidney transplantation  L  eft ventricular pressure and dogs, non-human primates and  nternal carotid catheterization I pulmonary arterial pressure minipigs (rodent model for cerebrovascular  Dialysis models in pigs and dogs   ubcutaneous and intramuscular S administration)   isease models (cardiac hypertrophy, D implantations in rats, rabbits and cardiac insufficiency, myocardial minipigs Non-human primate  Cerebrospinal fluid collection infarction & diabetes) Infrastructure   uodenal catheters in dogs, non- D  Multiple surgical suites (HEPA-filtered)  EEG monitoring using telemetry human primates and rats  S  eparate areas for pre- and   ontinuous intracerebral C   ontinuous lymph collection in dogs, C post‑operative care (parenchyma) infusion minipigs and rats  Kidney transplantation Equipment   emoral and jugular vein catheters F — June 2012 Dog in dogs, non-human primates, pigs,  X-ray minipigs and rats Fluoroscopy   emoral trochleoplasty and other F  orthopedic models  leal catheters in dogs, non-human I  Ultrasound primates and rats   dministration under intervention A  Micro-isolator caging radiography (cerebral artery infusion,  ntraarticular injection and synovial I fluid collection in dogs, non-human  Laminar hoods prostatic artery, etc.) primates, minipigs, pigs and rats  Multiple microsurgery stations  ntrathecal catheters in dogs and I non-human primates Species Rat, dog, non-human primate, rabbit and minipig www.citoxlab.com
    • Telemetry StudiesAs part of its safety pharmacology services, CiToxLAB offers the industry’s largest capacity for telemetry studies,thus making us an industry leader in the conduct of conscious cardiovascular safety pharmacology studies.In addition to implanted telemetry, our team offers a large range of non-invasive telemetry models using DSIjacketed external telemetry. Our telemetry studies are conducted using rigorously validated test systems, and aredesigned to support international regulatory requirements (e.g. ICH S7A & ICH S7B). A large, dedicated team ofexperienced veterinary scientists and surgeons is involved in all aspects of validation and study conduct and issupported by recognized experts in electrocardiography.Our colonies of pre-instrumented telemetered beagle dogs, Cynomolgus NHP and Göttingen minipigs allow us toprovide optimal timelines, using well-established conscious animal models. Validated computerized ECG analysiscombined with expert review by board certified veterinary cardiologists ensure that electrocardiographic andhemodynamic data are thoroughly and expertly evaluated.Our team also offers a wide range of continuous video-EEG models for seizure liability, sleep scoring, spectralanalysis and other CNS evaluations. World-renowned consultant neurologists specializing in seizure assessment,movement disorders and sleep studies provide thorough data interpretation using state-of-the-art analysis tools.Our telemetry studies often incorporate additional assessments, including respiratory function, thus maximizingthe data available from a single study.Species Equipment and infrastructure: Telemetry capacity Rat  S  everal Data Science International  M  ore than 120 animals concurrently Dog telemetry systems  C  ontinuous high resolution EEG-video Non-human primate  ndustry’s largest telemetry capacity I in 12 animals simultaneously Minipig   odern surgical facilities and M recording environment for telemetry, Quantitative parameters Guinea pig equipped with continuous video  A  rterial blood pressure (systolic,  ermanent dog, non-human primate P monitoring diastolic, mean) and minipig implanted telemetry   ans Rudolph & Scireq respiratory H  Left ventricular pressure colonies system  ECG intervals   edicated animal rooms for safety D  Activity pharmacology  Core body temperature   ultiple surgical suites M  Pleural pressure  maging (X-ray and fluoroscopy) I  Biopotentials (ECG, EEG, EMG)
    • BioanalysisBioanalysis and Pharmacokinetics CiToxLAB offers GLP-compliant bioanalytical services for nonclinical studies performed in-house and for studies conducted in a Sponsor’s facility. Analysis of plasma/serum or other biological matrices is performed to determine the concentration of the test substance for pharmacokinetic/toxicokinetic analysis. CiToxLAB performs method development of new compounds or method transfer of existing methods. In each case, the method is fully validated according to GLP principles. Equipment Activities Support services M  ultiple systems at each facility include:  Method development  S  everal highly experienced senior   PLC systems with a variety of H  Method transfer bioanalytical chemists are available to detection methods provide sponsors experienced staff  Method validation with scientific and regulatory guidance   C systems with a variety of detection G   ample analysis to support S methods   hemists are supported by C pharmacokinetic/toxicokinetic studies well‑trained analysts with experience  LC-MS and inhalation toxicology studies in bioanalytical method development/  LC-MS/MS  Dried blood spot sample analysis method validation/sample analysis  LC-ICP/MS using LC-MS/MS or other technologies  UV spectrophotometer — June 2012 www.citoxlab.com
