2.6 Methylisothiazolinone

On this page: Referred scheduling proposal | Scheduling application | Current scheduling status and relevant scheduling history | Australian regulatory information | International regulations | Substance summary | Pre-meeting public submissions | Summary of ACCS-ACMS advice to the delegate | Delegate's considerations | Delegate's interim decision

Referred scheduling proposal

A delegate from the Therapeutic Goods Administration has referred a scheduling proposal to amend the Schedule 6 entry for methylisothiazolinone.

Scheduling application

This was a delegate initiated application. The delegate's proposed amendments to the Poisons Standard are:

The reasons for proposal include:

• Methylisothiazolinone (MI) has exhibited skin sensitisation effects and may also cause systemic acute toxicity and local effects such as eczema and contact allergy reactions.
• On the basis of the December 2015 SCCS Opinion Report on MI, the EU have proposed a change to the MI restrictions at the time (maximum concentration of 0.01% of MI). The report stated that:
  • the information provided does not support the safe use of MI as a preservative in rinse-off cosmetic products up to a concentration limit of 100 ppm (0.01%) from the view of induction of contact allergy;
  • for rinse-off cosmetic products, a concentration of 15 ppm (0.0015%) MI is considered safe for the consumer from the point of view of induction of contact allergy; and
  • it is also not safe to use MI as a preservative in leave-on hair cosmetic products up to a concentration limit of 100 ppm (0.01%) from the point of view of induction of contact allergy.
• At the time of the December 2015 delegate's final decision, the committee noted that should the EU 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.

Current scheduling status and relevant scheduling history

Methylisothiazolinone is currently listed in the Poisons Standard as follows:

The delegate's final decision for methylisothiazolinone referred to the August 2015 Joint ACCS-ACMS meeting, due to be implemented on 1 October 2017, is to amend the current Schedule 6 entry for methylisothiazolinone as follows:

Advisory Committee on Chemicals Scheduling (ACCS) (July 2014)

In July 2014, the Advisory Committee on Chemicals Scheduling (ACCS), considered toxicological data on methylisothiazolinone (MI) and noted that its toxicological profile met the Schedule 6 factors of the Scheduling Policy Framework (SPF). MI is not a carcinogen or genotoxic. Based on the toxicity profile of MI, 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 MI. However, the committee proposed that a low concentration exemption cut-off to exclude MI from the schedules is not warranted.

The committee was concerned about the reports that indicate an increased number of incidents of clinical sensitisation to MI. 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, which was expected to be published later that year.

The committee recommended that a new Schedule 6 entry be created for MI and that the delegate seek further information on non-cosmetic uses and possible exemptions. The committee agreed that the name MI should be used in the Poisons Standard.

The delegate noted the committee's recommendation and public submissions. It was agreed that the sensitising potential was the key driver for scheduling MI in Schedule 6 with an appropriate exemption for cosmetics and other products containing a low concentration of MI. The delegate agreed with the proposal to defer further consideration of scheduling MI pending the publication of the final US CIR decision.

Joint ACCS-ACMS (August 2015)

In August 2015, the Joint ACCS-ACMS considered new information on MI and noted that MI was a preservative with increasing prevalence for skin sensitisation due to its increased use pattern in cosmetics, therapeutic goods, industrial and household products. The joint committee recommended that a new Schedule 6 entry for MI be created with certain exemption cut-offs. The delegate agreed and made an interim decision to create a new Schedule 6 entry for MI with a 0.0015 per cent exemption cut-off for rinse-off cosmetic preparations or therapeutic goods intended for topical rinse-off application and an exemption cut-off of 0.1 per cent in other preparations that are not intended for human use.

In December 2015, the delegates' final decision was to vary the interim decision, raising the exemption cut-off from 0.0015% to 0.01% (clause (a)) and clarifying that the exemption cut-off of 0.1% only applied to products that are not intended for direct skin contact (clause (b)). The delegate also proposed 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% was to align with current international standards for such products. The committee based its advice on an appropriate cut-off for rinse-off preparations on a proposal from the EU SCCS that was yet to be ratified. The submissions received as part of the interim decision consultation period included comment 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. At the time of the December 2015 delegate's final decision the committee noted that should the EU reject these industry 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.

Australian regulatory information

According to the TGA Ingredient Database, methylisothiazolinone (MI) is available for use as an:

• Excipient in biologicals, devices, export only, listed medicines, over-the-counter and prescription medicines; and
• Active pharmaceutical ingredient in biologicals and prescription medicines.

