Scheduling delegate's final decisions. ACMS/ACCS, December 2015
Scheduling medicines and poisons
1.1 Methylisothiazolinone (MI)
Part A - Final decisions on matters referred to an expert advisory committee
1. Scheduling proposals referred to the August 2015 joint meeting of the Advisory Committee on Medicines Scheduling and Advisory Committee on Chemicals Scheduling (ACMS-ACCS#11)
1.1 Methylisothiazolinone (MI)
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS) and the Advisory Committee on Medicines Scheduling (ACMS):
- creating a new entry in an appropriate schedule for cosmetic/personal care preparations containing methylisothiazolinone; and
- an exemption from scheduling for preparations with low concentrations of methylisothiazolinone.
The reasons for the request were:
- Methylisothiazolinone produced skin sensitisation effects in several animal and human studies. Although the potency of these effects varied across the studies, skin sensitisation was sufficiently noted across all the studies to support the Safe Work Australia's HSIS classification of 'May cause sensitisation by skin contact'. Further, the chemical was found to produce an exceptionally high response rate of 11.3% among patients patch tested in Australian dermatological clinics;
- Methylisothiazolinone may also cause systemic acute toxicity (by all route of exposure) and local effects (skin corrosion and the possibility of causing serious damage to eyes);
- Methylisothiazolinone is one of the most commonly used cosmetic preservatives on the Australian market;
- The Cosmetic Ingredient Review (CIR) expert panel concluded that 'MI is safe for use in rinse-off cosmetic products at concentrations up to 100 ppm and safe in leave-on cosmetic products when they are formulated to be non-sensitizing, which may be determined based on a quantitative risk assessment (QRA)' (CIR 2014).
- In 2013, the Scientific Committee on Consumer Safety (SCCS 2013) concluded that “Current clinical data indicate that 100 ppm MI in cosmetic products is not safe for the consumer.
- For leave-on cosmetic products (including 'wet wipes'), no safe concentrations of MI for induction of contact allergy or elicitation have been adequately demonstrated.
- For rinse-off cosmetic products, a concentration of 15 ppm (0.0015%) MI is considered safe for the consumer from the view of induction of contact allergy. However, no information is available on elicitation.
The use of the chemical is restricted to a maximum level of 0.01 g/100 g (100 ppm) in both wash-off and leave-on cosmetics in Japan. The use of the chemical in wash-off and leave-on cosmetics in the European Union (EU) and in the Association of Southeast Asian Nations (ASEAN) is restricted to a maximum concentration of 0.01% (Burnett et al., 2010). In the EU, 6.02% of dermatology clinic patients in Germany were found to be sensitised to the chemical even under these restrictions.
The delegate asked the committees the following questions:
- Scheduling of methylisothiazolinone was referred to the July 2014 meeting of the ACCS. Skin sensitisation potential was identified as the key toxicological issue, driving towards listing in Schedule 6 according to SPF criteria. At that time, the ACCS was aware that the EU SCCS and US CIR had considered possible thresholds for leave-on and rinse-off cosmetics containing methylisothiazolinone, below which the risk of skin sensitisation was considered to be acceptable. Both authorities appeared to reach different views on the sensitisation thresholds, and the ACCS advised waiting for a final decision from the US CIR before it could advise to the delegate on possible exemption cut-off(s) from a Schedule 6 entry. The US CIR published its final report in October 2014. The ACCS/ACMS is asked to advise on whether to adopt either the US CIR or EU SCCS sensitisation thresholds as an exemption cut-off from a new Schedule 6 entry for methylisothiazolinone.
- Alternatively, does the ACCS/ACMS support NICNAS advice that Schedule 6 controls are insufficient to protect the public and that consideration be given to listing in Appendix C (Schedule 10) with appropriate exemption cut-offs?
- Noting that the US CIR has specified that the 100 ppm (0.01%) threshold is only suitable for rinse-off cosmetic products, and that a cut-off for leave-on cosmetic products has not been specified, other than that it be based on a product-by-product quantitative risk assessment, the ACCS is asked to advise on whether the EU SCCS proposal for a 15 ppm (0.0015%) for rinse-off cosmetics is a more appropriate general cut-off from Schedule 6.
