# Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, Division 4.2.3: Toxicology

Extent: E+W+S+N.I.

a)) Single-dose toxicity
A single-dose toxicity test shall mean a qualitative and quantitative study of the toxic reactions, which may result from a single administration of the active substance or substances contained in the medicinal product, in the proportions and physico-chemical state in which they are present in the actual product.
The single-dose toxicity test must be carried out in accordance with the relevant guidelines published by the Agency.
b)) Repeat-dose toxicity
Repeated dose toxicity tests are intended to reveal any physiological and/or anatomo-pathological changes induced by repeated administration of the active substance or combination of active substances under examination, and to determine how these changes are related to dosage.
Generally, it is desirable that two tests be performed: one short term, lasting two to four weeks, the other long-term. The duration of the latter shall depend on the conditions of clinical use. Its purpose is to describe potential adverse effects to which attention should be paid in clinical studies. The duration is defined in the relevant guidelines published by the Agency.
c)) Geno-toxicity
The purposes of the study of mutagenic and clastogenic potential is to reveal the changes which a substance may cause in the genetic material of individuals or cells. Mutagenic substances may present a hazard to health since exposure to a mutagen carries the risk of inducing germ-line mutation, with the possibility of inherited disorders, and the risk of somatic mutations including those leading to cancer. These studies are obligatory for any new substance.
d)) Carcino-genicity
Tests to reveal carcinogenic effects shall normally be required:
1.. These studies shall be performed for any medicinal product whose expected clinical use is for a prolonged period of a patient's life, either continuously or repeatedly in an intermittent manner.
2.. These studies are recommended for some medicinal products if there is concern about their carcinogenic potential, e.g. from product of the same class or similar structure, or from evidence in repeated dose toxicity studies.
3.. Studies with unequivocally geno-toxic compounds are not needed, as they are presumed to be trans-species carcinogens, implying a hazard to humans. If such a medicinal product is intended to be administered chronically to humans a chronic study may be necessary to detect early tumorigenic effects.
e)) Reproductive and developmental toxicity
Investigation of possible impairment of male or female reproductive function as well as harmful effects on progeny shall be performed by appropriate tests.
These tests comprise studies of effect on adult male or female reproductive function, studies of the toxic and teratogenic effects at all stages of development from conception to sexual maturity as well as latent effects, when the medicinal product under investigation has been administered to the female during pregnancy.
Omission of these tests must be adequately justified.
Depending on the indicated use of the medicinal product, additional studies addressing development when administering the medicinal product of the offspring may be warranted.
Embryo/foetal toxicity studies shall normally be conducted on two mammalian species, one of which shall be other than a rodent. Peri- and postnatal studies shall be conducted in at least one species. If the metabolism of a medicinal product in particular species is known to be similar to that in man, it is desirable to include this species. It is also desirable that one of the species is the same as in the repeated dose toxicity studies.
The state of scientific knowledge at the time when the application is lodged shall be taken into account when determining the study design.
f)) Local tolerance
The purpose of local tolerance studies is to ascertain whether medicinal products (both active substances and excipients) are tolerated at sites in the body, which may come into contact with the medicinal product as a result of its administration in clinical use. The testing strategy shall be such that any mechanical effects of administration or purely physico-chemical actions of the product can be distinguished from toxicological or pharmaco-dynamic ones.
Local tolerance testing shall be conducted with the preparation being developed for human use, using the vehicle and/or excipients in treating the control group(s). Positive controls/reference substances shall be included where necessary.
The design of local tolerance tests (choice of species, duration, frequency and route of administration, doses) will depend upon the problem to be investigated and the proposed conditions of administration in clinical use. Reversibility of local lesions shall be performed where relevant.
Studies in animals can be substituted by validated in vitro tests provided that the test results are of comparable quality and usefulness for the purpose of safety evaluation.
For chemicals applied to the skin (e.g. dermal, rectal, vaginal) the sensitising potential shall be evaluated in at least one of the test systems currently available (the guinea pig assay or the local lymph node assay).

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Source: https://www.legislation.gov.uk/eudr/2001/83/annex/I/part/I/division/4/division/4.2/division/4.2.3 (the official version)
Page: https://openlegislation.uk/eu-directive-2001-83/annex-I/part-I/division-4/division-4.2/division-4.2.3
Contains public sector information licensed under the Open Government Licence v3.0. Source: legislation.gov.uk, The National Archives.