Pharmacokinetic studies

Source

Non-harmful / below threshold / severity degree 0 Mild / severity degree 1 Moderate / severity degree 2 Severe / severity degree 3
Directive 2010/63/EU, Annex VIII

  Pharmacokinetic study where a single dose is administered and a limited number of blood samples are taken (totalling < 10% of circulating volume) and the substance is not expected to cause any detectable adverse effect. Frequent application of test substances which produce moderate clinical effects, and withdrawal of blood samples (>10% of circulating volume) in a conscious animal within a few days without volume replacement.  
Federal Food Safety and Veterinary Office FSVO (2018)   Examples:Administration of substances and blood sampling in freely mobile rats and mice at intervals of several minutes to hours by venous catheter, with replacement of the sampled blood volumes by plasma expander or donor blood, with or without a stay in the metabolic cage <7 days. Steady state measurement by infusion in freely mobile rats by vascular catheter, without a stay in the metabolic cage. Steady state measurement by infusion in the dog, in a suspension belt for <4 hours, with or without a bladder catheter. Application of test substance in non-toxic doses followed by euthanasia of the animals (drug-receptor binding ex vivo, tissue level by autoradiography).

Studies which are expected to cause transient moderate or chronic mild reactions, local or systemic, and do not cause severe strain on the animals owing to the mode of administration or sample collection routes.

Examples: Administration of test substance and blood sampling in freely mobile rats at intervals of several minutes to hours by venous catheter, without replacement of the sampled blood volumes by plasma expander or donor blood, with or without a stay in the metabolic cage for max. 14 days. Measurement of substance concentration in the brain or cisterna magna in the rat, using the microdialysis method or chronically implanted cannula in the cisterna magna. Freely mobile rat with bile fistula <4 days. Skin resorption in the mini pig (<30 days metabolic cage, indwelling catheter).

Studies causing long-term moderate to severe pain and injury.

Examples: Rats with bile fistulae or lymph fistulae with significantly restricted freedom of movement.​

 

Toxicity studies in general

Source

Non-harmful / below threshold / severity degree 0 Mild / severity degree 1 Moderate / severity degree 2 Severe / severity degree 3
Directive 2010/63/EU, Annex VIII

  Acute dose-range finding studies, chronic toxicity / carcinogenicity tests, with non-lethal endpoints.    
Federal Food Safety and Veterinary Office FSVO (2018)   Tolerance studies which are expected to cause transient mild reactions, local or systemic, and do not cause substantial strain on the animals owing to the mode of administration or sample collection routes. Examples:Genetic toxicity tests. Tolerance studies which are expected to cause transient moderate or chronic mild reactions, local or systemic, and do not cause severe strain on the animals owing to the mode of administration or sample collection routes (no lethality expected). Examples: Acute toxicity tests and acute tolerance tests in dogs. Subacute and subchronic toxicity tests. Range finding studies with rodents, rabbits and dogs. Bioaccumulation tests in fish. Chronic toxicity tests/carcinogenicity tests with oral administration of test substances. Reproductive toxicology tests.Toxicokinetics with oral administration of the test substance and collection of body fluids.

Tolerance studies that cause long-term moderate to severe pain and injury or are expected to cause death.

Examples: same test models as under Severity Degree 2 with expected severe effects.

Working Group of Berlin Animal Welfare Officers (2010)*

* It is basically an exceptional case when laboratory animals in toxicity tests are exposed to mild stress, since the OECD guidelines principally ask for the highest tested dose (of usually 2-3 dosage groups) to cause clear toxic effects.
  Compatibility studies in which animals, due to type of application or sampling, are exposed to only mild stress, and only temporary, mild local or systemic reactions are to be expected. Procedures under lethal anaesthesia. Short-term compulsory measures, combined with few pain/distress. Compatibility studies in which animals, due to type of application or sampling, are exposed to no severe stress, and permanent, moderate local or systemic reactions are to be expected. Lethality is not expected. Procedures under anaesthesia with recovering from anaesthesia and minor subsequent damage (analgesia not necessary). Short-term compulsory measures, combined with considerable pain/distress. Permanent compulsory measures (e.g. jacket for infusion pump), combined with few stress.

Compatibility studies in which severe pathophysiological states are induced, and fatalities are to be expected. Procedures under anaesthesia with recovering from anaesthesia, in which subsequent analgesia is necessary or longer convalescence periods are needed.