- Does the ACCS/ACMS advise that any schedule listing for methylisothiazolinone be specific for cosmetic products, as outlined in the NICNAS report? Should different thresholds be proposed for products that are not intended to be directly applied to skin (e.g. cleaning products, deodorisers, antimicrobial gels and sprays)?
- To what extent should the estimates of sensitisation potential derived from animal tests (LLNA and Buehler test) suggest a higher sensitisation threshold than the conclusions of the CIR and SCCS?
- Noting that methylisothiazolinone is used at comparable concentrations in some therapeutic goods, but notably in sunscreen products that are directly applied to the skin, does the ACCS/ACMS advise that a schedule entry should specifically exempt such therapeutic goods or should they be subjected to the same exemption cut-offs as cosmetics?
- Noting that there have been a significant number of reports of allergies associated with the use of methylisothiazolinone in cosmetic and consumer products. It was designated as 'contact allergen-of-the-year' in 2013 by the US Contact Dermatitis Society and there have been Australian case reports of contact dermatitis associated with its use in 'wet wipes'. What weight should be given to the apparent lack of adverse reaction reports associated with its use in therapeutic goods?
- What regulatory impact might be expected in relation to registered AgVet products, given APVMA advice that the maximum concentration of MI is of the order of 0.1-0.2%?
For full substance summary please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) human health Tier II assessment report for 3-isothiazolone, 2-methyl-. This report is publicly available on the NICNAS website.
Figure 1. Chemical structure of methylisothiazolinone
Toxicokinetic studies in rats using the chemical and its analogue (CAS No. 55965-84-9) show that it is readily absorbed and metabolised. The major metabolic products of the chemical are N-methyl malonamic acid (NMMA) and the 3-mercapturic acid conjugate of 3-thiomethyl-N-methyl-propionamide. These studies did not report accumulation of the chemical or its metabolites in tissues. It is widely distributed to all tissues in the body, with the highest level seen in the liver and lowest in the bone. The chemical is eliminated within 24 hours through urine > bile > faeces. In an in vitro human skin absorption study conducted in accordance with OECD Test Guideline (TG) 428, aqueous solutions of products containing the chemical were applied by occlusion for 24 hours at doses of 52.2, 104.3 or 313 µg/mL. Potential systemic bioavailability was estimated as a maximum of 75.5% of the applied dose (SCCS, 2009).
Acute toxicity - Oral
The chemical had high acute toxicity in animal tests following oral exposure. The median lethal dose (LD50) in rats (Crl:CD®BR strain) was 209 mg/kg bw (235 for male and 183 mg/kg bw for female rats). The chemical (99.7%) was administered as a single dose through gavage at concentrations of 75, 150, 180, 225 and 300 mg/kg bw. Observed sub-lethal effects included passivity, ataxia, scant or no faeces, mucus in faeces, yellow or brown stained anogenital area, red-stained muzzle and/or lacrimation. Additionally, at necropsy reddened intestines and/or stomach mucosa, reddened glandular portion of the stomach, and distended stomachs were observed (CIR, 2010; SCCNFP, 2003).
Based on the available data, the chemical is recommended for classification as hazardous with the risk phrase 'Toxic if swallowed' (T; R25) in HSIS (Safe Work Australia).
Acute toxicity - Dermal
The chemical had high acute toxicity in animal tests following dermal exposure. The median lethal dose (LD50) in rats (Crl:CD®BR strain) was 242 mg/kg bw for both sexes. The chemical (97.5%) was administered undiluted at a single 24-hour occluded topical application on shaved intact skin. Observed sub-lethal effects included decrease in body weight in both sexes at higher dose groups (200 mg/kg and above). Local effects included blanching, oedema, erythema, desiccation, darkened or reddened areas, scabs, eschar, and/or sloughing (CIR, 2010).
Based on the available data, the chemical is recommended for classification as hazardous with the risk phrase 'Toxic in contact with skin' (T; R24) in HSIS (Safe Work Australia).
Acute toxicity - Inhalation
The chemical had high acute toxicity in animal tests following inhalation exposure. The median lethal concentration (LC50) for aerosol in rats (Crl:CD®BR strain, 6 animals/group) after four-hour exposure was 0.11 mg/L. The necropsy showed signs of slight to severe redness in all lobes of the lung in all treatment groups (CIR, 2010).
