Table of Validated & Accepted Alternative Methods

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Table of Validated & Accepted Alternative Methods

Last updated: May 24, 2016

EndpointMethod NameTest Type1Endorsement of Scientific Validity: ESAC Statements; EURL ECVAM Recommendations; ECVAM Protocols; ICCVAM Evaluations; ICCVAM Protocols; JaCVAM Evaluations; JaCVAM StatementsRegulatory Acceptance
Lead AuthoritySubsequent Endorsement(s)International (Links to OECD: OECD TGs; Draft TGs; GDs; Draft GDs)

National/ Regional2

Acute mammalian toxicity (oral)Acute oral toxicityIn vivoESAC (2000)OECD TG 401 (2002) – Deleted
Acute toxic class methodIn vivoESAC (2007)OECD TG 423 (2001)
Fixed dose procedureIn vivoESAC (2007)OECD TG 420 (2001)
Up-and-down procedureIn vivoICCVAM (2001)ESAC (2007)OECD TG 425 (2006)EPA OPPTS 870.1100 (2002)
Normal human keratinocyte neutral red uptake (NHK NRU) assayIn vitro3ICCVAM (2008)JaCVAM (2011)OECD GD 129 (2010)
Balb/c 3T3 neutral red uptake assayIn vitro3ICCVAM (2008)

JaCVAM (2011)

OECD GD 129 (2010)
3T3 NRU Assay supporting identification of substances not requiring classification for acute oral toxicityIn vitro3EURL ECVAM (2013)
Acute mammalian toxicity (hematotoxicity)Colony Forming Unit-Granulocyte/Macrophage Assay for acute neutropenia in humansIn vitroESAC (2006)
Acute mammalian toxicity (inhalation)Acute toxic class methodIn vivo

OECD TG 436 (2009)

OECD GD No. 153 (2011)

Fixed concentration procedureIn vivoDraft OECD TG 433 (2015)
Acute toxicity testing of pesticidesGuidance for waiving or bridging of mammalian acute toxicity tests for pesticides (acute oral, dermal, inhalation; primary eye and dermal; dermal sensitization)In vivoEPA OPP (2012)
Biologics & VaccinesELISA for swine erysipelas vaccines batch potency testingIn vitroESAC (2002)ICCVAM agency: USDA (2009)

European Pharmacopeia, Monograph 064 (2004); USDA Supplemental Assay Method 613 (2009)

ELISA for human tetanus vaccines batch potency testingIn vitroESAC (2000)European Pharmacopeia (2003); FDA, 21 CFR 610.10 (accepted on case-by-case basis)
Toxin binding inhibition test for human tetanus vaccines batch potency testingIn vitroESAC (2000)European Pharmacopeia (2013); FDA, 21 CFR 610.10 (accepted on case-by-case basis)
Deletion of target-animal safety test for batch safety testing of veterinary vaccines after consistency in 10 consecutive batchesNAESAC (2002)VICH GL50 (2013)
ELISA for in vitro batch potency testing of Leptospira veterinary vaccinesIn vitroICCVAM agency: USDA (2008)USDA Supplemental Assay Methods 624, 625, 626, and 627
Use of humane endpoints in animal testing of veterinary biologics, including rabies vaccinesIn vivoICCVAM agency: USDA (2004; 2012)OECD GD No. 19USDA: 9 CFR Part 113, Notice No. 04-09 (2004); 9 CFR 113, CVB Notice No. 12-12
Veterinary vaccine potency assays: exemptions from Standard Requirements tests; master reference qualification and requalificationNAICCVAM agency: USDAUSDA: 9 CFR 113.409(c), Memorandum 800.114 (2012)
Vaccines for veterinary useIn vitroVaccines for Veterinary Use (0062) and ~40 inactivated vaccine-specific monographs (European Pharmacopoeia, 2015 (effective January 1, 2017))30
Cell-based assay for stability and potency of botulinum neurotoxin type A products15In vitroICCVAM agency: FDA; ICCVAM Workshop (2006)US FDA: Allergan, Inc., method accepted (2011)
Alternative test procedure for tuberculin, PPD Bovis, intradermicIn vivoICCVAM agency: USDAUSDA: 9 CFR 113.409(c), Memorandum 800.114 (2012)
CarcinogenicityThree Cell Transformation Assays (CTAs): Syrian Hamster Embryo CTA (SHE CTA): SHE CTA performed at pH 6.7, SHE CTA performed at pH 7.04In vitroEURL ECVAM (2012)

