Historic Control Data for Mammalian Toxicity Studies
All Approval Holder Letter 06/2004
23 March 2004
The interpretation of mammalian toxicity studies on pesticides can often be aided by consideration of the values or findings normally present in untreated animals, in addition to those of the concurrent control group for the particular study. To be really meaningful this “historic control” information should come from studies performed under conditions that were as close as possible to those of the study being considered. Information on appropriate historic control data is described in Annex 1, section 5.5 or 5.6 of Directive 94/79/EC. Recently PSD has received dossiers that have either referenced historic control data but not actually supplied the information, or supplied data that are of questionable relevance. This has resulted in delays to evaluations while the data holder is contacted and requested to provide the appropriate information. This letter clarifies PSD’s position on historic control data so that appropriate information can be presented in the dossier when first submitted.
Appropriate historic control data must be submitted when either the text of a study report or a summary dossier contains a case to discount findings, in any study, because they are within the normal biological range for the test animals.
The submitted historic control data should be from studies that are identical or closely related to the study under consideration in terms of:
- Species, strain and supplier.
- Test facility.
- Housing conditions (single or multiple) and diet.
- Survival rates (especially for carcinogenicity studies).
- Date of performance - typically +/- two years. Values and incidences vary with time and it is essential to have information on studies performed within a relatively short time period. Although retrospective data will only be available at the time of writing a study report, additional studies will normally be available by the time a dossier is submitted. The more recent data are particularly relevant and should be submitted. Periods greater than +/- 2 years might be justifiable if the test facility does not perform the particular study type routinely.
- Assessment criteria (e.g. terminology / definitions for histopathology and developmental findings or clinical chemistry assay methodology).
- Age or weight of animals at initiation of study and / or the time of investigation (especially for short-term studies).
- Group size.
- Dose route. The submission must provide adequate supporting information to permit independent confirmation of the applicability of the historic control data, based on the above criteria. There should also be a statement that the data cover all appropriate studies performed by the test facility during the period under consideration, and have not been selected in any way.
Where it is not possible, for example when a test facility has closed down, to provide historic control data that meet all the above conditions, alternative data can be submitted. These must be accompanied by a case that outlines their applicability and an explanation of why more directly comparable data are unavailable. The onus is on the notifier to demonstrate the relevance of the historic control data to the case being made.
The historic control data should be presented on a study by study basis giving absolute values plus percentage, relative or transformed values where these would assist in the evaluation. If combined or summary data are submitted, these must contain information on the range of values, the mean, median and, if applicable, standard deviation.
There is no guarantee that historic control data that meet the criteria defined above will be used in an assessment. For example where pre-dosing data, or incidences in lower dose groups, are consistent with the concurrent controls the assumption would be that the concurrent controls are truly representative of the background levels pertaining at the time of the study.
Contact Information
If you have any queries concerning the contents of this letter, please do not hesitate to contact Ian Dewhurst by fax on 01904 455711, by e-mail to ian.dewhurst@hse.gsi.gov.uk, or in writing.
Information on appropriate historic control data is described in Annex 1, section 5.5 or 5.6 of Directive 94/79/EC