Sensitising substances

OECD. 1999a. Detailed review document on classification systems for sensitising substances in OECD member countries. OECD Series on Testing and Assessment No. 13. Environment Directorate, Joint Meeting of the Chemicals Committee and the Working Party on Chemicals. ENV/JM/MONO(99)3. Paris OECD. 

Hydroxypropyl methacrylate (HPMA) is labelled as irritant (Xi) in EC, including Denmark, while it is classified as a skin sensitiser in Sweden. Concentration limits for sensitising substances in formulations is 1%, and for irritant substances it is 10% before appropriate hazard labelling is required. Toxicological information used for these interpretations is derived from the same source. It may be hoped that such Scandinavian issues should start to resolve themselves when these EFTA countries combine with EC to form EEA. 

In this book, we are largely concerned with the threat posed to normal skin by contact with irritant and sensitising substances it is worth noting that whilst both substances and/or mixtures thereof can be irritating, for skin sensitisation it is the substances themselves that must be allergens (haptens). In this section, approaches to the identification of skin irritants are described briefly, together with a description of how the data may be interpreted in terms of a MSDS. Subsequently, a similar succinct account for skin sensitisers is presented. 

Thus, the user of the MSDS has in effect three options take the information at face value, ignore the information or treat the information as a stimulus to undertake a more detailed search followed by an analysis of the information in the context of the known/expected skin exposure. This last course of action is the one that is recommended if the need for a clinical or safety evaluation is of importance. Information on product ingredients should also be given for sensitising substances present at concentrations lower than 1%. Therefore, better MSDSs and product declarations should be required from industries before their products are put on the market. 

Adverse effects of cutaneous preparations may be undesirable systemic effects, (photo) toxicity, irritation or (photo) allergic responses after sensitisation. Substance monographs [15], package leaflets or SmPCs of licensed products and medicine databases give information about these adverse effects. 

When an individual breathes in polluted air, any substance may enter the respiratory tract causing direct harm to the respiratory system and indirect harm due to uptake via ingestion. Especially sensitising substances may require attention. As airways and the lung caimot be closed off, only ventilation (exhaustion) and filtration of inhaled air remain as protective measures, such as working in safety cabinets and wearing masks with air filters (respirators). 

In an exceptional situation the actual exposure can be determined (see Sect. 26.5.3), the hazards of the substance has been defined sufficiently (see Sect. 26.3.5) and above all, the exposure limit to the substance has been set by the competent authority. This may apply for instance to working with ethanol, see also Sect. 26.7.2. In such an ideal situation it is possible to claim completely safe working conditions or, in case of genotoxic and sensitising substances, safe with a societally accepted minor health risk (see Sect. 26.7.2). In practice for pharmacy preparation and reconstitution medicines hardly any exposure limits exist at the moment. In most situations risk mitigation means ... 

OELs for Genotoxic and Sensitising Substances Target Risk Levels... 

However, as long as such substances are indispensable (or put differently as long as Society accepts the use of such substances, e.g. many antineoplastics), the risk of exposure, and thus the risk of cancer, cannot be completely avoided. The same applies to limits for sensitising substances (see Sect. 26.3.3). Limiting the risk level is the general approach for these substances. Limits are set based on an accepted risk of 10 (the value of p being decided upon by Society). 

Bronchial asthma is defined as breathlessness due to narrowing of the small airways and it is reversible, either spontaneously or as a result of treatment. It may follow inhalation of a respiratory sensitiser or an irritant toxic substance. S5unptoms due to sensitisation may be delayed for weeks, months or even years S5miptoms due to a toxic substance occur within hours of inhalation, resolve spontaneously but can persist indefinitely. The toxic response is called reactive airways dysfuncticm (RAD) syndrome. Most cases of occupational asthma are due to sensitisation and are listed as prescribed diseases for purposes of statutory compensation. The sensitising substances listed are ... 

Besides NO, other sGC-activating substances have been reported Carbon monoxide (CO) is known to bind to heme groups with high affinity but has been shown to activate the enzyme only marginally (three- to fivefold). The compound YC-1 ([3-(5 -hydroxymethyl-2 -fury 1)-1-benzyl indazole]) is a prototype of a new class of so-called NO-sensitisers. YC-1 causes a tenfold activation of NO-sensitive GC. Pharmacologically more interesting, YC-1 increases GC s sensitivity towards NO and CO suggesting potential beneficial effects of... 

It does have a number of draw backs. It has poor thermal stability (a property common to most formaldehyde release biocides) and, in some instances, may cause blackening of metalworking fluid concentrates if heated above 50°C for a period of time. Recently, this active ingredient was placed on Annex 1 of the Dangerous Substances Directive having been identified as a potential skin sensitiser. This means that formulations containing efficacious levels of this class of triazine in them would have to be labelled with R43 - may cause sensitisation by skin contact. This is unacceptable to many UK customers. As this material is only bactericidal, it needs to be co-formulated with a fungicide to provide complete protection for a product. 