Draft OECD TG (2013)

OECD Detailed Review Paper No. 31

Bhas 42 Cell Transformation Assay (Bhas 42 CTA)4In vitroEURL ECVAM (2013)Draft OECD TG (2013)
Chronic toxicityEnding 1-year dog studies of pesticidesIn vivoESAC (2006)Revised US EPA Pesticide Data Requirements
Dermal absorption/penetrationIn vitro skin absorption methodsIn vitroOECD Expert Group (2002)

OECD TG 428 (2004)

OECD GD 28 (2004)

OECD Guidance Notes No. 156

EcotoxicityAcute aquatic toxicity: Upper threshold concentration step-down approachIn vivoESAC (2006)OECD GD 126 (2010)EU Biocides Regulation and REACH Guidance
Acute avian toxicity (oral): Sequential testing procedure to minimize numbers of birds usedIn vivoOECD TG 223 (2010)
Zebrafish embryo acute toxicity test (ZFET)18In vivoEURL ECVAM (2014)OECD TG 236 (2013)
Endocrine active substancesAndrogen receptor binding assay (rat prostate cytosol)Ex vivoOPPTS TG 890.1150 (EPA, 2009)
Aromatase inhibition assay (human recombinant)In vitroOPPTS TG 890.1200 (EPA, 2009)
Performance-based Test Guideline for stably transfected transactivation in vitro assays to detect estrogen receptor agonistsIn vitroOECD/ US EPA

OECD TG 455 (2012); updated 20155

Draft OECD TG 455: Annex 4 (2015)

OPPTS TG 890.1300
Estrogen receptor binding assay rat uterine cytosol (ER-RUC)Ex vivoOPPTS TG 890.1250 (EPA, 2009)
H295R steroidogenesis assay5In vitroOECD/US EPAOECD TG 456 (2011)OPPTS TG 890.1550 (EPA, 2009)
US EPA Tier 1 Screening Battery5In vitro/In vivoUS EPA (2009)
BG1Luc ER TA test method for estrogen agonists and antagonists6In vitroICCVAM (2012)JaCVAM (2013)

OECD TG 457 (2012)

Draft Performance Standards for TG 457 (2012)

Performance-based Test Guideline for human recombinant estrogen receptor (hrER) in vitro assays to detect chemicals with ER binding affinity

OECD TG 493 (2015)21

Stably Transfected Human Androgen Receptor Transcriptional Activation Assay for Detection of Androgenic Agonist and Antagonist ActivityDraft OECD TG XXX (2015)
Eye corrosionBovine corneal opacity permeability (BCOP) testEx vivoICCVAM (2007)

ESAC (2007)

JaCVAM (2009)

OECD TG 437 (2009; updated 2013)10
Isolated chicken eye (ICE) testEx vivoICCVAM (2007)

ESAC (2007)

JaCVAM (2009)

OECD TG 438 (2009; updated 2013)10

Draft revised 2015

Cytosensor Microphysiometer modifiedIn vitroESAC (2009)7ICCVAM (2010)8Draft OECD TG (2012)
Fluorescein LeakageIn vitroESAC (2009)9JaCVAM (2012)

OECD TG 460 (2012)

OECD Summary Document No. 180

Hen’s egg test-chorioallantoic membrane (HET-CAM)In vitroEU Competent Authorities for Dangerous Substances Directive
Isolated rabbit eye test

Ex vivo

EU Competent Authorities for Dangerous Substances Directive

Short Time Exposure (STE) in vitro test method for identifying chemicals inducing serious eye damageIn vitroICCVAM (2013)OECD TG 491 (2015)
Routine use of topical anesthetics, systemic analgesics, and humane endpointsIn vivoICCVAM (2010)

Updated OECD TG 405 (2012)