In another study, the LC50 in rats (Crl:CD®BR strain, 5 animals/group) after four-hour aerosol exposure was reported at 0.33 mg/L. Observed sub-lethal effects included body weight reduction in females at higher dose groups (0.25 mg/kg and above). Signs of pale and/or reddened lungs, distended intestines, and/or wet muzzles were observed at necropsy (CIR, 2010).
Based on the available data, the chemical is recommended for classification as hazardous with the risk phrase 'Very toxic by inhalation' (T; R26) in HSIS (Safe Work Australia).
Based on the available data, the chemical is recommended for classification as hazardous with the risk phrase 'Causes burns' (R34) in HSIS (Safe Work Australia).
The chemical was applied undiluted as a single semi-occluded application of 0.5 mL to shaved intact skin of New Zealand White rabbits for three minutes, one hour, and four hours. The three-minute exposure resulted in a very slight to well-defined erythema through to day seven and slight oedema at 1- and 48-hours observations. At 1 and 4 hour exposures to the chemical, skin irritation indicative of corrosivity (concave eschar) was observed on days 7 and 14, respectively (CIR, 2010; SCCNFP, 2003). In an in vitro study with skin constructs, exposure to 1.7% of the chemical for three or 60 minutes was not corrosive to the skin. However, the chemical was corrosive at higher concentration of 51.1% at an exposure period of 60 minutes (CIR, 2010).
The chemical is recommended for classification as corrosive. It is expected that undiluted chemical will be severely damaging to the eyes.
The chemical (undiluted) was found to be an irritant in a bovine cornea study measuring opacity and permeability. Eye irritation studies using formulations containing the chemical at 100 ppm (body lotion, shampoo and sunscreen) were found non-irritating (CIR, 2010).
Sensitisation - Skin sensitisation
The chemical produced skin sensitisation effects in several animal and human studies. Although the potency of these effects varied across the studies, skin sensitisation was sufficiently noted across all the studies to support the classification (refer to Recommendation section) (SCCS, 2009; CIR, 2010; Lundov et al., 2011; Yazar et al., 2011; Boyapati et al., 2013; Cahill et al., 2014; SCCS, 2013; Lammintausta et al., 2014).
Methylisothiazolinone, in combination with methylchloroisothiazolinone (MCI) in a ratio of 1:3, has been used in industrial and consumer products as a preservative since the beginning of the 1980s. The first cases of contact allergy caused by these chemicals were published in 1985. Although MCI has been considered a more potent sensitiser than MI, this chemical is still classified as a strong sensitiser. As a result of the sensitising potential of these chemicals, the maximum permitted concentration in the EU of the mixed preservative in cosmetics in the ratio of 1:3 (MI:MCI) is 15 ppm (0.0015%); the allowed concentration of MI in the mixture is 3.75 ppm. Following a review of the safety of MI, the chemical was allowed in cosmetic products in the EU at a maximum concentration of 100 ppm in 2005 (see Restrictions) (SCCNFP, 2003; Lundov et al., 2011). The CIR expert panel recommended that the United States cosmetic manufacturers use the chemicals at the same concentrations as allowed in the EU (CIR, 2010).
Following its approval for use as a preservative in cosmetic products in 2005 at a maximum concentration of 100 ppm, several reports have indicated the emergence of the issue of contact allergy to the chemical (see Sensitisation: observation in humans). The permitted use of the chemical at 100 ppm in cosmetic products is approximately 25-fold the permitted concentration of the chemical in the MI/MCI combination (3.75 ppm MI in 15 ppm of MI/MCI).
The chemical, in a combination with MCI (1:3 ratio), is also used as a preservative in industrial products and there are no restrictions on the use of this chemical in industrial products. The chemical-induced occupational contact allergy and dermatitis were also reported after contact with wall covering glue and in a paint factory (Lundov et al., 2011; Boyapati et al., 2013; SCCS, 2013).
Although several reports on the sensitisation potential of the mixture (MI:MCI) are available in animals, the most comprehensive studies conducted on the chemical (MI) are reported below.