    • AnalysisCiToxLAB offers GLP-compliant analytical chemistry support for all types of nonclinical study performed in-houseor at the client’s facility. Analysis of test formulations is performed to confirm the concentration, homogeneity andstability. We can perform method development of new compounds or method transfer of existing methods. Ineach case, the analytical method is fully validated according to GLP principles.Equipment Activities Support servicesMultiple HPLC systems at each facility  Method development  Several  highly experienced senior  Method transfer analytical chemists are available to provide sponsors experienced staff  Method validation with scientific and regulatory guidance  ample analysis to support toxicology S  hemists are supported by well- C studies: trained analysts with experience in - Solutions analytical method development/ - Suspensions method validation/ sample analysis using HPLC or other technologies - Dietary admixtures -  tmosphere (inhalation studies) A
    • Pharmacokinetic/Toxicokinetic Studies/ADMEBioanalysis and Pharmacokinetics CiToxLAB offers 32, 000m2 of vivarium and supporting laboratories for the conduct of GLP‑compliant pharmacokinetic and toxicokinetic studies on pharmaceuticals and biotechnology‑derived products. Studies are conducted in all rodent and non-rodent species, including non-human primates and minipigs, to determine the time course of a drug candidate and its major metabolites after drug administration. These studies are supported by CiToxLAB’s bioanalytical and immunology services which provide LC-MS/MS, GC-MS/MS, HPLC and immuno-assay (e.g. ELISA) analyses in biological matrices. Non-compartmental modelling is conducted using fully GLP validated WinNonLin software. In addition, to routine blood collection (e.g. sublingual, retro-orbital sinus or tail vein in rats), our technicians use a specialised jugular sampling technique to collect serial blood samples from individual rats without the need for anesthesia or cannulation. Intrajugular catheters, which do not require surgery, are routinely used in minipigs. Study durations Routes of administration Bioanalytical support  Single dose  Oral (gavage, capsules, pills)  7 LC-MS/MS  Repeated dose  Intravenous (bolus)  GLP-validated analytical software  ntravenous infusion (intermittent, I  GC-MS Species cyclic and continuous)  LC-ICP/MS  Rodent  Subcutaneous  ELISA  Dog  Dermal  Dedicated scientists  Non-human primate  Inhalation  Rabbit  Intradermal Specialties  Mini and micropig  Intramuscular  Radiolabelled studies  Poultry  Intraperitoneal  P  ermanent dog, non-human primate  Marmoset and minipig PK colonies  Intrathecal   ustom-designed PK studies using C  Intranasal surgical and non-surgical techniques  Intravaginal/intraurethral (in vivo drug-drug interaction, Pgp  Intrarectal interaction, brain penetration, CSF collection, enterohepatic recirculation,  Intravesicular etc.)  Intravitreal  n vitro plasma/blood partitioning, I — June 2012  Intratracheal instillation plasma protein binding  Ocular  In vitro cutaneous penetration   ndoscope-assisted administration E (e.g. directly into the duodenum)  Intraportal  Intraarticular www.citoxlab.com
    • Drug MetabolismCiToxLAB offers GLP-compliant preclinical studies, designed to investigate absorption, distribution, metabolism,and excretion (ADME), to support drug discovery, safety evaluation and clinical development programs.Equipment Services Facilities Metabolism  cages for mice, rats, dogs,  Mass  balance/excretion studies Dedicated laboratory with controlled non-human primates, minipigs including CO2 collection and bile access and multiple formulation rooms CO2 rodent cages (Metabolica) excretion to prevent cross-contamination. ully validated ß-counters : (Beckman F   nalysis of all matrices (blood/serum/ A plasma, urine, feces, milk, saliva, tears, Species LS600YA and Perkin Elmer Tri-Carb 2910TR) bile and tissues)  Rodent ample Oxidizer (307 Perkin Elmer) S Isotopes used: C, H 14 3  Dog PLC/UV/on-line radioactivity H Establishing mass balance and  Non-human primate (LB507A Radioactivity monitor) excretion routes of an administered  Minipig radioactive drug candidate is  Rabbit important in order to determine compound distribution and assist the  Poultry interpretation of toxicology findings. An understanding of excretion Specialties routes in animals provides guidance •  ass balance studies in rodents, M in the evaluation of patients with minipigs, dogs and non-human compromised physiological functions primates (e.g hepatic and renal impairment). •  pecialized techniques in PK/mass S Tissue distribution studies (QTD) balance sampling for rodents and non-rodents Knowing the time course of a drug candidate’s tissue distribution •  ully validated instrumentation to F after administration may help to comply with regulatory agencies understand the mechanism and course of action, and this helps Support services explain any observed toxicity. These  Bioanalytical Chemistry studies provide an estimate of human  P  harmacokinetic modelling exposure to radioactivity (dosimetry) (WinNonLin) in human radiolabelled mass balance/ excretion studies. QTD studies can be combined with mass balance studies, plasma/blood pharmacokinetics in a single protocol to save time and money.