PCMC has been placed on Annex 1 of the Dangerous Substances Directive having been identified as a potential skin sensitiser. 

Before nitrates and particularly ammonium nitrate were readily available commercially, explosives were developed based on chlorates and perchlorates. These also are still used in some countries. In general perchlorates are considered less dangerous than chlorates and therefore preferred. They are easily sensitised, so that in addition to explosives of this type based on nitroglycerine, others have been based on various organic liquids, particularly nitrobodies. History shows that chlorates and perchlorates must be regarded as temperamental substances, liable in bulk to lead to inexplicable accidents. Particularly when mixtures of chlorates and oxidising materials are allowed to become wet and then dry out, conditions can arise in which there is an appreciable sensitiveness to friction and impact. Explosives of this type have an unfortunate record of accidents. They are used, therefore, to a limited extent only, now that safer compositions are available. 

Given the low incidence of severe withdrawal symptoms and the modest effects on the mesolimbic dopamine (reward) system, most investigators have found that cannabis has a low abuse or addiction potential. However, it has been argued that if cannabis is a non-addictive substance, why is its use so widespread and why are there so many longterm and heavy users Finally, contrary to the evidence that cannabis can produce chronic tolerance, some regular users report that they require less drug to achieve the same high, or sensitisation (Chapter 3). Three possible explanations may account for this. First, chronic users may focus on the effects that they wish to achieve. Second, the... 

The dangerous properties of acute toxicity, irritation, corrosivity, sensitisation, repeated-dose toxicity and CMR are evaluated in terms of their potential toxic effects to workers, consumers and man exposed indirectly via the environment, based on the use for each stage in the lifecycle of the substance from which exposure can occur. Risk assessment is also required if there are reasonable grounds for concern for potential hazardous properties, e.g., from positive in vitro mutagenicity tests or structural alerts. The risk assessment involves comparing the estimated occupational or consumer exposure levels with the exposure levels at which no adverse effects are anticipated. This may be a quantitative risk assessment, based on the ratio between the two values, or a qualitative evaluation. The principles of human health risk assessment are covered in detail by Illing (a.30) and more briefly in Chapter 7 of (73). 

Mutagenicity and carcinogenicity are generally considered to be non-threshold effects, unless a non-genotoxic mechanism can be established with a NOEL (or NOAEL or LOAEL). Risk assessment is based on establishing whether exposure is prevented. A similar process of preventing exposure also applies for skin and respiratory sensitisers, since there is no means of identifying a dose or concentration below which adverse effects will not occur in someone already sensitised to a particular substance. 

Substitution in 98/8/EC is maintained indirectly though the application of comparative risk assessment, which is mandated in Article 10 of the directive. In order to include active substances in Annex I, lA or IB, several requirements have to be fulfilled. For example, active substances cannot be incorporated in the list if they are carcinogenic, mutagenic, toxic for reproduction, sensitising or bioaccumulative. 

Over a period of 20 years, CESIO [1] has conducted reviews of the toxicological data available on marketed surfactants in order to provide guidance to its member companies on classification and labelling in accordance with European legislation and, initially, the requirements of Annex VI of the Fifth Adaptation to Technical Progress [2] of the Dangerous Substances Directive. The first review was carried out in 1984 [3] and the second several years later, being completed in 1990 [4]. Recommendations were made based on data available at that time on acute oral toxicity, skin and eye irritation and skin sensitisation studies. 

Although sensitising properties can be also detected in the classical development program of a drug substance, the need for dermal sensitization studies is of importance for the development of certain drugs. The increasing importance of trans-dermal formulations demonstrate the need of testing for dermal sensitization on the one side, on the other side, there are classical examples which cause dermal sensitization (e.g. neomycin, procaine, sulphonamides). 

Anaphylaxis is a severe, whole-body allergic reaction. After an initial exposure ( sensitising dose ) to a substance such as bee sting toxin, the immune system becomes sensitised to that allergen. On a subsequent exposure ( shocking dose ), an allergic reaction occurs. This reaction is sudden, severe, and involves the whole body. 

Recently, certain microbial systems have demonstrated the ability to generate electricity directly (with little or no hydrogen production) in fuel celllike devices. TTrese will be described in section 3.7. Production of hydrogen by photoelectrochemical devices may employ microbial sensitisers and enzymes or engineered substances derived from bacterial constituents. These will be mentioned in section 2.1.6 after the inorganic devices. 

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