The potential for MI to cause skin sensitisation was investigated in an OECD Test Guideline (TG) 406 study (Buehler test). In this study, four groups of Hartley guinea pigs (five/sex/group) were treated with the chemical in the form of 6 hours' induction with three doses each week for 3.5 weeks under an occlusive condition. The chemical was administered at 0.4 mL/dose containing concentrations of 1000, 5000, 15000 and 30000 ppm suspended in distilled water on shaved intact skin. The animals were allowed to rest for two weeks before the challenge application. During the challenge phase, the animals were patched with the chemical at doses 1000, 5000, or 15000 ppm in distilled water. The treated animals were monitored for erythema for 24 or 48 hours following the application. Appropriate controls were also used in this study. The results showed no erythema reactions in the non-induced control animals at any challenge concentration. However, incidences of erythema were observed in animals induced and challenged with the chemical at 1000 ppm or higher (Burnett et al., 2010; SCCS, 2013).
In another study (maximisation test), 60 female Hartley guinea pigs received six intradermal injections containing induction doses of 500 ppm or 800 ppm of the chemical. After a week, the treated animals were given a single 24-hour topical exposure to 0.1 mL of the chemical under occlusive conditions. The animals were challenged with 500 ppm or 800 ppm after two weeks and were evaluated for reactions at 24 and 48 hour periods. The animals were also subjected to rechallenge with 1000 ppm. The results showed that 550 ppm did not cause dermal reactions. Only one reaction was noted at 800 ppm dose challenge after the 48-hour observation. During the rechallenge, less than 30% of the animals displayed grade one erythema. Based on these results, the chemical was not considered a sensitiser at concentrations up to 800 ppm (Burnett et al., 2010).
Furthermore, several mouse local lymph node assay (LLNA) studies have reported evidence suggesting that the chemical is a potential skin sensitiser. In one study, female CBA/Ca mice were treated with the chemical (19.7% purity in water) at the concentrations of 0.049, 0.099, 0.197, 0.493, 0.985% in acetone and olive oil (4:1; v/v) and also at the concentrations of 0.99, 1.97, 4.93, 9.85% in propylene glycol (PG). The induction phase consisted of applying the chemical, positive controls (formaldehyde, glutaraldehyde, MCI/MI mixture) or vehicles over the ears (25 µL/ear) for three consecutive days (days one, two and three). After two rest days, the proliferation of lymphocytes in the lymph node draining the application site was measured by incorporating tritiated methyl thymidine (day six) for five hours. A linear interpolation of the dose response data was used to estimate concentrations required to induce stimulation indices (SI) of 3, relative to concurrent vehicle-treated controls (the EC3 value). The EC3 values of 0.4 and 2.2% were calculated for the chemical for acetone and olive oil (4:1; v/v) and PG solutions, respectively. It was concluded that the chemical has strong sensitising potential, with potency being comparable to that of the formaldehyde although much lower than the mixture of the chemical with MCI in 1:3 ratio. Similar findings were noted in another study, indicating that the chemical is a sensitiser at concentrations greater than 0.76% in acetone/olive oil (4:1) with a reported EC3 value of 0.86% (SCCS, 2013).
Overall, these data suggest that the chemical is a potential skin sensitiser.
Observation in humans
Contact allergy to the chemical and the mixed preservative (MI:MCI) has been commonly reported following its approval for use in cosmetics in 2005. Increased incidence of clinical sensitisation to MI was more evident following the introduction of patch test for MI alone. The prevalence of sensitisation increased from 1.94% of all dermatological clinic patients in 2009 to 6.02% in 2012 in Germany. This increase was mainly stated to be driven by female patients aged ≥40 years, patients with face dermatitis, and the use of cosmetics. Additionally, the chemical was named the 2013 "Contact Allergen of the Year" by the American Contact Dermatitis Society, indicating increased incidence of the chemical-induced contact dermatitis (Cahill et al., 2014). Painters, beauticians, and patients with ano-genital dermatitis were identified as being potentially at risk for sensitisation to the chemical (Lundov et al., 2011; Uter et al., 2013; Gameiro et al., 2014; Lammintausta et al., 2014).
In a series of repeat insult patch tests (RIPT) in human volunteers, exposure to the chemical at doses 200, 300, 400, 500, or 600 ppm did not cause dermal sensitisation (CIR, 2010; Burnett et al., 2010). Conversely, cases of allergic contact dermatitis were also reported in patients who had come into contact with coolant solutions containing biocides and those who were exposed to paint additives containing 7-10% of the chemical. In addition, a lowest eliciting dose of 1.47 µg of the chemical (49 ppm) was observed in a sensitisation studies conducted in 11 MI-allergic patients (CIR, 2010).