    • reach & CLP ServicesReach CiToxLAB has close to 30 years of experience in working with the chemical industry and offers all the studies that are required under REACH (Registration, Evaluation and Authorization of Chemical Substances). All of our studies are performed according to GLP regulations and follow standard OECD guidelines. Services Registration of all existing chemicals Experience  REACH Data Gap Analysis manufactured, imported, transported, Our facility in Hungary has used as intermediates or placed on the extensive experience in  CLP classification market in Europe should be completed REACH projects with a wide   SAR, SAR, literature search, data Q by the appropriate REACH deadlines. range of chemicals, including metals waivers All new chemicals are subject to the and other inorganic chemistry, as well  Robust Summaries same regulations. Similar regulations as a wide range of physical forms of exist in a number of other world regions, organic chemicals and mixtures.   dvice, guidance and full regulatory A CiToxLAB can provide consultancy on The facility is able to deal with difficult support for dossier preparation and national requirements. submission substances where special procedures Since May 2009, the Hungarian facility are required to allow testing to be   ata submission in ECHA format D has had a partnering agreement with performed across the full range of (IUCLID 5) CS Regulatory Ltd, an ISO 9001:2008 study types from aquatic toxicology to   ull support for the whole registration F accredited organization with 40+ years long-term inhalation toxicology. process experience of regulatory submissions,  Project management providing our clients in the chemical Tests required industry with a complete service   epresentation - Third Party and Only R REACH testing schedules are offering full regulatory assistance and Representative dependent on the number of tonnes safety evaluations. produced per year, but involve a  Physical chemistry wide range of tests from simple  Genetic toxicology Services include physico-chemical studies to long-term  Analytical services  R  EACH Specialist: advice, compliance mammalian toxicology tests. The time and consultancy packages for required to complete such testing   cute and chronic mammalian A chemicals programs is as follows: toxicology by the oral, dermal or inhalation routes >1 tonne/annum substances ~ 3 months  Worldwide registration of chemicals   eproductive toxicology, including R >10 tonnes/annum substances ~ 6 months multigeneration rodent (one, two or P  roduction of chemical safety >100 tonnes/annum substances ~ 10 months extended generation studies) and documents >1000 tonnes/annum substances ~ 3 years avian reproduction -  aterial Safety Data Sheets (CLP/ M   cotoxicology (aquatic, terrestrial, E Ext-SDS / GHS formats) REACH timelines avian) — June 2012 - Chemical Safety Reports 1 June 2013  Soil studies Deadline for registration of phase-in - Hazard Assessments   ioaccumulation and other long-term B substances > 100 tonnes/annum environmental studies CLP Regulation 1 June 2018 - Correct classification of mixtures Deadline for registration of phase‑in -  Late” CLP notification to the “ substances > 1 tonne/annum inventory -  reparation of Material Safety Data P Sheets www.citoxlab.com
    • Environmental ScienceCiToxLAB has more than 15 years of experience in supporting the studies for environmental assessment requiredfor EMA registration, agrochemical registration and industrial chemical notification.This service is located at our site in Hungary, with a research focus on environmental quality with regard to safetyof the natural environment. The fully GLP-compliant purpose-built facility and state-of-the-art instrumentationprovide an efficient and reliable service to their global client base.Services Terrestrial ecotoxicology Bacterial toxicity, biodegradation Aquatic ecotoxicology We offer a variety of terrestrial testing and environmental fate Terrestrial ecotoxicology ecotoxicology studies, with significant T  he following types of studies are experience in a range of species: conducted under this category:  acterial toxicity and biodegradation B   cute oral and contact toxicity to A   ctivated sludge respiration inhibition A Environmental fate honey bees test   aboratory and extended laboratory L   acterial toxicity (Pseudomonas BAquatic ecotoxicology toxicity studies with non-target putida)Studies conducted within CiToxLAB arthropods (NTA)Hungary include, but are not limited to:   eady