Aggregate consumer exposure to isothiazolinones

Abstract

The number of chemical substances that are contained in a wide range of consumer products and to which humans are exposed is continuously increasing. Although these synthetic organic chemicals bring several benefits to our modern society, their environmental and human health impact can be catastrophic if not adequately assessed and regulated. For many consumer products their safe use is assured by risk assessment, which is based on the comparison of a potential adverse health effect of the substance with the exposure to this substance. Consumer products with high water content, such as cosmetics and cleaning agents, are predisposed to be contaminated by microorganisms, such as Pseudomonas aeruginosa, which could pose a health risk to the consumer. In order to avoid a microbial contamination in such consumer products, biocidal substances such as isothiazolinones can be added to the products. The isothiazolinones are heterocyclic organic chemicals containing sulphur. The substances 5–Chloro–2–methyl–4–isothiazolin–3–one (CMI) and 2–Methylisothiazol–3(2H)–one (MI) are either used as a 3:1 mixture (CMI:MI; CAS: 55965–84–9) or as single substances in a wide range of consumer goods such as household cleaning agents, personal care products, indoor paints, disinfectants, and other consumer products. Several other isothiazolinones have been used for preservation of industrial, household, and other consumer products, including 1,2–benzisothiazol–3–(2H)–one (BIT) and 2–Octyl–3(2H)–isothiazolinone (OIT). In some of these appliances, they are used either as biocidal agents (e.g. fungicides or algicides) or as preservatives, implying smaller weight fractions in the product. BIT, OIT, MI and CMI are well known to cause allergic contact dermatitis (ACD). ACD develops in two distinct phases. The first one is called induction. In this phase the dermal exposure of a subject to an appropriate concentration of a contact allergen will result in immunological priming and the acquisition of a contact allergy (i.e. sensitized). Subsequently, if the sensitized individual is dermally exposed again to the same allergen, at the same or even at a different body location, the so called elicitation phase will be initiated. The elicitation phase is associated with a fast and more vigorous secondary immune response resulting in a dermal inflammatory reaction, which is clinically described as ACD. Knowledge regarding consumer exposure to hazardous chemicals in our environment is essential to understand the risk related to these chemicals. Such information is also crucial for planning effective prevention strategies. Therefore, the overall scope of this doctoral thesis is to gain a thorough understanding of the aggregate dermal exposure to isothiazolinones among the Swiss population, including the identification of the major exposure sources. However, the current database for input parameters is insufficient for a refined aggregate exposure assessment. Therefore, in this thesis, the first two steps aimed at estimating these relevant parameters. The first step was to design and perform a questionnaire in three languages in order to collect data at individual–level on the use–patterns of household care (HCP) and personal care product (PCP) among Swiss people (Chapter 2). The second step consisted in determining the occurrence and concentration of isothiazolinones in a range of household care and personal care products (HC&PCPs) relevant for the Swiss market (based on the results of Step 1; Chapter 3). The final step was to use the input data collected in the first two steps for modelling and calculating the dermal exposure to isothiazolinones on different body areas through multiple HC&PCP categories using a new in–house developed version of PACEM (Probabilistic Aggregate Consumer Exposure Model) and explore the contributions of different product categories to the aggregated exposure (Chapter 4). In the study presented in Chapter 2, the use–patterns of 12 household care products, 5 laundry products, and 22 personal care products were collected among the Swiss population (N= 759; ages 0–91) by postal questionnaire, providing for the first time in Europe comprehensive information regarding the use of HC&PCP for the same study population. The majority of respondents (99%) reported having used at least one of the investigated consumer product categories recently. Apart from the investigation of use frequency, quantity, duration, and habits, also a co–use analysis was separately performed for HC&PCP. Use–patterns are presented for both genders and all age groups, including children below the age of 12, who may be more vulnerable to the adverse effects attributed to certain chemicals. Also, the currently missing use–factors for cosmetic/baby wet