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Scheduling delegate's final decisions. ACMS/ACCS, December 2015
Scheduling medicines and poisons
1.2 Methylchloroisothiazolinone (MCI)
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)
1.2 Methylchloroisothiazolinone (MCI)
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):
- to create a scheduling entry to prevent the use of methylchloroisothiazolinone when used in rinse-off cosmetics/personal care products or domestic products at concentrations above 0.0015%, and
- to create a schedule entry parallel to the restrictions for methylisothiazolinone for leave-on cosmetic/personal care products.
The reasons for the request were:
- the scheduling issue raised in relation to methylchloroisothiazolinone (MCI) have much in common with those raised by methylisothiazolinone (MI) and should be addressed by the ACCS/ACMS after consideration of MI.
Scheduling of the closely related preservative methylisothiazolinone (MI) was first referred to the July 2014 meeting of the ACCS, but this is the first time that methylchloroisothiazolinone (MCI) has been considered. The two preservatives are often used together in a proprietary 1:3 MI/MCI combination.
Skin sensitisation potential has been identified as the key toxicological issue, driving towards listing in Schedule 6 according to SPF criteria. Both the EU SCCS and US CIR have considered possible sensitisation thresholds for leave-on and rinse-off cosmetics containing MI and MCI at various times, although the detailed consideration of MCI is not so recent.
The delegate asked the committee the following questions:
- 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 methylchloroisothiazolinone. Is there sufficient evidence that MCI may be a more potent sensitiser than MI, and therefore require lower cut-offs? Given the difficulty of discriminating between the sensitisation potential of MCI when used alone, rather than in a MI/MCI combination, should the cut-offs for MCI mirror those recommended for MI?
- 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?
- Does the ACCS/ACMS advise that any schedule listing for methylchloroisothiazolinone 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)?
- Noting that methylchloroisothiazolinone 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?
- What weight should be given to the apparent lack of adverse reaction reports associated with the use of MCI in therapeutic goods (Attachment Y)?
- What regulatory impact might be expected in relation to registered AgVet products, given APVMA advice that the maximum concentration of MCI is of the order of 0.1-0.2% (Attachment X)?
For the full NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) human health Tier II assessment report for 3(2H)-Isothiazolone, 5-chloro-2-methyl-, refer to the NICNAS website.
Figure 1: Chemical structure of methylchloroisothiazolinone
Toxicokinetic studies in rats using the chemical (CAS No. 26172-55-4) 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-methylmalonamic 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. The chemical is widely distributed to all tissues in the body, with the highest level in the liver and lowest in the bone. It is eliminated within 24 hours mainly through urine, followed by bile and, finally, faeces.
An in vitro human skin absorption study conducted in accordance with OECD Test Guideline (TG) 428 reported maximum potential systemic bioavailability of the chemical as 84.5% of the applied dose (NICNASa; SCCS, 2009).
Acute toxicity - Oral
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).
The analogue (3:1 mixture of methylchloroisothiazolinone and methylisothiazolinone, MCI/MI-CAS No. 55965-84-9) had high acute toxicity in animal tests using oral exposure. Two studies where rats were administered the analogue chemical at 14% reported the median lethal dose (LD50) at 64 mg/kg bw (69 mg/kg bw for male and 59 mg/kg bw for female rats). Observed sub-lethal effects included gastric irritation, lethargy and ataxia (CIR, 1992; SCCNFP, 2009).
Acute toxicity - Dermal
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).
The analogue chemical (MCI/MI, CAS No. 55965-84-9) had high acute toxicity in animal tests using dermal exposure. A study administered in rats using the analogue chemical as 14% reported the LD50 at 141 mg/kg bw for both sexes. A similar study (administered as a 1.5% formulation) in rabbits reported the LD50 as 113 mg/kg bw (CIR, 1992; SCCNFP, 2009).
Acute toxicity - Inhalation
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).
The analogue chemical (MCI/MI, CAS No. 55965-84-9) exhibited high acute toxicity in animal tests using inhalation exposure. The median lethal concentration (LC50) in rats after a four-hour aerosol exposure was reported as 0.17 mg/L (IUCLID, 2000). Another study in rats reported the LC50 as 0.33 mg/L after a four-hour aerosol exposure. The major signs of toxicity were marked dyspnoea, salivation and death, and the principal lesions included pulmonary congestion, oedema, and haemorrhages (CIR, 1992; SCCS, 2009).