Regulatory compliance for chemical, cosmetic and biocidal products.
SAR
Structure–activity relationships, read across, and chemical grouping
Services
(Quantitative) structure–activity relationships [(Q)SARs] allow the prediction of properties of chemicals without testing, and therefore have positive benefits of cost, timing, and animal welfare. SAR is of growing regulatory importance in the control of chemical and cosmetic products. It is now a central part of a progressive testing strategy.
Alchemy Compliance can use SAR to assess chemical substances for likely hazardous effects, eg from the use of structural alerts (epoxides as an alert for carcinogenicity), read-across and chemical groups (also known as categories), and computational modelling (eg EUSES, EPIWIN).
SAR is available to predict physico-chemical, toxicological, and ecological properties, either from structural features, physico-chemical properties, or from structurally related substances. Alchemy Compliance can advise on the appropriate use of SAR, and its reliability, validation, and likely acceptance by regulatory authorities.
Further information
(Quantitative) structure–activity relationships [(Q)SARs]
With continued concern over toxicity testing in animals, and also over the lack of hazard data for many substances in commerce, there is an increasing trend for regulatory authorities to allow other data to be used. Some progress has been made in the validation of in vitro techniques for irritation, sensitisation, and corrosivity, but a potentially more general approach is the use of structure-activity relationships (SAR), ie predicting the hazardous properties of a substance from its chemical structure.
There are several types of structure–activity relationships available for regulatory purposes:
-
the use of structural elements of a substance as alerts for particular hazardous properties (eg the epoxide group as an alert for carcinogenicity)
-
the transfer (or read-across) of the hazard profile of one substance to another with a similar structure
-
groups of chemicals (sometimes known as categories) containing similar structural features and thus expected to have similar properties, or properties that are predictable across the group (such as in an homologous series)
-
computational systems that use a combination of features of the molecule (electronic, physico-chemical, size, hydrophobicity, etc.) to predict properties (eg EPIWIN)
-
knowledge (or rule) based systems that compare many parameters of a data set of chemicals (training set), and make predictions of the properties of other chemicals (eg DEREK, for sensitisation and carcinogenicity).
Many physico-chemical properties are inter-related, eg boiling point and vapour pressure, and so missing endpoints can be predicted if other ones are available. Sometimes these values can be estimated through structure alone, using simple equations, or through more sophisticated computer prediction. Generally, the more information that is used to determine the property, the more accurate the prediction will be.
Physico-chemical properties are more open to prediction as the results are quantitative and objective, but toxicological endpoints can also be estimated. Prediction from structure is a potentially very powerful approach, because assessing similar substances with known properties to can quickly validate the procedures. This validation step is important, because the prediction system is often based on certain assumptions about the new chemical. These may be very specific (ie the substance is a simple ester with no other functional groups), or general (the substance is organic). Using the system outside its intended scope may lead to erroneous results.
DEREK, a commercial system available from LHASA UK is an example of computer-based approach to toxicological assessment. This database contains structural considerations, mainly for the prediction of genotoxicity and sensitisation. Some expert knowledge is required for the interpretation of results. Other toxicological endpoints, particularly repeat-dose toxicity and reproductive–developmental parameters, are difficult to predict either from structure or from in vitro techniques.
The use of SAR for environmental effects is well advanced. Many neutral organic chemicals produce simple narcosis on aquatic organisms. This tocicity is enhanced with some types of chemicals, for example esters, amines, and phenols. The EPA EPIWIN system is able to predict toxicity to aquatic organisms, as well as biodegradation and bioaccumulation rates, although the results for an unknown substance should be validated against similar substances with known properties. An environmental risk assessor will need access to physico-chemical parameters and degradation rates to model the fate of the substance in the environment. The EUSES programme combines available data with SAR to provide a package for environmental risk assessment.
Read-across and grouping
Read-across of hazard data between structurally related substances is a well accepted by some regulatory authorities. The UK authority advocate that at least the acute oral toxicity and an Ames test is available for both substances in order to support the read-across of toxicological data.
The successful read-across of data requires similarity in the two substances of:
-
purity/impurity profiles, as small amounts of impurities can lead to large differences in toxicology
-
physico-chemical properties, particularly physical form, molecular weight, water solubility, partition coefficient and vapour pressure, as these strongly affect the bioavailability of the substance
-
toxicokinetics, including metabolic pathways, although this is difficult to predict
Read-across, of course, can only be successful if good quality data is available for the known substance.
Chemical grouping (or category formation) is similar in principle to read-across, but involves proposing a group of structurally related chemicals in which data on a few of the members can be shared amongst the whole group. Industry benefit from reduced testing times and costs compared with testing of each individual member of the group, particularly through fewer repeat-dose toxicity tests. Substances in a group have similar or predictably variable structural features, physico-chemical and/or toxicological properties. The group may have one or more of the following features:
-
a common functional group, eg ketone
-
similar breakdown or metabolic products, eg hydrolysis of esters; or oxidation of primary alcohols and aldehydes to carboxylic acids
-
incremental change across a group, eg carbon chain length
Once the membership of the group has been proposed, the proposer should use available information to check the coherence of the group, and establish the rules for inclusion or exclusion from the group (the applicability domain), with a view to maximising the size of the group. Grouping has a tendency to overclassify, so the proposer should take care in indclugin in a group any substances where the classification has a large commercial impact. The members at the edge of the group are tested, because the authorities prefer interpolation of results within a group, rather than extrapolation.
Regulatory application of SAR
The UK HSE have stated that 10% of new chemical notifications contain some read-across, and the proportion is rises to ca. 30% in pre-notification enquiries.
The US EPA make extensive use of structural alerts in their New Chemicals Program (NCP). Before manufacturing a new chemical substance, as US company must file a Pre-Manufacturing Notice (PMN) with the EPA. The EPA recommends a testing package for the PMN based on structural considerations given in their Chemical Categories guidance. For example, acid chlorides can be toxic in the environment, so the recommended strategy involves a two-step process of testing: firstly the rate of hydrolysis, and secondly the toxicity to aquatic or terrestrial species, depending on the likely exposure. The EPA utilise read-across to a lesser extent in the NCP, but the analysis of over 200 acid dyes means that they are sometimes able to predict the hazard profile of new mono-acid dye by analogy to a previously assessed dye.
The International Fragrance Association advocates the safety testing of fragrances based on an integrated approach using structural alerts. The assessor assigns to the new substance separate scores for topical effects, acute/systemic effects and carcinogenic/mutagenic effects based on structural fragments. The scoring indicates, along with other factors such as the amount manufactured, the likely exposures, and the other properties of the substance, those toxicological properties that should be evaluated most urgently.
The OECD successfully advocated the chemical grouping of chemicals in the assessment of high-production-volume chemicals (HPVs).
With the common position of the REACH legislation, the current HPV schemes, and the right-to-know initiative in the US, there are over 30 000 chemicals that will require evaluation in the coming decade. SAR allows the evaluation, or at least screening, of many chemicals in a short time, and will provide an increasingly important role in protecting the workforce and the public at large from the potentially harmful effects of chemicals.
Copyright Alchemy Compliance Disclaimer
FOR MORE INFORMATION PLEASE EMAIL: INFO@ALCHEMYCOMPLIANCE.COM