wipes were assessed. Stratification of the data by gender, age and other socio–demographic factors, such as region affiliation, allowed us to identify differences between population sub–groups, emphasizing the need for region–specific exposure factors. A great challenge in the design of a questionnaire on exposure factors is how to ensure that the studied population is representative for the whole population of interest considering the general declining response rates in surveys. Therefore, a mobile application (app) may be an interesting complement or even an alternative to paper–based questionnaires. Compared to the paper–based questionnaire, an app has a series of advantages such as the possibility of getting information on the participant’s position, of helping avoid inconsistencies in the dataset, etc. Especially younger adults, who are no longer accessible by random sampling from phone books, may be attracted by such app–based survey methods. Nonetheless, with the rising market penetration of smartphones and the concurrent decline of paper media individuals across all age groups have become more familiar with the use of apps. For this reasons, an iPhone survey app was developed. The basis for the development of the app was the mailed paper–based questionnaire on exposure factors across the Swiss population. With a barcode scanner via smartphone, the product recognition was ensured and helped the consumer to complete the questionnaire rapidly. In Appendix Section A1, we compare the performance of a mobile app and a paper–based questionnaire on exposure factors with an observational study. The performance criteria assessed were costs, response rate, representativeness, and reliability. For the reported study the cost efficiency of the paper–based questionnaire was 16 US–$ per valid response. The app was less favorable regarding cost efficiency. With adequate promotion, however, the comparable cost efficiency of the app would be around 39 US–$ per valid response, and would further improve with more respondents. Hence, the app is especially recommended for large surveys. Representativeness was shown to be best for a mixed–mode questionnaire: by using an app in addition to a paper–based questionnaire the age group of 20–40 years olds that is often underrepresented in paper–based surveys can effectively be reached. Barcode scanning of consumer products implemented in the app saved participants’ time and effort. The objective of Chapter 3 is to examine the current frequency of occurrence and the concentrations of isothiazolinones BIT, OIT, MI and CMI in a wide array of detergents and cosmetics relevant for the Swiss population. By means of a market survey, the occurrence of isothiazolinones was investigated in 1948 consumer products. Of these, 88 products were analyzed by liquid chromatography–high–resolution mass spectrometry after ultrasonic extraction. Only 7.6% of all PCPs contained isothiazolinones, but their prevalence in HCPs was much higher. The measured concentration ranges in HCPs were 4.3–10, 3.5–279, 3.8–186 and 7.9 ppm (one product only) for CMI, MIT, BIT, and OIT, respectively. For PCPs, these were 1.3–133 and 4.8 ppm (one product only) for MI and CMI, respectively. Our study has shown that high concentrations of isothiazolinones (including MI) can be found in a large variety of products, in particular in HCPs. Therefore, the safe use of these preservatives should be re–evaluated by including HCPs in the exposure assessment. Finally, in Chapter 4, we used the previously collected data and evaluated the aggregate dermal exposure of the Swiss population to isothiazolinones via the use of HC&PCPs. Individual–based aggregate dermal exposure to the four isothiazolinones was estimated using the newly proposed Probabilistic Aggregated Consumer Exposure Model – Kinetic, Dermal (PACEM–KD). PACEM–KD advances the original PACEM by considering exposure duration, product dilution and skin permeability, instead of using a fixed fractional absorption. PACEM–KD–based higher–Tier exposure (99th percentile) was 15.4 ng/cm2, 1.3 ng/cm2, 0.9 ng/cm2, and 0.08 ng/cm2 for BIT, OIT, MI, and CMI, respectively. Major sources of exposure to BIT included all–purpose cleaners, dishwasher detergent, and kitchen cleaner, while exposure to OIT mainly stemed from a fungicide. For MI the main contributors were dishwashing detergent and all–purpose wet wipes, and for CMI all–purpose cleaner. A quantitative risk assessment (QRA) for BIT using conservative Sensitization Assessment Factors (SAFs) indicated that 1.14% of the Swiss population is exposed above the threshold for induction of skin sensitization. In summary, the new higher–Tier modelling approach suggests that household cleaners are important sources of isothiazolinone exposure and that especially BIT may pose a risk to consumers.