Scheduling delegate's final decisions. ACMS/ACCS, December 2015

Scheduling medicines and poisons

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8 December 2015

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)

Scheduling proposal

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)?
Substance summary

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

Figure 1: Chemical structure of methylchloroisothiazolinone

Toxicokinetics

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).

Corrosion/Irritation - Skin irritation
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 analogue chemical (MCI/MI, CAS No. 55965-84-9) was found to be corrosive to rabbit skin when applied as a single semi-occluded application (at concentrations of 1.5% and 14%) to shaved intact skin of New Zealand White rabbits in several studies (CIR, 1992; IUCLID, 2000). No other details were specified.

Corrosion/Irritation - Eye irritation

The chemical is recommended for classification as corrosive. It is expected that the undiluted chemical would be severely damaging to the eyes.

The analogue chemical (MCI/MI, CAS No. 55965-84-9) was found to be corrosive to rabbit eyes in numerous Draize eye irritation studies using concentrations ranging from 1.1% to 14% (560–56,000 ppm). An aqueous dilution of 0.0056% (56 ppm) was found non-irritating when tested in rabbit eyes for a period of four weeks (five days per week) (CIR, 1992).

The analogue chemical (CAS No. 55965-84-9) (undiluted) was also found to be an irritant in a bovine cornea study that measured opacity and permeability (CIR, 2010).

Sensitisation - Skin sensitisation

The chemical is considered to be a skin sensitiser based on the positive results seen in several animal (guinea pig maximisation tests, Buehler test and local lymph node assays) and human studies.

In an in vitro assay, the chemical (MCI, CAS No. 26172-55-4) was found to be highly reactive towards glutathione, histidine and lysine and formed stable adducts (CIR, 2010).

A modified Buehler guinea pig maximisation test using Dunkin-Hartley guinea pigs found the chemical (MCI) to be a strong sensitiser at 0.1%. A re-challenge with the chemical found that 50% of the animals reacted to a lower concentration of 0.02% (CIR, 2010).

A local lymph node assay (LLNA) study showed that the chemical (MCI) induced a strong lymph node cell proliferation in mice which correlated with protein binding and a guinea pig sensitisation assay (Potter and Hazelton, 1994). The PC200value (the concentration that produces a two-fold increase in mouse lymph node cell proliferation over controls) was 11 µg. The concentrations required to induce (IC50) and elicit (EC50) a response in 50% of guinea pigs was 774 and 38 µg, respectively.

In an LLNA study with the analogue chemical (MCI/MI, CAS No. 55965-84-9), EC3 values (an estimated concentration that will induce a stimulation index of 3 following topical application of the chemical) of 0.0082 (in acetone and olive oil vehicle) and 0.063 (propylene glycol vehicle) were determined. The chemical was characterised as a strong sensitiser. The data obtained correlated with cytokine profiling indicative of a skin sensitiser (NICNASa).

Observation in humans

The chemical has been reported to be a sensitiser in both cosmetic and occupational settings (NICNASa).

Data from multiple research centres conducted between 2010 and 2013 in Europe illustrates a rise in the frequency of sensitisation to the chemical from 4.4 to 8.3%. Further, other pan-European data conducted between 2006 and 2008 illustrates a high prevalence of sensitisation (approximately 2-2.5%) in eczema patients (SCCS, 2013).

In a study, 22 patients who were positive for sensitisation to the analogue (MCI/MI) were patch tested with the chemical at 300 ppm and all reacted positively. A follow up study showed that of 12 patients previously sensitised to MCI/MI, all tested positive for the MCI/MI at 150 ppm (SCCS, 2013).

Results from several patch tests indicate that the chemical has a strong potential to cause skin sensitisation and which correlated with the Open Epicutaneous Test (OET) (SCCS, 2013; NICNASa).

Further, patients sensitised to MI also react to MCI while the opposite is not necessarily true (SCCS, 2013).

Repeated dose toxicity - Oral

Based on the available data, the chemical is not considered to cause serious health damage from repeated oral exposure.

