General toxicity

Single, as well as short and long-term repeated-dose toxicity studies, are possible at INA. Our team of experienced researchers includes certified toxicologists, pathologists and doctorate holders, and is supported by certified laboratory animal technicians. The various tests required for entering Phase I clinical trials, including genotoxicity and safety pharmacology studies, can be completed, from initial testing to final report submission, in as little as 6 months.

• Main study options
  Single dose studies, extended single dose toxicity studies, 2-, 4-(1-month), 13-(3-month), 26-(6-month), 39-(9-month) and 52-week (12-month) repeated dose studies, dose-finding studies and general toxicity.

• Animal species
  Mice, rats, rabbits, guinea pigs, hamsters, canines and cynomolgus monkeys

• Routes of administration
  Oral (gavage, dietary admixture), intravenous (bolus, long-term continuous intravenous infusion), intraperitoneal, subcutaneous, intracutaneous, intramuscular, ocular instillation, percutaneous (direct application, adhesive skin patch), intrarectal, intraarticular, oral mucosal, etc.

• Observations and measurements
  Clinical observations, body weight, food and water consumption, ophthalmologic and auditory tests, electrocardiography, blood pressure, body temperature, clinical pathology, necropsy, organ weights, histopathology, etc.

• Toxicokinetics
  Analysis of drug and metabolite concentrations in biological samples.

Reproductive and developmental toxicity

INA possesses extensive experience and historical data for reproductive and developmental toxicity studies in all areas deemed necessary by ICH guidelines. Studies in mice, rats and rabbits can be carried out via oral, intravenous, intravenous and subcutaneous administration.

• Effects on fertility and early embryonic development to implantation (ICH-I, mice, rats)
• Effects on pre- and postnatal development including maternal functions (ICH-II, rats)
• Effects on embryo-fetal development (ICH-III, mice, rats and rabbits)
• Single study design (rats)

In addition, clinical pathology, histopathology and toxicokinetic analyses are also available.

Genotoxicity

Our staff possess vast experience in screening, as well as the various toxicity studies necessary for New Drug Applications.

• Bacterial reverse mutation (Ames)
• Chromosome aberration in mammalian cells
• in vitro micronucleus tests
• Chromosome aberration in human lymphocytes
• Photocytotoxic tests (3T3 cells)
• Micronucleus tests in mice and rats (bone marrow, peripheral blood)
• Chromosome aberration in rats
• Micronucleus tests in hepatocytes of juvenile rats
• in vivo comet assays

Carcinogenicity

Carcinogenicity studies are conducted in mice and rats via various routes, including oral, percutaneous and subcutaneous administration, and short and mid-term studies using transgenic mice and two-step oncogenesis mouse models are also possible. INA's expertise lies in accurate tumor diagnosis, and we can also offer peer-reviews by leading tumor pathologists from both Japan and abroad.

Local irritation

The following studies are available using mice, rabbits, guinea pigs, and hamsters.

• Conjunctive irritation (rabbits)
• Effects of contact lenses on the cornea (rabbits) - ISO 9394 compliant
• Skin irritation (rabbits)
• Vascular irritation (rabbits)
• Muscular irritation (rabbits)
• Nasal mucosa irritation (rats and rabbits)
• Oral mucosa irritation (hamsters)
• Rectal mucosa irritation (rabbits)
• Vaginal mucosa irritation (rabbits)
• Knee cavity irritation (rabbits and canines)
• Phototoxicity (mice and guinea pigs)
• In vitro hemolysis (rabbit blood, dog blood, human blood, other)

Immunotoxicity

Immunotoxicity studies are conducted using mice and guinea pigs.

• Immediate-type hypersensitivity

● Active systemic anaphylaxis tests (ASA, guinea pigs)
● Passive cutaneous anaphylaxis tests (PCA, guinea pigs)
● Hetero-PCA tests (mice-rats)
• Delayed-type hypersensitivity tests

● DTH intracutaneous reactivity (guinea pigs)
● Popliteal lymph node assay tests (PLNA, mice)
● Skin sensitization (guinea pigs)
   Maximization test, Adjuvant and Patch test, Buehler test, etc. (guinea pigs)
   Local lymph node assay tests (LLNA, mice)
● Skin photosensitization (guinea pigs)

Screening Toxicity

INA can propose the appropriate study design, using minimal amounts of test article in mice, rats, canines or cynomolgus monkeys, to best suit your developmental needs. In particular, we offer dose escalation studies in non-human primates, the closest model to humans, to obtain as much information as possible from a small number of animals in a short period of time. By conducting periodic ambulatory ECG monitoring in addition to regular toxicity parameters in non-human primates or canines, it is possible to detect the arrhythmia induction potential of a test article. By periodically measuring blood drug concentration, it is also possible to check the exposure to or accumulation of a drug at each dose level. Seperate PK and TK screening studies are also available.

Toxicity in juvenile animals

INA has a wealth of experience in single and repeated dose toxicity studies in juvenile rats and canines.

• Juvenile rats
  Oral or intravenous administration to rats is possible from 4 days of age.
• Juvenile canines
  Juvenile canines raised by artificial suckling can be administered from 3 weeks of age via oral, intravenous or subcutaneous routes of administration.

Biological safety tests on medical devices

INA conducts various biological safety studies on medical devices and raw materials.

• Cytotoxicity (extraction and direct contact methods)
• Sensitization
  ● Maximization method (guinea pigs)
  ● Adjuvant and patch test (guinea pigs)
• Irritation
  ● Intracutaneous reaction (rabbits)
  ● Skin irritation (rabbits)
  ● Ocular irritation (rabbits)
• Systemic toxicity
  ● Acute toxicity (mice)
  ● Subacute toxicity (rats)
• Implantation
  ● Short-term intramuscular implantation (rabbits)
  ● Subcutaneous implantation (rabbits)
  ● Bone implantation (rabbits)
• Genotoxicity
  ● Ames test (using bacteria)
  ● Chromosome aberration (using mammalian cultured cells)
  ● Micronucleus tests (mice and rats)
• Hemocompatibility (rabbit blood)
• Effects of contact lenses on the cornea (rabbits) −ISO9394 compliant

Other

In addition to general toxicity studies, our experienced technicians also conduct other specialty toxicity studies, including functional tests, all conducted in accordance with international guidelines.

• Ocular toxicity
  Ocular agents are evaluated by frequent repeated administration to the eyes of rabbits, canines and cynomolgus monkeys. Ophthalmologic examinations available include intraocular pressure, slit lamp, funduscopy and electroretinography (ERG), tear volume measurements, corneal thickness and endothelium observations (specular microscope), anterior eye protein concentration measurements (laser flare-cell meter), and light and electron microscopy.

• Renal toxicity
  Measurements of blood urea nitrogen, blood and urinary creatinine, urinary protein, urinary N-acetyl-β-Dglucosaminidase (NAG), renal blood flow, calculation of creatinine clearance, and phenolsulfonphthalein (PSP) excretion can be measured in rabbits, canines and non-human primate. Histopathological examinations including light microscopy with special staining, as well as electron microscopy, are also possible.