OECD GD No. 19

Sequential testing strategy for eye irritation and corrosionIn vitro/Ex vivo/In vivoICCVAM16Updated OECD TG 405 (2012)
Alternate testing framework for classification of eye irritation potential of EPA pesticide products28In vitroEPA OPP (2015)
Eye irritationCytosensor Microphysiometer modifiedIn vitroESAC (2009)7ICCVAM (2010)8Draft OECD TG (2012)
Short Time Exposure (STE) in vitro test method for identifying chemicals not requiring classification for eye irritation or serious eye damageIn vitroICCVAM (2013)OECD TG 491 (2015)
Reconstructed Human Cornea-like Epithelium (RhCE) test for identifying chemicals not requiring classification and labelling for eye irritation/corrosion22In vitroEURL ECVAMOECD TG 492 (2015)
Bovine Corneal Opacity Permeability (BCOP) TestEx vivoICCVAM (2007)

ESAC (2007)

OECD TG 437 (2009; updated 2013)10
Isolated chicken eye (ICE) testEx vivoICCVAM (2007)

ESAC (2007)

OECD TG 438 (2009; updated 2013)10

Draft revised 2015

Draft Position Paper on ICE for UN GHS No Category

Routine use of topical anesthetics, systemic analgesics, and humane endpointsIn vivoICCVAM (2010)

Updated OECD TG 405 (2012)

OECD GD No. 19

Sequential testing strategy for eye irritation and corrosionIn vitro/Ex vivo/In vivoICCVAM16Updated OECD TG 405 (2012)
Alternate testing framework for classification of eye irritation potential of EPA pesticide products28In vitroEPA OPP (2015)
Genotoxicity25Bacterial reverse mutation (Ames) testIn vitroOECD TG 471 (1997)
In vitro mammalian cell gene mutation tests using the Hprt and xprt genesIn vitroOECD TG 476 (1997; updated 2015)
In vitro mammalian cell gene mutation test using the thymidine kinase geneIn vitroOECD TG 490 (2015)19
In vitro mammalian chromosomal aberration testIn vitroOECD TG 473 (1983; updated 2015)
In vitro mammalian cell micronucleus testIn vitroESAC (2006)ICCVAM16

OECD TG 487 (2010; updated 2015)

ICH (2011)

In vitro sister chromatid exchange testIn vitroOECD TG 479 (1986)
In vitro unscheduled DNA synthesis testIn vitroOECD TG 482 (1986)
Saccharomyces cerevisiae gene mutation assayIn vitroOECD TG 480 (1986)
Saacharomyces cerevisiae mitotic recombination assayIn vitroOECD TG 481 (1986)
MetabolismHuman cytochrome P450 (CYP) n-fold induction in vitro test methodIn vitro

Draft OECD TG XXX (2014)

Draft Performance Standards (2014)

Phototoxicity3T3 Neutral Red Uptake Phototoxicity TestIn vitroESAC (1997)OECD TG 432 (2004)
3T3 NRU Phototoxicity Test: Application to UV filter chemicalsIn vitroESAC (1998)OECD TG 432 (2004)
Reactive Oxygen Species (ROS) Photosafety Assay (non-biological method)23In vitroJaCVAM26 (2013)ICH S10 (2013)
Preclinical and nonclinical safety studies for drug development (harmonized guidance can reduce use of animals)Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals M3(R2)In vivoICH (2010)FDA; EMA; PMDA
Preclinical safety evaluation of biotechnology-derived pharmaceuticals, ICH S6(R1)In vivoICH (1997; updated 2011)FDA; EMA; PMDA
PyrogenicityFive human cell assays for detecting pyrogenicity produced by Gram-negative endotoxins27: Human whole blood IL-1; Human whole blood IL-6; Human cryopreserved whole blood IL-1; PBMC IL-6; PBMC IL-6In vitroESAC (2006)ICCVAM (2008)12European Pharmacopeia; FDA
Limulus amebocyte lysate (LAL) testIn vivo/In vitroEU, US, and Japanese Pharmacopeia (2005); ICH harmonized text (2010)
Reproductive & developmental toxicityEmbryonic stem cell test for embryotoxicity17In vitroESAC (2002)
Micromass embryotoxicity assayEx vivoESAC (2002)
Whole rat embryotoxicity assayEx vivoESAC (2002)
Extended one-generation reproductive toxicity studyIn vivoICCVAM16Updated OECD TG 443 (2012)
Skin corrosionIn vitro skin corrosion: reconstructed human epidermis (RHE) test method: Episkin™, Epiderm™, SkinEthic™, epiCS® (formerly EST-1000)In vitroESAC (1998; 2000; 2006; 2009)ICCVAM 2002OECD TG 431 (2004; updated 2015)13a
In vitro Membrane Barrier test method for skin corrosion: CORROSITEX™In vitroICCVAM (1999)ESAC (2000)OECD TG 435 (2006; updated 2015)
Rat skin transcutaneous electrical resistance (TER) test methodEx vivoESAC (1998)ICCVAM (2002)OECD TG 430 (2004; updated 2015)
Vitrolife-Skin™ human reconstructed epidermisIn vitroJaCVAM (2008)JaCVAM (2008)
Skin irritationReconstructed human epidermis test method: Episkin™, modified Epiderm™, SkinEthic™In vitroESAC (2007; 2008; 2009)JaCVAM (2010; 2012)OECD TG 439 (2010; updated 2015)13b
Reconstructed human epidermis test method: LabCyte EPI-MODEL24In vitroJaCVAM (2013)OECD TG 439 (2010; updated 2015)13b
Skin SensitizationLocal lymph node assay (LLNA)In vivoICCVAM (1999; 2009)ESAC (2000)OECD TG 429 (2002; Updated 2010)
Reduced LLNA: rLLNA11In vivoESAC (2007; 2008)