The following restrictions for MI apply to listed medicines:

Only for use in topical medicines for dermal application.
The concentration of methylisothiazolinone in the medicine must be no more than 0.01%.
The total concentration of methylchloroisothiazolinone and methylisothiazolinone in the medicine must be no more than 0.0015%.

MI is in the Therapeutic Goods (Permissible Ingredients) Determination No. 3 of 2017 as follows:

Table 2.6.1: Permissible ingredients and requirements applying to methylisothiazolinone when contained in a medicine

Column 1	Column 2 Ingredient Name	Column 3 Purpose of the ingredient in the medicine	Column 4 Specific requirements(s) applying to the ingredient in Column 2
3303	METHYLISOTHIAZOLINONE	E	Only for use in topical medicines for dermal application. The concentration of methylisothiazolinone in the medicine must be no more than 0.01%. The total concentration of methylchloroisothiazolinone and methylisothiazolinone in the medicine must be no more than 0.0015%.

Methylisothiazolinone is used in 5 proprietary ingredient (PI) formulations and is in 97 Australian Register of Therapeutic Goods (ARTG) entries:

• 21 Export Only products;
• 59 Listed Medicines;
• 14 Medicinal Devices;
• 2 Non-Prescription Medicines; and
• 1 Other Therapeutic Good (OTG) Devices.

Products that contain MI include domestic cleaners, sunscreen, mouth wash, cleansing gels, antiseptic wipes and shampoo.

International regulations

The Korean Ministry of Food and Drug Safety (MFDS) has amended the usage limit of compounds of methylchloroisothiazolinone (MCI) and MI. The compounds are used as preservatives in rinse-off products at maximum level of 0.0015% in a ratio 3:1 of the two substances. In Japan, MI is restricted to a maximum level of 0.01 g/l 00 g (100 ppm [0.01%]) in both wash-off and leave-on cosmetics.

MI has been reviewed and approved for use up to 0.01% (100 ppm) in both leave-on and rinse-off products by the following nations: the Association of South East Asian Nations (ASEAN) (Brunei Darussalam, Cambodia, Indonesia, Laos, Malaysia, Myanmar, the Philippines, Singapore, Thailand, Vietnam), Argentina, Brazil, Canada, Iceland, Israel, Korea, Mexico, Norway, Russia, Switzerland, and Turkey.14

China

According to Hygienic Standard for Cosmetics 2007, the limit level and requirements are same as the original version of (EC) No. 1223/2009. From 1 Dec 2016, Technical Safety Standard for Cosmetics will come into force to replace Hygienic Standard for Cosmetics 2007. The limit level of MI is still 0.01% in cosmetics. The mixture of methylchloroisothiazolinone (MCI) and MI is only available to rinse-off products with the limit level of 0.0015% in a ratio 3:1 of the two substances. For rinse-off products, the mixture of MCI and MI could not be used with additional MI in cosmetics. The requirements are the same as revised (EC) No. 1223/2009 (COMMISSION REGULATION (EU) No 1003/2014 of 18 September 2014).^[10]

USA and the EU

The use of MI in wash-off and leave-on cosmetics in the EU and in the USA is restricted to a maximum concentration of 0.01%.

In 2010, the Cosmetic Ingredient Review expert panel concluded that 'MI is safe for use in cosmetic formulation at concentrations up to 100 ppm (0.01%)' (Cosmetic Ingredient Review (CIR), 2010).

The Scientific Committee on Cosmetic Products and Non-Food Products (SCCNFP) is also of the opinion that 'the proposed use of MI as a preservative at a maximum concentration of 0.01% (100 ppm) in the finished cosmetic product does not pose a risk to the health of the consumer' (SCCS, 2003).

MI was authorised as a preservative in cosmetics products through Annex V, entry 57, of Regulation (EC) No 1223/2009 ("Cosmetics Regulation") at a maximum concentration of 0.01% (100 ppm). The Cosmetics Regulation also authorised the mixture of methylchloroisothiazolinone (MCI) and MI as a preservative in rinse-off cosmetic products at a maximum concentration of 0.0015% (15 ppm) in a ratio 3:1 of the two substances (since 16 July 2015).

The first SCCS opinion related to MI was adopted by the Scientific Committee on Cosmetic Products and Non-Food Products (SCCNFP) in March 2003.