The chemical has been reported to be an emerging and important allergen in both cosmetic and occupational settings in Australia. Baby wipes and facial wipes containing the chemical were reported to be an important cause of hand dermatitis in carers. Facial dermatitis in children was also noted following the use of moist wipes containing the chemical. It was concluded that the continued use of the chemical in baby wipes and facial wipes will lead to increased rates of allergy to these preservatives in adults. The present study also noted three cases of contact allergy as occupational exposure from hand cleansers containing the chemical (Boyapati et al., 2013). Based on the results of a series of patch test conducted from 2011-2013, the Medical Journal of Australia reported a significant increase in the incidence of contact dermatitis in adult patients from the use of the baby wipes which contain the chemical (Cahill et al., 2014). In this report, the authors highlighted this remarkable rise of contact dermatitis from 3.5% in 2011 to 11. 3% in 2013 among their patient population. The authors also noted that the chemical is now the most common cause of allergic contact dermatitis in their patient population (Cahill et al., 2014).
The Scientific Committee on Consumer Safety (SCCS) presented its opinion on the safety of the chemical (methylisothiazolinone) in consumer products. The committee concluded that, on the basis of current clinical data, the use of the chemical at 100 ppm in cosmetic products is not safe for the consumer. The committee also concluded that, for leave-on cosmetic products (including wet wipes), safe concentrations of the chemical for induction of contact allergy or elicitation have not been adequately demonstrated. Although a concentration of 15 ppm (0.0015%) of the chemical was considered safe for the consumer with respect to induction of contact allergy for rinse-off cosmetic products, no information was available for these products with respect to elicitation of contact allergy (SCCS, 2013).
Repeated dose toxicity - Oral
Based on the available data, the chemical is not considered to cause serious damage to health from repeated oral exposure. No treatment related effects were observed in rats (Crl:CD BR strain) exposed to the chemical (up to 1000 ppm, equivalent to 65.7 and 93.5 mg/kg bw/day in males and females, respectively) in drinking water for three months. Dogs fed with diets prepared with the chemical for three months had a NOAEL of 1500 ppm (41 mg/kg bw/day) (CIR, 2010; US EPA, 1998).
Repeated dose toxicity - Dermal
No data were available for the chemical. Based on the available toxicity study for the analogue chemical (3:1 mixture of methylchloroisothiazolinone and methylisothiazolinone, CAS No. 55965-84-9), in which there was no evidence of toxicity, the chemical is not considered to cause serious damage to health from repeated exposure.
A formulation containing analogue chemical (2.55:1 ratio) was applied once daily for 91 days to the intact skin of Sprague Dawley (SD) rats by semi-occlusive dressing at doses of 0, 0.75, 3.75, or 18.75 mg/kg bw/day. Treatment-related skin reactions at all doses included slight to moderate erythema and desquamation, slight oedema and atonia, and eschar formation. Microscopic findings revealed treatment-related lesions such as inflammation, parakeratosis, and acanthosis at the treated sites. The LOAEL and NOAEL identified for local effects in this study, were = 0.104 and < 0.104 mg/kg bw/day (SCCS, 2009).
Repeated dose toxicity - Inhalation
No data were available for the chemical. Based on the available inhalation toxicity study for the analogue chemical (3:1 mixture of methylchloroisothiazolinone and methylisothiazolinone, CAS No. 55965-84-9), in which there was no evidence of inhalation toxicity, the chemical is not considered to cause serious damage to health from repeated exposure through this route.
In a study conducted in accordance with OECD TG 413, Charles River Crl: CD(SD) BR rats were exposed to an aerosol product containing 14% of the analogue chemical for 13 weeks (0, 0.34, 1.15, or 2.64 mg/m3, at 6 hours/day, 5 days/week). At the top dose, effects included decreased bodyweight gain and signs consistent with sensory irritation such as chromorhinorrhoea, rhinorrhoea, eye squint, bradypnoea, and dyspnoea. Slight to moderate eosinophilic droplets in the anterior mucosa of the nasal turbinates and slight rhinitis in the lining of the nasal cavity were also reported at the top dose. At the mid-dose, slight incidence of rhinitis was observed. The study authors noted that eosinophilic droplets in the nasal turbinates and rhinitis were possibly reversible responses to upper respiratory tract inflammation. The lowest-observed-adverse-effect-concentration (LOAEC) and no-observed-adverse-effect-concentration (NOAEC) for this study were 2.64 and 1.15 mg/m3, respectively (SCCS, 2009; US EPA, 1998).