ICCVAM (2009)

JaCVAM (2012)

OECD TG 429 (Updated 2010)
Nonradiolabelled LLNA: DAIn vivoICCVAM (2010)JaCVAM (2012)OECD TG 442A (2010)
Nonradiolabelled LLNA: BrdU-ELISAIn vivoICCVAM (2010)JaCVAM (2012)OECD TG 442B (2010)
LLNA for Potency Categorization of Skin SensitizersIn vivoICCVAM (2011)UN GHS (2009)Some US agencies (2012)
ARE-Nrf2 luciferase test method20a: KeratinoSens™In vitroEURL ECVAM (2014)OECD TG 442D (2015)REACH regulation
Direct Peptide Reactivity Assay (DPRA)20bIn chemico

EURL ECVAM (2013)

JaCVAM (2015)

OECD TG 442C (2015)REACH regulation
Human Cell Line Activation Test (h-CLAT)20cIn vitroEURL ECVAM (2015)Draft OECD TG (2015)29REACH regulation

1 Table content is limited to in vitro, ex vivo, in chemico and/or in silico test methods, and in vivo methods or test schemes proposed to reduce or refine animal use.
2 National and regional regulatory acceptance is not fully documented here
3 Replaces animal use for initial dose setting, but in vivo test required to complete assessment
4 In vitro cell transformation assays (CTAs) can detect both genotoxic and non-genotoxic carcinogens, which can be distinguished by parallel use of genotoxicity test(s). CTA results are recommended for use as part of a testing strategy and/or weight-of-evidence approach for the assessment of carcinogenic potential, and may reduce the use of in vivo testing.
5 The two reference test methods that provide the basis for this guideline are: the Stably Transfected TA (STTA) assay using the (h) ERα-HeLa-9903 cell line, and the BG1Luc ER TA assay. These methods are proposed for screening and prioritization purposes, but also provide mechanistic information that can be used in a weight of evidence approach.
6 BG1Luc ER TA test method has been adapted to a high throughput screening (HTS) format and incorporated into Tox21 screening
7 Recommended for use as initial step within a Top-Down Approach to identify ocular corrosives and severe irritants (EU R41, GHS Category 1, and EPA Category I) for water-soluble chemicals and/or as initial step within a Bottom-Up Approach to identify non-irritants (EU:NC; GHS: NC; EPA: cat IV) for water-soluble surfactants and water-soluble surfactant-containing mixtures; does NOT correctly identify moderate and mild ocular irritants (EU: R36; GHS: Cat 2A/B; EPA: Cat II/III) so can be used for only two of the three EU and GHS classification categories for ocular irritation; cannot be used for default categorization; additional limitations on equipment availability
8 Can be used as screening test to distinguish water-soluble surfactant chemicals and certain types of surfactant-containing formulations that are not labeled as irritants (i.e., EPA Category IV, EU Not Labeled, FHSA Not Labeled) from all other hazard categories (i.e., EPA Category I, II, III; EU R41, R36; FHSA Irritant) for hazard classification and labeling under EPA, EU and FHSA classification systems; high false negative rate (24%-40%) for non-surfactant substances and formulations; high false positive rate (50% to 69%) for substances not labeled as irritants. Can be used as a screening test to identify water soluble substances as ocular corrosives and severe irritants (i.e., EPA Category I, EU R41, GHS Category 1) in tiered-testing strategy as part of weight-of-evidence approach; negative results need to be tested in another test method
9 Recommended for use as initial step within a Top-Down Approach to identify ocular corrosives and severe irritants (EU R41, GSH Category 1, and EPA Category I) for water-soluble chemicals; further refinement with respect to variability and applicability domain recommended
10 BCOP and ICE methods can be used to identify chemicals as either 1) causing “serious eye damage” (category 1 of GHS, or 2) not requiring classification for eye irritation or serious eye damage according to GHS (new to the 2013 TG updates).
11 rLLNA can be used for hazard classification when dose-response information is not needed
12 Subject to product-specific validation to demonstrate equivalence to the rabbit pyrogen test (RPT)
13a Four validated test methods using commercially available RhE models are included in TG 431: EpiSkin™ Standard Model (SM), EpiDerm™ Skin Corrosivity Test (SCT) (EPI-200), SkinEthic™ RHE, and epiCS® (previously named EST-1000).
13b Four validated test methods adhere to TG 439: EpiSkin™, EpiDerm™ SIT (EPI-200), SkinEthic™ RHE, and LabCyte EPI-MODEL24 SIT. “Depending on the regulatory framework and the classification system in use, this procedure may be used to determine the skin irritancy of test substances as a stand-alone replacement test for in vivo skin irritation testing, or as a partial replacement test, within a tiered testing strategy.”
