Go to page 2 – Fulfilling toxicological data requirements

Within the context of REACH, toxicological information is required for the specific purposes of classification and labelling, determination of the Persistent, Bioaccumulative and Toxic (PBT) status, Chemical Safety Assessment (CSA) and Report (CSR) and determination of any need for risk management measures. The toxicological information that shall be submitted for registration and substance evaluation purposes is specified in REACH annexes VI to XI. For an overview, see information requirements for registration. The health effects to be considered by registrants are detailed below.

Health effects considered

Skin and eye irritation/corrosion and respiratory irritation

Irritation and corrosion are local effects, i.e. changes occur at the site of first contact of the substance with the skin, eye, or mucous epithelia such as the respiratory tract. Corrosive substances may destroy living tissues with which they come into contact after single exposure. Irritant substances are non-corrosive substances which, through immediate contact with the tissue under consideration may cause inflammation after single exposure. Substances that cause irritant effects only after repeated exposure are not classified as irritants. Skin and/or eye irritation refers to the production of fully reversible changes following application of a substance (in the case of eye irritation, when application is performed to the anterior surface of the eye). Corrosive substances produce irreversible effects such as necrosis through the epidermis and into the dermis, ocular tissue damages or decay of vision. Chemicals which are classified for respiratory irritation may provoke irritations similar to skin or eye irritations. They may also cause other toxic effects, in relation with interactions with the vegetative nervous system and leading to reflex responses (sneezing, coughing, respiratory symptoms, etc). These effects are reversible. Testing for respiratory irritation is not required under REACH as no validated guidelines are available. Nevertheless, existing and available data that provide evidence of the respiratory irritation potential of a substance should be taken into account.

Skin and respiratory sensitisation

A sensitiser is an agent that is able to cause an allergic response in susceptible individuals. The allergic reaction occurs if a previous exposure has led to the development of immunity against the substance (i.e. sensitisation step). The effects arise on the occasion of later contact: allergic contact dermatitis, allergic rhinitis, asthma.,etc. No information requirements are present under REACH for respiratory sensitisation. However, respiratory sensitisers are indicated for harmonised classification and labelling in article 36 of regulation (EC) no 1272/2008.

Acute toxicity

Acute toxicity concerns the adverse effects, which may result from a single exposure or multiple exposures within 24 hours to a substance. Exposure relates to the oral, dermal or inhalation routes. Assessment of the acute toxic potential of a chemical is necessary to determine the adverse health effects that might occur following accidental or deliberate short-term exposure: the types of toxic effects, their time of onset, duration and severity, the dose-response relationships, and the sex differences in response. The investigated damages can be clinical signs of toxicity, abnormal body weight changes, and/or pathological changes in organs and tissues, which in some cases may result in death.

Repeated dose toxicity

The repeated dose toxicity comprises the general toxicological effects occurring as a result of repeated daily exposure to a substance for a part of the expected lifespan (sub-acute or sub-chronic exposure) or for the major part of the lifespan (chronic exposure).
These general toxicological effects include effects on body weight and/or body weight gain, absolute and/or relative organ and tissue weights, alterations in clinical chemistry, urinalysis and/or haematological parameters, functional disturbances in the nervous system as well as in organs and tissues in general, and pathological alterations in organs and tissues as examined macroscopically and microscopically. Besides this information on possible adverse general toxicological effects, repeated dose toxicity studies may also provide other information on e.g. reproductive toxicity or carcinogenicity or may identify specific manifestations of toxicity such as e.g., neurotoxicity, immunotoxicity, endocrine-mediated effects...
The objectives of assessing repeated dose toxicity are to evaluate:

• whether repeated exposure of humans to a substance has been associated with adverse toxicological effects; these human studies potentially may also identify populations that have higher susceptibility;
• whether repeated administration of a substance to experimental animals causes adverse toxicological effects; effects that are predictive of possible adverse human health effects;
• the target organs, the potential cumulative effects and the reversibility of the adverse toxicological effects;
• the dose-response relationship and the threshold for any of the adverse toxicological effects observed in the repeated dose toxicity studies;

Reproductive toxicity

Reproductive toxicity is of obvious high concern because the continuance of the human species is dependent on the integrity of the reproductive cycle. It is characterised by multiple diverse endpoints, such as impairment of male and female reproductive functions or capacity (fertility), induction of non-heritable harmful effects on the progeny (developmental toxicity) and effects on or mediated via lactation.
The objectives of assessing reproductive toxicity are to establish:

• whether exposure of humans to the substance of interest has been associated with reproductive toxicity;
• whether, on the basis of information other than human data, it can be predicted that the substance will cause reproductive toxicity in humans;
• whether the pregnant female is potentially more susceptible to general toxicity;
• the dose-response relationship for any adverse effects on reproduction.

Mutagenicity and carcinogenicity

Mutagenicity refers to the induction of permanent transmissible changes in the amount or structure of the genetic material of cells or organisms. These changes may involve a single gene or gene segment, a block of genes or chromosomes.
Alterations to the genetic material of cells may occur spontaneously or be induced as a result of exposure to ionising or ultraviolet radiation, or genotoxic substances. In principle, human exposure to substances that are mutagens may result in increased frequencies of mutations above baseline. Heritable damage to the offspring, and possibly to subsequent generations, of parents exposed to substances that are mutagens may follow if mutations are induced in parental germ cells (reproduction cells). Mutations in somatic cells (cells others than reproduction cells) may be lethal or may be transferred to daughter cells with deleterious consequences for the affected organism. There is considerable evidence of a positive correlation between the mutagenicity of substances in vivo and their carcinogenicity in long-term studies with animals. The aims of testing for mutagenicity are to assess the potential of substances to induce effects which may cause heritable damage in humans or lead to cancer.

Chemicals are defined as carcinogenic if they induce tumours, increase tumour incidence and/or malignancy or shorten the time to tumour occurrence. Carcinogenic chemicals have conventionally been divided into two categories according to the presumed mode of action. Non-genotoxic modes of action include epigenetic changes, i.e., effects that do not involve alterations in DNA but that may influence gene expression, altered cell-cell communication, or other factors involved in the carcinogenic process. The objective of investigating the carcinogenicity of chemicals is to identify potential human carcinogens, their mode(s) of action, and their potency.
Once a chemical has been identified as a carcinogen, there is a need to elucidate the underlying mode of action, i.e. whether the chemical is directly genotoxic or not. For genotoxic carcinogens it is assumed that, unless exception, there is no discernible threshold and that any level of exposure carries a risk. For non-genotoxic carcinogens, no-effect-thresholds are assumed to exist and to be discernable. Human studies are generally not available for making a distinction between the above mentioned modes of action; and a conclusion on this, in fact, depends on the outcome of mutagenicity testing and other mechanistic studies. In addition to this, animal studies may also inform on the underlying mode of carcinogenic action.
The cancer hazard and mode of action may also be highly dependent on exposure conditions such as the route of exposure. Therefore, all relevant effect data and information on human exposure conditions are evaluated.

Toxicokinetics

The expression of toxicity arising from exposure to a substance is a consequence of a chain of events that results in the affected tissues of an organism receiving the ultimate toxicant in amounts that cause an adverse effect. The concentration of the ultimate toxicant at the biological target site depends on the absorption, distribution, metabolism and excretion. According to REACH annexe VIII, the assessment of these processes, i.e. the toxicokinetics behaviour is required from the relevant available information. There is no obligation to generate new data.

Go to page 2 – Fulfilling toxicological data requirements