Based on the weight of evidence from the available in vitro and in vivo genotoxicity studies the chemical is not considered to be genotoxic.
The chemical was not mutagenic in Ames tests in Salmonella typhimurium, with or without metabolic activation (CIR, 2010; SCCNFP, 2003). The chemical (0.5-40 µg/mL) was also negative in an in vitro chromosome aberration study using the Chinese hamster ovary (CHO) cells, both with and without metabolic activation. In another study using CHO cells, chromosomal aberrations (at 3.75 µg/mL without S-9 activation (28% aberrant cells) and at 7.50 µg/mL with S-9 activation (34% aberrant cells) were seen accompanied by significant cytotoxicity (29-48% reductions). The chemical was reported to be negative in an in vivo mouse micronucleus assay (CIR, 2010; SCCNFP, 2003).
No data are available for the chemical. Based on the weight of evidence from the available carcinogenicity study for the analogue chemical - 3:1 mixture of methylchloroisothiazolinone and methylisothiazolinone (CAS No. 55965-84-9), in which there was no evidence of carcinogenicity, the chemical is not likely to be a carcinogen.
In a two-year drinking water study on rats (CRL:CD BR) exposed to the analogue chemical, no treatment related neoplasms were observed up to the highest dose tested, 300 ppm (equivalent to 17.2 mg/kg bw/day). Hyperplasia of the forestomach was seen at mid and top doses. This was attributed to the corrosive nature of the chemical (CIR, 2010).
Reproductive and developmental toxicity
The chemical does not show specific reproductive or developmental toxicity.
In a two-generation reprotoxicity study, no treatment related effects were noted in rats (Crl:CD IGS BR strain) exposed to the chemical (up to 86 mg/kg bw/day in males and 115 mg/kg bw/day in females) through drinking water (CIR, 2010; US EPA, 1998).
Two teratogenicity studies showed no treatment related effect in rats (Crl:CD(SD) IGS BR strain) and rabbits (New Zealand White) exposed to the chemical at concentrations up to 40 and 30 mg/kg bw/day respectively. Based on the results, the maternal NOAELs were 20 (rats) and 10 (rabbits) mg/kg bw/day and developmental NOAELs were 40 (rats) and 30 (rabbits) mg/kg bw/day (CIR, 2010; US EPA, 1998).
Other health effects
An acute in vitro neurotoxicity study of the chemical using cultures of embryonic rat (SD) cortical neurons and glia observed widespread neuroronal cell death within 24 hours in the cortical cultures exposed to 100 and 300 µM (highest concentration tested) concentrations. Gliotoxicity was low. Another 14-hour in vitro neurotoxicity study of the chemical concluded that prolonged exposures to the chemical and related isothiazolones may damage developing nervous systems (based on cell death observed in cultures treated with 3 µM concentration of the chemical along with changes in signalling complexes normally found in developing neurons) (CIR, 2010). However, no evidence of neurotoxicity was observed in vivo in the repeat dose or reproductive and developmental animal studies.
Methylisothiazolinone is not specifically scheduled.
Methylisothiazolinone has been previously considered for scheduling. In July 2014, the Advisory Committee on Chemicals Scheduling (ACCS), considered toxicological data on methylisothiazolinone and noted that its toxicological profile met the Schedule 6 factors of the Scheduling Policy Framework (SPF). The chemical is not a carcinogen or genotoxic. Based on the toxicity profile of this chemical, the committee considered that a Schedule 6 entry was warranted. The committee noted the maximum use concentration levels in both leave-on and rinse-off products (0.01%) overseas. In cleaning preparations the concentration level is typically reported to be <1% of methylisothiazolinone. The committee proposed, however, that a low concentration exemption cut-off to exclude methylisothiazolinone from the schedules is not warranted.
The committee was concerned about the reports that indicate an increased number of incidents of clinical sensitisation to methylisothiazolinone. They also noted a pre-meeting public submission that proposed deferral of the scheduling decision for cosmetic and domestic products intended for skin contact until the finalisation of the US Cosmetic Ingredients Review (CIR) report has been finalised and which was expected to be published later that year.