14 Recommended as screening test or as part of sequential testing strategy; only positive test results accepted in the 2007 endorsement
15 Cell-based assay for botulinum toxin potency testing is limited to products produced using the Allergan method
16 Contributed to OECD TG development and/or review
17 Draft OECD GD 43, see page 18
18 EURL ECVAM reports that: “TG236 does not indicate whether the fish embryo acute toxicity test can be used as an alternative to the OECD TG203; however, several recently published papers demonstrate that the LC50 values produced with the fish embryo acute toxicity test correlate well with those observed in juvenile or adult fish (Lammer et al, 2009; Knoebel et al 2012; Belanger et al (2013).”
19 The assays using the thymidine kinase (TK) locus were originally contained in TG 476.
20 In vitro and in chemico methods endorsed as valid for supporting the discrimination between skin sensitizers and non-sensitizers in accordance with the UN GHS. The guidelines explain it is likely that combinations of non-animal methods using integrated testing approaches will be needed to substitute for the animal tests.
20a In vitro method endorsed as valid for supporting the discrimination between skin sensitizers and non-sensitizers in accordance with the UN GHS. The guidelines explain it is likely that combinations of non-animal methods using integrated testing approaches will be needed to substitute for the animal tests. The only ARE-Nrf2 luciferase test method covered currently by this TG, is the KeratinoSens™ test method.
20b In chemico method endorsed as valid for supporting the discrimination between skin sensitizers and non-sensitizers in accordance with the UN GHS. The guidelines explain it is likely that combinations of non-animal methods using integrated testing approaches will be needed to substitute for the animal tests.
20c In vitro method endorsed as valid for supporting the discrimination between skin sensitizers and non-sensitizers in accordance with the UN GHS. The guidelines explain it is likely that combinations of non-animal methods using integrated testing approaches will be needed to substitute for the animal tests.
21 This guideline describes assays providing the methodology for human recombinant in vitro assays to detect substances with estrogen receptor binding affinity, and comprises two similar reference test methods: Freyberger-Wilson (FW) in vitro estrogen receptor binding assay…, and Chemical Evaluation and Research Institute (CERI) in vitro estrogen receptor binding assay…; proposed for screening and prioritization purposes, and provide mechanistic information that can be used in a weight of evidence approach.
22 The only method currently covered by this TG is the EpiOcular™ Eye Irritation Test (EIT) developed using human skin cells.
23 ROS assay can be used in an integrated photosafety testing and decision strategy for drug research and development where negative results would not require further testing, while positive and inconclusive results would proceed to the next level of testing in an in vitro test system such as the 3T3 Phototoxicity Assay.
24 OECD Series on Testing and Assessment contains additional useful guidance and performance standards. For example, Guidance Document No. 211: Guidance for describing non-guideline in vitro test methods to facilitate their consideration in regulatory applications, and the draft Guidance Document on Revisions to OECD Genetic Toxicology Test Guidelines.
25 Also see: Draft Guidance Document on Revisions to OECD Genetic Toxicology Test Guidelines (2015) and Report on Statistical Issues Related to OECD Test Guidelines (TGs) on Genotoxicity (Series on Testing and Assessment, No. 198, 2014)
26 “The JaCVAM peer review panel concluded that the reproducibility and predictivity of the ROS assay is sufficient to support its use in an integrated photosafety testing and decision strategy for drug research and development…[where] negative results in the ROS assay would not require further testing in animals or other tests, while positive, weakly positive, and inconclusive results would proceed to the next level of testing in an in vitro test system such as the 3T3 Phototoxicity Assay (OECD Test Guideline 432).”
27 The in vitro pyrogenicity methods are not considered valid for use in Japan at this time.
28 Includes explanation of expanded use of BCOP for antimicrobial testing, and decision tree approach using 3 assays:

  • Bovine Corneal Opacity and Permeability test (BCOP)
  • EpiOcular assay
  • Cytosensor Microphysiometer assay


29 hCLAT was approved by the OECD Working Group in April 2016
30 Around 40 inactivated vaccine-specific monographs and the general monograph Vaccines for Veterinary Use (0062) were adopted at the European Pharmacopoeia 153rd Session in November 2015 – to be published in the 9th Edition and shall be effective from 1st January 2017. After harmonising the technical requirements for the registration of veterinary vaccine products to align them with VICH guidelines 41 and 44 and deleting the target animal batch safety test (TABST) from the European Pharmacopoeia for all veterinary vaccines – in force since 1st April 2013(1), resulting in a considerable reduction in testing on animals.

Supplemental Information

A. ECVAM: Summary of test methods endorsed by ECVAM and accepted by EU regulatory authorities; ESAC statements; DB-ALM (DataBase service on ALternative Methods); TSAR (Tracking System for Alternative test methods Review)

B. ICCVAM: Summary of test methods evaluated by ICCVAM; table showing validation and acceptance status of all methods reviewed; ICCVAM-recommended protocols

C. JaCVAM: Summary of test methods evaluated and accepted by Japan’s regulatory authorities

D. OECD Test Guidelines (TGs), Guidance Documents, Draft Test Guidelines

E. OECD Guidance Document for Describing Non-Guideline In Vitro Test Methods (No.211): intended to harmonize the way non-guideline in vitro test methods are described.

F. ICH test guidelines: technical requirements for medicinal products containing new drugs accepted by the regulatory bodies of EU, Japan, and USA

G. VICH test guidelines: EU-Japan-USA programme aimed at harmonising technical requirements for veterinary product registration

H. ISO: toxicity test guidelines for the biological evaluation of medical devices and ecotoxicity (soil quality, water quality, fire effluents, biocides used for anti-fouling systems on ships)

I. USDA APHIS Supplemental Assay Methods (SAMs) (updated March 17, 2016)

Acronyms:

CFR: Code of Federal Regulations

EMA: European Medicines Agency

EPA: US Environmental Protection Agency

ESAC: ECVAM Scientific Advisory Committee

EURL ECVAM: European Union Reference Laboratory for alternatives to animal testing

FDA: United States Food and Drug Administration

GD: OECD Guidance Document

GHS: Globally Harmonized System of Classification and Labeling of Chemicals

ICCVAM: US Interagency Coordinating Committee on the Validation of Alternative Methods

ICH: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

ISO: International Organization for Standardization

JaCVAM: Japanese Center for the Validation of Alternative Methods

OECD: Organisation for Economic Cooperation and Development

OPPTS: US EPA’s Office of Prevention, Pesticides and Toxic Substances

PMDA: Japan’s Pharmaceuticals and Medical Devices Agency

TG: OECD Test Guideline

USDA: United States Department of Agriculture

VICH: International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products