biodegradability R   cute and extended toxicity A  cute and prolonged toxicity to fish A  Adsorption/desorption (reproduction) to earthworms  cute toxicity and reproduction tests A   ydrolysis studies H   cute and reproductive toxicity to A in daphnia magna springtails (Collembola) Algal growth inhibition test   vian acute studies, dietary studies A Lemna toxicity test and reproduction studies Our ecotoxicology team has vastOur ecotoxicology team has extensive experience in performing avian studiesexperience and expertise in the testing with different test species.of difficult substances with challengingphysico-chemical properties (e.g. lowwater solubility, instability or coloration).The fish toxicity studies are performedroutinely in rainbow trout, carp andzebra fish.Our analytical laboratory offersanalytical techniques suitable foruse with all matrices used in aquaticecotoxicology studies.
    • Physical ChemistryReach CiToxLAB Hungary offers close to 30 years experience in the physical chemistry area, along with a full range of studies necessary to support global product registration. CiToxLAB offers a comprehensive product characterization service to the agrochemical and chemical industries. CiToxLAB Hungary offers fast and Additionally, CiToxLAB offers a The guidelines supported include: flexible start times in order to support comprehensive range of CIPAC   U directive 91/414 annex II, E your global registration activities. Our methods supporting high temperature, and 1107/2009 (active ingredient) dedicated analytical team can provide: low temperature and long‑term   U directive 91/414 annex III, E regulatory storage stability/shelf life Typical study types studies for agrochemical, biocide, and 1107/2009 (formulations) veterinary and pharmaceutical global   ECD guidelines 101 – 123 inclusive O  Physical state testing requirements.  EU CLP and REACH guidelines  pH  Melting point/boiling point  Relative density  Vapour pressure  Water solubility  Hydrolysis  Soil adsorption/desorption  Surface tension  Dissociation constant  Viscosity  Partition cœfficient  Flammability  Auto-ignition temperature  Oxidizing properties — June 2012 www.citoxlab.com
    • Structure-Activity Relationship (SAR) AnalysisWith over 20 years of experience and expertise, CiToxLAB can provide a full SAR analysis and expert reporting.CiToxLAB has extensive background knowledge and experience in the requirements for the regulatory authoritiesas well as in screening and predictive toxicology.The system used is a computer package which predicts the toxicity of molecular structures based on a definedset of rules. These rules are specified and regularly updated through collaboration with experts in the majorityof large pharmaceutical companies, and regulatory authorities, such as the US-FDA. A Cooperative Researchand Development Agreement (CRADA) exists between the software supplier and the ICSAS (Informatics andComputational Safety Analysis Staff) group at the US Food and Drug Administration (FDA), Center for DrugEvaluation and Research (CDER) and the CFSAN (Center for Food Safety and Applied Nutritian) group. The resultsare quickly obtained from the chemical structure, with no need to use chemicals or animals. SAR provides anestimate of toxicity, which can be used in regulatory submissions, to select candidate and identify possible toxicimpurities.Key functions Services I dentification of the genotoxic or Expert reports on the genotoxic  E  valuating the risks from intermediates neurotoxic potential of chemical potential of pharmaceutical impurities and impurities, thus often avoiding structures (FDA and EMA submissions) the need for synthesis and toxicology t predicts whether a chemical has I Expert reports on the genotoxic or testing of minor components of mutagenic or carcinogenic properties neurotoxic potential of metabolites technical products t predicts whether a chemical will be a I (EU agrochemical submissions)  dentifying the potential risks of I skin sensitizer   creening candidate molecules to S intermediates for the different identify those least likely to cause synthetic routes, as part of the t is a high throughput screen for I toxicity decision process for route selection genotoxicity/mutagenicity   valuating leading candidate E   roubleshooting - to aid in the T t highlights a wide range of potential I molecules, to help prioritize safety identification of the root causes of toxicological hazards, from irritancy to mutagenic or sensitization issues in hepatotoxicity tests (“Cross The Biggest Hurdles First”, or “Fail Early–Fail Cheap”) batches of final products  he SAR system is used in conjunction T   etermination of what organizations D   AR will play a major role in the S with literature and available data to REACH process, in the triage of compile expert reports like the FDA or EPA may identify when you submit molecules for priority testing, and as a screen to avoid direct testing   elping to anticipate questions from H regulatory agencies