The committee recommended that a new Schedule 6 entry be created for methylisothiazolinone and that the delegates seek further information on non-cosmetic uses and possible exemptions. The committee agreed that the name methylisothiazolinone should be used in the Poisons Standard.
The delegates noted the committee's recommendation and public submissions. He noted that the sensitising potential is the key driver for any scheduling action and the SPF criteria suggest this would warrant inclusion in Schedule 6 with and appropriate exemption for cosmetic and other products containing a low concentration of methylisothiazolinone. Therefore, the delegates decided to defer further consideration of scheduling methylisothiazolinone pending the publication of the final US CIR decision.
Pre-meeting public submissions
Five public submissions were received. Most submissions pointed to the current international standards in place and one referred to a recent medical publication on acute dermatitis incidents related to MI. The international standards referred to those in the USA, where MI use is permitted at 100 ppm or less for rinse-off products and in leave-on products when formulated to be non-sensitising, and in the EU, where MI is still permitted at 100 ppm but is officially reported to only to be safe in rinse-off products at 15 ppm or less. One submission also pointed to adverse events data to one of their sunscreen products where no events were recorded for over a million items sold. Two submissions respectively requested that non-human use products, those not intended for skin use, such as paints, should be exempt from scheduling if containing levels 1000 ppm or 100 ppm or less.
All industry submissions requested a timeframe of 24 months to reformulate if scheduling was to progress for MI.
The submission that comprised of a medical publication presented data of increasing incidences of acute dermatitis reactions to MI, along with a public health warning by the SA Department of Health for products including MI as a result of this medical publication, and warned of specific products such as baby wipes.
Edited versions of these submissions are available at Public submissions on scheduling matters.
Summary of ACCS/ACMS advice to the delegates
The committee recommended a new Schedule 6 entry be created for methylisothiazolinone with certain exempt cut-offs.
The committee recommended an implementation date of 1 October 2017.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance.
The reasons for the recommendations comprised the following:
- Preservative with increasing prevalence for skin sensitisation
- Preservative for use in cosmetics, therapeutic goods, industrial and household products
- Meets the criteria for Schedule 6; strong skin sensitiser
Delegates' interim decision
The key issue driving the need to regulate methylisothiazolinone (MIT) by scheduling is its sensitisation potential. Following initial consideration by the ACCS in July 2014, and the publication of US Cosmetic Ingredients Review (CIR) and EU Scientific Committee on Consumer Safety (SCCS) reviews, the delegates have accepted advice from the joint meeting of the ACCS/ACMS to list methylisothiazolinone in Schedule 6, with exemptions for some types of cosmetics and therapeutic goods containing low concentrations. The delegates noted the increasing prevalence of reported skin sensitisation reactions and determined that the exemption cut-off of 0.0015% proposed by the EU SCCS could be protective for rinse-off cosmetics and therapeutic goods, but not for products applied to the skin and not intended to be washed off. The delegates determined that cosmetic and therapeutic goods intended for application to the skin without washing off posed an unacceptable sensitisation risk and should be included in Schedule 6.
The delegates also determined that when methylisothiazolinone is present in products not intended for direct application to the skin, a higher exemption cut-off (0.1%) could be made in the Schedule 6 entry. The delegates noted that the proposed schedule changes could result in product sponsors needing to re-label, or possibly deciding to re-formulate products using other preservatives, and determined that a reasonably long period be allowed for such actions prior to implementation of the scheduling decision. The delegates noted that the proposed EU restrictions could already be driving such changes. The delegates noted that some agricultural fungicides, insecticides and external use parasiticides could be affected by the scheduling change, but that most such products would fit within the 0.1% exemption.
The delegate considered the following in regards to this proposal:
- Scheduling proposal;
- Public submissions received;
- Joint ACCS/ACMS advice;
- Section 52E of the Therapeutic Goods Act 1989;
- Scheduling factors1;
- Other relevant information.
Public submissions on the interim decision
Three submissions were received. Two submissions were similar in their comments to the delegates' interim decision. Two submissions supported the decision for leave-on products and had no objections to the implementation date of 24 months. One submission preferred an implementation period of 30 months. All three submissions objected to the decision for a cut-off of 15 ppm for rinse-off cosmetics and topical therapeutic goods, with a main concern being that the MI will not be effective as a preservative at this concentration and proposed a cut-off of 100 ppm to align with international standards. Two submissions also requested to defer the final decision until the release of a European Union SCCS draft report on MI.