 

Acute toxicity (e.g. OECD 402-406, 420, 423, 425, 429)

Source

Non-harmful / below threshold / severity degree 0 Mild / severity degree 1 Moderate / severity degree 2 Severe / severity degree 3
Directive 2010/63/EU, Annex VIII

    Acute dose-range finding studies, chronic toxicity / carcinogenicity tests, with non-lethal endpoints. Toxicity testing where death is the end-point, or fatalities are to be expected and severe pathophysiological states are induced. For example, single dose acute toxicity testing (see OECD testing guidelines).
Working Group of Berlin Animal Welfare Officers (2010)   Acute toxicity tests, local compatibility tests, and
sensitisation tests, limited to the induction phase (e.g. LLNA), and without use of adjuvant, in which only mild pathophysiological reactions and no fatalities are to be expected.
Acute toxicity tests and local compatibility tests, in which moderate pathophysiological reactions and no fatalities are to be expected
- Sensitisation tests with application of adjuvant, or challenge (e.g. maximization test, optimisation test), in which moderate pathophysiological reactions are to be expected.
Acute toxicity tests in which severe pathophysiological states or fatalities are to be expected
- local compatibility tests and sensitisation tests, in which severe local or systemic reactions are to be expected.

 

Subacute toxicity (e.g. OECD 407-413, 424)

Source

Non-harmful / below threshold / severity degree 0 Mild / severity degree 1 Moderate / severity degree 2 Severe / severity degree 3
Working Group of Berlin Animal Welfare Officers (2010)   Subacute and subchronic toxicity tests with repeated application up to 3 months, where no or only mild pathophysiological reactions and no fatalities are to be expected. Subacute and subchronic toxicity tests with repeated application up to 3 months, where moderate pathophysiological reactions and no fatalities are to be expected. Subacute and subchronic toxicity tests with repeated application up to 3 months, where severe pathophysiological reactions and fatalities are to be expected.

 

Chronic toxicity (e.g. OECD 451-453)

Source

Non-harmful / below threshold / severity degree 0 Mild / severity degree 1 Moderate / severity degree 2 Severe / severity degree 3
Working Group of Berlin Animal Welfare Officers (2010)   Chronic toxicity tests / cancerogenity tests with application of the test substance in food or drinking water, in which no or only mild pathophysiological reactions and no fatalities are to be expected. Chronic toxicity tests / cancerogenity tests with oral application of the test substance, in which moderate pathophysiological reactions and no fatalities are to be expected - parenteral, dermal, and inhalative application with minor pain or stress exposure. Chronic toxicity tests / cancerogenity tests, in which the application of the test substance is combined with considerable pain or stress exposure, or in which severe pathophysiological reactions or fatalities are to be expected.

 

Reproductive toxicology (e.g. OECD 414-416, 421-422)

Source

Non-harmful / below threshold / severity degree 0 Mild / severity degree 1 Moderate / severity degree 2 Severe / severity degree 3
Working Group of Berlin Animal Welfare Officers (2010)   Reproductive toxicology tests in one or several generations, where no or only minor maternal toxicity is to be expected, and the surviving offspring is expected to experience no to little impact - prenatal development toxicity tests (teratogenity tests) in which no or only mild pathophysiological reactions and no fatalities are to be expected. Reproductive toxicology tests in one or several generations, where moderate maternal toxicity is to be expected (meaning an effect exceeding that of a slight decrease in body weight gain), or where the surviving offspring is expected to experience moderate impact - prenatal development toxicitiy tests (teratogenity tests) in which moderate pathophysiological reactions and no fatalities are to be expected. Reproductive toxicology tests in one or several generations, where considerable maternal toxicity is to be expected, and the surviving offspring is expected to experience considerable impact - prenatal development toxicitiy tests (teratogenity tests) in which severe pathophysiological reactions and fatalities are to be expected.

 

Batch testing

Source

Non-harmful / below threshold / severity degree 0 Mild / severity degree 1 Moderate / severity degree 2 Severe / severity degree 3
Federal Food Safety and Veterinary Office FSVO (2018)

 

Studies which are expected to cause transient mild reactions, local or systemic, and cause only mild strain on the animals owing to the mode of administration or sample collection routes.

Examples:Application of vaccine batches for subsequent testing of immunity in accordance with Ph. Eur.
Studies which are expected to cause transient moderate or chronic mild reactions, local or systemic, and do not cause severe strain on the animals owing to the mode of administration or sample collection routes.

Batch testing that causes long-term moderate to severe pain and injury or is expected to cause death.

Example: Abnormal toxicity. Efficacy tests of vaccine batches (tests of antigenic efficacy). Tests of the biological activity of growth hormone in hypophysectomised rats.

 

This page was updated on 01 January 2021

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