A second SCCS opinion on MI adopted in April 2004 concluded that MI, as a preservative at a maximum concentration of 0.01% (100 ppm) in the finished cosmetic product, does not pose a health risk to the consumer. However, there is an increasing problem all over Europe of sensitization in young children from moist toilet tissue/hygiene moist tissues (wet wipes) and cosmetics. Due to this, the Commission requested that the SCCS reassess the safety of MI at concentrations of 100 ppm.

A third SCCS opinion was adopted in December 2013. The conclusions include but are not limited to:

• 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.
• Information on the actual concentration of MI present in individual cosmetic products will allow future evaluation of safe concentrations.
• Labelling is only helpful to a consumer who has a known (established by diagnostic patch test investigations) allergy. It is unknown what proportion of the general population is now sensitised to MI and has not been confirmed as sensitised
• Consumers cannot find information on the presence of MI in products except in cosmetics and household detergents because, as yet, there is no harmonised classification of MI as a skin sensitiser. The risk for skin sensitisation by MI is at least equivalent to that of other substances which have received a harmonised classification according to the CLP Regulation

In December 2015, the SCCS adopted the fourth opinion. It was concluded that the information provided does not support the safe use of MI as a preservative in rinse-off cosmetic products up to a concentration limit of 100 ppm from the view of induction of contact allergy. For rinse-off cosmetic products, a concentration of 15 ppm (0.0015%) MI is considered safe for the consumer from the point of view of induction of contact allergy. It was not safe to use MI as a preservative in leave-on hair cosmetic products up to a concentration limit of 100 ppm (0.01%) from the point of view of induction of contact allergy.

Substance summary

Methylisothiazolinone (MI) is used in domestic (e.g. car wash soaps, floor finishing/protection products), industrial (e.g. coatings and paint), and cosmetic (e.g. baby wipes, hand and body lotions, shampoos, surfactants and conditioners) products.

Table 2.6.2: Chemical information for methylisothiazolinone

Property	Methylisothiazolinone
Chemical structure
Molecular formula	C4H5NOS
Molecular weight	115.2 g/mol
CAS name	3(2H)-Isothiazolone, 2-methyl
CAS number	2682-20-4
IUPAC and/or common and/or other names	2-methyl-1,2-thiazol-3-one (IUPAC); 2-methylisothiazol-3(2H)-one.

The following information was extracted from the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) human health Tier II assessment report for 3-isothiazolone, 2-methyl-, publicly available on the NICNAS website.

Table 2.6.3: Acute toxicity end-points for methylisothiazolinone

Toxicity	Species	Methylisothiazolinone	SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw)	Rat	209 (183-235)	Schedule 6
Acute dermal toxicity LD50 (mg/kg bw)	Rat	242	Schedule 6
Acute inhalational toxicity LC50 (mg/L/4h)	Rat	0.11	Schedule 7
Skin irritation	Animal and Human	1.7% not corrosive 51.1%-100% corrosive	Schedule 7
Eye irritation	Bovine	100 ppm found as non-irritating. Expectation is that undiluted MI will be severely damaging to the human eye – classification: severely damaging.	Schedule 7
Skin sensitisation (LLNA)	Mouse	Buehler test positive at 1000 ppm or higher GPMT not a sensitiser at concentrations up to 800 ppm EC3 0.4% (acetone and olive oil) EC3 2.2% PG solution HRIPT up to 600 ppm did not cause dermal sensitisation, but once sensitised, the lowest eliciting dose of 49ppm has been observed (CIR, 2010) Strong sensitising potential	Schedule 6

Toxicokinetics

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 concentrations 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 oral toxicity

MI 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). MI (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, MI is recommended for classification as hazardous with the risk phrase 'Toxic if swallowed' (T; R25) in HSIS (Safe Work Australia).

Acute dermal toxicity

MI 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. MI (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, MI is recommended for classification as hazardous with the risk phrase 'Toxic in contact with skin' (T; R24) in HSIS (Safe Work Australia).

Acute inhalation toxicity

MI 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, MI is recommended for classification as hazardous with the risk phrase 'Very toxic by inhalation' (T; R26) in HSIS (Safe Work Australia).

Skin irritation

Based on the available data, MI is recommended for classification as hazardous with the risk phrase 'Causes burns' (R34) in HSIS (Safe Work Australia).