Edited versions of these submissions are available at Public submissions on scheduling matters.
Delegates' final decision
The delegates note the submissions received in response to publication of the interim decision and have determined to vary the interim decision. The proposed variations address:
- the wording of clause (a), raising the exemption cut-off from 0.0015% to 0.01%; and
- the wording of clause (b) to clarify that the proposed exemption cut-off of 0.1% only applies to products that are not intended to be applied directly to human skin;
- a staged implementation to allow for an earlier date to control all cosmetics and therapeutic goods applied directly to the skin, with a longer period allowed to phase in scheduling that allows for exemptions on only those products intended to be rinsed off.
The reason for raising the cut-off in clause (a) to 0.01% is to align with current international standards for such products. As pointed out in the submissions, the ACCS/ACMS based its advice on an appropriate cut-off for rinse-off preparations on a proposal from the EU SCCS that is yet to be ratified. The submissions included advice that industry has submitted data on quantitative risk assessments (QRA) for different product types that demonstrate an adequate safety profile at up to 0.01% MI for some types of cosmetic products. Should the EU reject these submissions and confirm its proposed cut-off for rinse-off products at 0.0015%, there will be sufficient time prior to the proposed implementation date of 1 October 2017 for the current scheduling decision to be revised accordingly.
The delegates note that the submissions did not object to there being no cut-off to exempt for the Schedule 6 listing of cosmetics and therapeutic goods applied to the skin, but not intended to be washed off, so any such products containing methylisothiazolinone will eventually need to be re-formulated or re-labelled with the signal heading POISON and the appropriate Appendix F warning statement.
The delegates note that it would be possible for restrictions that align with current international standards to be implemented more quickly (say 6 months), and desirable from the point of limiting the potential for sensitizing reactions that have already been documented to occur. Accordingly, the delegates have decided to implement the proposed scheduling changes over two periods. Leave-on products (i.e. those not intended to be rinsed off the skin after application) will need to meet international standard (i.e. contain 0.01% MI or less) or be labelled as Schedule 6 poisons within the proposed six months implementation timeframe. The exemption cut-off for leave-on products will be withdrawn in October 2017, when the Schedule 6 entry will be amended to allow only rinse-off products that meet international standards for MI concentration to qualify for the Schedule 6 exemption. This will achieve the ultimate goal of allowing the Schedule 6 exemption to apply only to products intended to be rinsed off, and therefore present a lower risk of skin sensitization.
The same 1 October 2017 implementation date will also see the introduction of a 0.1% exemption cut-off for products other than cosmetics and therapeutic goods that are not intended to be directly applied to the skin. Both proposed periods of implementation will allow for re-formulation or re-labelling of products that do not meet international standards or the exemption cut-offs proposed by the delegates.
The delegates considered the relevant matters under subsection 52E (1) of the Therapeutic Goods Act 1989: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance.
While one submission requested an implementation period of 30 months, other submissions accepted that two years should be sufficient to re-label and/or re-formulate products affected by the scheduling decision. The delegates' proposal that the implementation be over two periods, with six months for leave-on cosmetics and therapeutic goods having an exemption cut-off of 0.01%. Other products would remain unscheduled until 1 October 2017, when the amended Schedule 6 entry would apply to all products, with exemptions only for rinse-off cosmetics and therapeutic goods meeting the 0.01% cut-off and other preparations not intended to be applied to the skin having a higher (0.1%) cut-off. One submission raised an issue about whether the two years should start from the date of the final decision, rather than the date of the interim decision. In fact, the implementation date is fixed by the date proposed for publication of the Poisons Standard.
Schedule 6 - New Entry
METHYLISOTHIAZOLINONE in leave-on cosmetic products or therapeutic goods intended for leave-on topical application, except in preparations containing 0.01 per cent or less of methylisothiazolinone.
|Poison||Warning statements||Safety direction|
|METHYLISOTHIAZOLINONE||28||(over)(repeated) exposure may cause sensitisation|
Implementation date: 1 June 2016.
Schedule 6 - Amendment
- in rinse-off cosmetic preparations or therapeutic goods intended for topical rinse-off application containing 0.01 per cent or less of methylisothiazolinone; or
- in other preparations that are not intended for direct application to the skin containing 0.1 per cent or less of methylisothiazolinone
Implementation date: 1 October 2017.