    • Lead Optimization: LeadScreen™Mechanistic Toxicology CiToxLAB France offers services to clients in the pharmaceutical industry to optimize the selection of lead candidates for drug development with our LeadScreen™ package of tests. Key services have been optimized for the non-regulatory environment to offer quality data in a timely manner. LeadScreen™ services cover the areas of genotoxicity, safety pharmacology, pharmacokinetics and multi-endpoint in vivo toxicology. Key decisions can be made faster, saving time and money in the development of drugs. Choosing the right lead candidate can take as little as 14 days. Give us 14 days and we’ll give you a lead… Study types LeadScreen Tox LeadScreen Genotox devTOX™ & cardioTOX™  Core Study  MiniAmes  Stemina hES lines - In life data  Micronucleus in vitro - Clinical pathology  BlueScreen HC™ LeadScreen Safety - Histopathology  In vivo QT prolongation LeadScreen Pharmacokinetics  Other CV parameters  In vivo genetic toxicology - In vivo half-life Genomics - In vivo bioavailability - Toxicogenomics - CYP induction - DrugMatrix™  Toxicokinetics Biomarkers -  ide range including troponine W and kindey injury biomarkers — June 2012 www.citoxlab.com
    • GenomicsMechanistic Toxicology CiToxLAB France offer extensive services in the field of genomics that can help clients elucidate mechanisms of toxicity and predict the toxicity of their drug candidates. With extensive expertise in DNA/ RNA (including µRNA) extraction from all sample types and multiple species, CiToxLAB France can be your partner in helping to advance drug candidates. In our laboratories, we offer services in expression analysis (approved Affymetrix service provider and PCR), biomarker discovery and biodistribution of gene therapy products. Key areas of expertise  2  7 chips (3 tissues: e.g. kidney, liver, Biodistribution of gene  C  ustomized toxicogenomics study heart; 3 groups; 3 animals per group) therapy products design (relevant species selection,   omplete Sponsor-customized data C Regulatory biodistribution studies choice of appropriate time-points analysis (from preprocessing up to are a pivotal requirement during the and dose-levels, sequenced organ pathway analysis and prediction preclinical safety evaluation of gene sampling at necropsy) scoring with DrugMatrix) therapy vectors (viral DNA or RNA,   arge panel of DNA/RNA/µRNA L   eporting in 10 days with raw data R plasmid, antisense). They provide extraction procedures to ensure top transferred onto a secured FTP server essential safety data on the persistence level quality DNA/RNA/µRNA from of DNA or RNA in the organs and its Gene expression analysis dissemination throughout tissues and more than 50 tissues, fluids, cells and swabs from rodents and non-human CiToxLAB France offers gene expression fluids. CiToxLAB France provides a primates analysis services based on either complete biodistribution study solution Affymetrix chips or real time PCR. which includes:   onitoring/detection of DNA and RNA M   rray based studies include : A  n vivo phase under BSL1/BSL2 I sequences using real-time quantitative PCR (Applied Biosystems 7900 HT µRNA 2.0, Human Genome U133 Plus conditions Fast) 2.0; Mouse Genome 430 2.0; Rat   nhanced necropsy procedures E Genome 230 2.0; Canine Genome 2.0; in order to avoid organ-to-organ   LP-compliant gene therapy products G Porcine and Bovine genome; Human contaminations biodistribution regulatory studies Gene ST 1.0; Rat Gene 1.0 ST and   NA and DNA extraction from tissues, R   hole transcriptome profiling (RNA W Mouse Gene 1.0 ST and µRNA ) on Affymetrix Genechip® fluids and swabs (separate treated and   linical genotyping (SNP clusters and C control group extraction rooms) arrays (whole genome and Gene ST copy number analysis) with Genome arrays, µRNA arrays)   bsolute quantitative simplex/ A Wide Human SNP 6.0 arrays multiplex PCR and RT-PCR including   linical genotyping with Affymetrix C   eal Time qPCR with Applied R validation of qPCR or RT-qPCR Human SNP 6.0 arrays Biosystems 