MI was applied undiluted as a single semi-occluded application of 0.5 mL to shaved intact skin of New Zealand White rabbits for 3 minutes, 1 hour, and 4 hours. The 3-minute exposure resulted in a very slight to well-defined erythema through to day 7 and slight oedema at 1 and 48 hour observations. At 1 and 4 hour exposures to MI, 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 MI for three or 60 minutes was not corrosive to the skin. However, MI was corrosive at higher concentration of 51.1% at an exposure period of 60 minutes (CIR, 2010).

Eye Irritation

MI is recommended for classification as corrosive. It is expected that undiluted MI will be severely damaging to the eyes.

MI (undiluted) was found to be an irritant in a bovine cornea study measuring opacity and permeability. Eye irritation studies using formulations containing MI at 100 ppm (body lotion, shampoo and sunscreen) were found non-irritating (CIR, 2010).

Skin sensitisation

MI 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 (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).

MI, 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, it 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, MI was allowed in cosmetic products in the EU at a maximum concentration of 100 ppm in 2005(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 MI (see Sensitisation: observation in humans). The permitted use of MI at 100 ppm in cosmetic products is approximately 25-fold the permitted concentration of MI in the MI/MCI combination (3.75 ppm MI in 15 ppm of MI/MCI).

MI, 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 MI in industrial products. MI-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 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 MI in the form of 6 hours' induction with three doses each week for 3.5 weeks under an occlusive condition. MI 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 MI 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 MI 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 MI. After a week, the treated animals were given a single 24-hour topical exposure to 0.1 mL of MI 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 500 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, MI 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 MI is a potential skin sensitiser. In one study, female CBA/Ca mice were treated with MI (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 MI, 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 MI for acetone and olive oil (4:1; v/v) and PG solutions, respectively. It was concluded that MI has strong sensitising potential, with potency being comparable to that of the formaldehyde although much lower than the mixture of MI with MCI in 1:3 ratio. Similar findings were noted in another study, indicating that MI 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 MI is a potential skin sensitiser.

Observation in humans

Contact allergy to MI 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 facial dermatitis, and the use of cosmetics. Additionally, MI was named the 2013 "Contact Allergen of the Year" by the American Contact Dermatitis Society, indicating increased incidence of MI-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 MI (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 MI 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 MI. In addition, a lowest eliciting dose of 1.47 µg of MI (49 ppm) was observed in a sensitisation studies conducted in 11 MI-allergic patients (CIR, 2010).

MI has been reported to be an emerging and important allergen in both cosmetic and occupational settings in Australia. Baby wipes and facial wipes containing MI 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 MI. It was concluded that the continued use of MI 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 MI (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 MI (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 MI is now the most common cause of allergic contact dermatitis in their patient population (Cahill et al., 2014).

The SCCS presented its opinion on the safety of MI in consumer products. The committee concluded that, on the basis of current clinical data, the use of MI 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 MI for induction of contact allergy or elicitation have not been adequately demonstrated. Although a concentration of 15 ppm (0.0015%) of MI 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

Repeated dose toxicity – Oral

Based on the available data, MI 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 MI (up to 1000 ppm, equivalent to 65.7 and 93.5 mg/kg bw/day in males and females, respectively) in drinking water for 3 months. Dogs fed with diets prepared with MI 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 MI. Based on the available toxicity study for the analogue chemical (3:1 mixture of methylchloroisothiazolinone and MI, CAS No. 55965-84-9), in which there was no evidence of toxicity; MI is not considered to cause serious damage to health from repeated exposure.

A formulation containing the 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 MI. 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, MI 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).

Genotoxicity

Based on the weight of evidence from the available in vitro and in vivo genotoxicity studies, MI is not considered to be genotoxic.

MI was not mutagenic in Ames tests in Salmonella typhimurium, with or without metabolic activation (CIR, 2010; SCCNFP, 2003). MI (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).

MI was reported to be negative in an in vivo mouse micronucleus assay (CIR, 2010; SCCNFP, 2003).

Carcinogenicity

No data are available for MI. Based on the weight of evidence from the available carcinogenicity study for the analogue chemical (3:1 mixture of methylchloroisothiazolinone and MI, CAS No. 55965-84-9), in which there was no evidence of carcinogenicity; MI 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 MI (CIR, 2010).

Reproductive and developmental toxicity

MI 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 MI (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 MI 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).

Neurotoxicity

An acute in vitro neurotoxicity study of MI using cultures of embryonic rat (SD) cortical neurons and glia observed widespread neuronal 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 MI concluded that prolonged exposures to MI and related isothiazolones may damage developing nervous systems (based on cell death observed in cultures treated with 3 µM concentration of MI 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.

Pre-meeting public submissions

Four (4) public submissions were received, two (2) in support and two (2) opposed.

Main points in support:

• Both submissions did not oppose the proposed amendment. However, it was requested that the decision be deferred until the EU restriction is finalised and the legislation is European law.
• One submission noted that clarification is required for the ongoing requirement of Appendix F warning, as the proposed concentration cut-off is considered safe, therefore deeming the warning unnecessary.
• Both submissions requested a realistic implementation date of 24-30 months.

Main points opposed:

• Australian cosmetic market is relatively small compared to major trading partners. Therefore, making regulatory decisions ahead of the EU could have a major impact across the industry.
• The EU decision is currently not known.
• Both submissions proposed for the committee and delegate to defer making the decision until the EU restriction has been finalised to allow alignment of both the concentration exemption level and the implementation timing of decision.
• One submission requested that any scheduling decision to include an adequate transition period of 12-24 months to allow for the reformulation of products.

The public submissions will be made available on the TGA website.

Summary of ACCS-ACMS advice to the delegate

The committee recommended that the Schedule 6 entry for methylisothiazolinone due to be implemented on 1 October 2017 stands, but that from 1 June 2018 the exemption cut-off of 0.01 per cent for rinse-off cosmetic preparations or therapeutic goods intended for topical rinse-off application be amended to 0.0015 per cent as follows:

The committee also recommended an implementation date of 1 June 2018.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice were:

• While preservatives are required in cosmetic and topical therapeutic products, MI has been found to be unsafe as a stand-alone preservative based on human data.
• MI is an effective biocide and preservative, is widely used in products intended for skin contact, but is a well-documented cause of contact allergy. Risk management through scheduling is therefore necessary to mitigate risk whilst allowing limited continued use.
• The incidence of skin sensitisation in human populations from MI use has been unacceptable. The acute toxicity parameters for MI are consistent with Schedule 6 factors. In particular the in vitro/animal study and human case reports and epidemiological evidence indicates that MI is a strong skin sensitiser.
• A low level exemption cut-off will limit MI use in cosmetics and therapeutic goods intended for rinse off skin application and minimises risk of induction of contact allergy.
• The proposed schedule entry will result in equivalent outcome to recently announced amended EU cosmetic regulation.
• There is a disparity between elicitation concentration seen by dermatologists test and induction seen in products.^[11]

Delegate's considerations

The delegate considered the following regarding this proposal:

• Scheduling proposal
• ACCS-ACMS advice
• Public Submissions received
• Section 52E of the Therapeutic Goods Act 1989
• Scheduling Policy Framework (SPF 2015)
• Other relevant information

Delegate's interim decision

The delegate's interim decision is that the Schedule 6 entry for methylisothiazolinone due to be implemented on 1 October 2017 stands. However, from 1 June 2018 the exemption cut-off of 0.01 per cent for rinse-off cosmetic preparations or therapeutic goods intended for topical rinse-off application be amended to 0.0015 per cent. The proposed Schedule entry is as follows:

The proposed implementation date is 1 June 2018. A later implementation date allows for industry alignment.

The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate 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; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the interim decision are:

• While preservatives are required in cosmetic and topical therapeutic products, MI has been found to be unsafe as a stand-alone preservative based on human data.
• MI is an effective biocide and preservative, is widely used in products intended for skin contact, but is a well-documented cause of contact allergy. Risk management through scheduling is therefore necessary to mitigate risk whilst allowing limited continued use.
• The incidence of skin sensitisation in human populations from MI use has been unacceptable. The acute toxicity parameters for MI are consistent with Schedule 6 factors. In particular the in vitro/animal study and human case reports and epidemiological evidence indicates that MI is a strong skin sensitiser.
• A low level exemption cut-off will limit MI use in cosmetics and therapeutic goods intended for rinse off skin application and minimises risk of induction of contact allergy.
• The proposed schedule entry will result in equivalent outcome to recently announced amended EU cosmetic regulation.
• There is a disparity between elicitation concentration seen by dermatologists test and induction seen in products.^[11]
• The EU adopted the SCCS 4^th opinion position on 6 July 2017, and requires all products in the EU market to be compliant by 27 April 2018.

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