7900 HT Fast technology assays (specificity, reproducibility,   omplete data analysis (from C and Taqman® chemistry, Taqman® stability, range linearity, detection limit, preprocessing up to pathway analysis) Low-Density Array (TLDA) formats inhibition monitoring, extraction yields available (from 12 to 380 simultaneous and limits) Study types gene detections with simplicate to   ll the study phases are GLP-compliant A quadruplicate) LeadScreen™ study package   bsolute quantitative simplex/ A CiToxLAB France proposes the multiplex PCR and RT-PCR, including following simple toxicogenomics study validation of qPCR or RT-qPCR design for the investigation of toxic assays (specificity, reproducibility, mechanisms and toxicity prediction, stability, range linearity, detection limit, using a dose/time combination that inhibition monitoring) produces maximum impact on gene expression. This design may be   uantification of any transcripts Q customized to your specific objective. with a known sequence (up to 380 transcripts on one card)   control and 2 test item-treated 1 groups (up to maximum tolerated dose) with 3 animals per group www.citoxlab.com
    • MetabolomicsMechanistic Toxicology CiToxLAB, working in collaboration with Stemina Biomarker Discovery, offers a broad suite of metabolomic services focused on identifying metabolites and biomarkers of many biological processes. By focusing on the small molecules, either secreted or consumed by cells, the metabolomics platform is capable of identifying metabolite patterns associated with toxicity, cellular responses to drugs or chemicals, or biomarkers associated with disease. Our team has experience in working with a spectrum of clients that include pharmaceutical, chemical, agricultural, and cosmetics companies. In addition to the identification of biomarkers, Stemina’s proprietary metabolomics database maps significantly changed small molecules to the molecular pathways in which they reside. The workflow begins with biological sample acquisition, sample preparation and evaluation by high performance liquid chromatography coupled to high resolution mass spectrometry, followed by univariate and multivariate bioinformatic analysis, data mining, evaluation, and interpretation. Technologies employed  Experience counts  Routine Service Offerings   C  ell culture, including stem cells, We routinely analyze materials and  D  evTOX-hES : Evaluation of test primary cells, and differentiated cells supernatant from cell culture, human compounds for the potential to cause such as neural and cardiomyocytes. tissue and body fluids, and plant developmental toxicity in human   hromatography methods include C samples. systems. In addition to a prediction HILIC Hydrophilic Interaction of the toxicity of the compound, Chromatography, C18 Reverse Phase Stemina’s devTOX assay provides Our team has extensive experience in information on the metabolic Chromatography, and other selected metabolomic analysis with methods. pathways which are disrupted by the a specialization in the use of human test compound.   C/MS utilizing the latest in high L derived stem cells for performing many resolution instrumentation including of these tests. We routinely conduct  D  evTOX-iPS : Similar to the TOF and QTOFs incorporating both studies in embryonic stem (hES) cells, DevTOX-hES above, but utilizing positive and negative electro-spray induced pluripotent stem (iPS) cells, induced pluripotent stem (iPS) cells. ionization methods. as well as a variety of cell types based This test is often attractive to those on selective differentiation into cells organizations which prefer to avoid   ioinformatic platform uses LC/MS B such as cardiomyocytes. using embryonic-derived cells. feature identification, alignment, and standardization protocols followed.  ardioTOX : iPS derived cardiomyocytes C  by both uni- and multi-variant model are used to evaluate the potential of Stemina was founded in 2006 and development and validation. compounds to induce cardiotoxicity. has its state-of-the-art facilities   iomarker confirmation by B in the United States. Stemina has — June 2012 MS/MS fragmentation and comparison partnered with CiToxLAB to provide its to reference standards. Metabolites metabolomic and cell based assays in identified are confirmed and Europe. evaluated in relation to biological pathways. Often, multiple metabolite perturbations are observed in a single pathway. www.stemina.com www.citoxlab.com
    • 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