No treatment-related effects were observed in rats (Charles River CD) exposed for three months to MCI/MI (up to 800 ppm, equivalent to 29 mg/kg bw/day) in their diet.

In a drinking water study, no signs of adverse effects to any tissues or organs distant from the site of dosing were observed in rats (COBS SD) exposed to up to 225 ppm (20.5 mg/kg bw/day) of MCI/MI for three months.

Dogs fed with diets prepared with MCI/MI for three months showed no signs of systemic toxicity up to the highest tested dose levels of 30 mg/kg bw/day (SCCS, 2013).

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 dermal toxicity, the chemical is not considered to cause serious damage to health from repeated exposure through this route (NICNASa).

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 (NICNASa).

Genotoxicity

Based on the weight of evidence from available in vitro and in vivo genotoxicity studies the chemical is not considered to be genotoxic (CIR, 1992; NICNASa; SCCS, 2009).

The genotoxic potential of the chemical was evaluated in several Ames (reverse mutation) tests with Salmonella typhimurium strains TA1535, TA1537, TA98 and TA100. The chemical was mutagenic in the strain TA100 only without metabolic activation. MCI/MI (CAS No. 55965-84-9) was mutagenic to strain TA100 and Escherichia coli in the Ames test. MCI/MI also resulted in an increase in the mutant frequency in two gene mutation tests (mouse lymphoma cell line) both in the absence and presence of metabolic activation. An in vitro unscheduled DNA synthesis (UDS) assay using primary rat hepatocytes treated with MCI/MI was negative. MCI/MI showed no clastogenic activity when evaluated in an in vitro chromosome aberration test using Chinese hamster lung cells.

MCI/MI in vitro studies yielded positive results that in vivo tests did not confirm. MCI/MI showed negative results in micronucleus tests (mouse), chromosome aberration tests (mouse and rats), sex-linked recessive lethal tests in Drosophila Melanogaster and in two UDS studies in the rat.

Based on results from negative in vivo mutagenicity studies, along with negative carcinogenicity study for the analogue, the chemical is not considered to be genotoxic.

Carcinogenicity

No data are available for the chemical. The weight of evidence from the available carcinogenicity study for the analogue chemical - 3:1 mixture of methylchloroisothiazolinone and methylisothiazolinone (MCI/MI, CAS No. 55965-84-9) - indicates there was no evidence of carcinogenicity. As this analogue contains the chemical at high concentrations, it also is not likely to be a carcinogen (NICNASa).

Reproductive and developmental toxicity

No data are available for this chemical. The weight of evidence from the available studies for the analogue chemical (MCI/MI, CAS No. 55965-84-9) indicates that the chemical is not a specific reproductive or developmental toxin. As this analogue contains the chemical at high concentrations, it also is not likely to be a reproductive or developmental toxin.

In a two-generation reproductive toxicity study, no treatment-related effects were noted in rats (Crl:CD BR strain) exposed to MCI/MI in drinking water (up to 300 ppm). A no observed adverse effect level (NOAEL) of 30 ppm was determined based on gastric irritation of the stomach at higher doses. The no observed effect level (NOEL) for reproductive toxicity was 300 ppm (the highest dose tested). There were no effects on fertility or foetal developmental parameters at any dose tested (SCCS, 2009).

Several teratogenicity studies showed no treatment-related effects in rats and rabbits exposed to MCI/MI. Pregnant rabbits administered with MCI/MI by gavage up to doses of 13.3 mg/kg bw/day, showed maternal toxicity at all doses. No visceral or skeletal malformations were found in the foetuses at any dose level. Pregnant Sprague Dawley (SD) rats exposed to MCI/MI by gavage (up to 15 mg/kg bw/day) showed maternal toxicity at all dose levels. Based on the absence of any treatment-related effects on surviving dams and foetuses, a developmental NOEL of 15 mg/kg bw/day was determined (CIR, 1992; SCCS, 2009).

Risk characterisation - Critical health effects

The critical health effect for risk characterisation is skin sensitisation. The chemical may also cause systemic acute toxicity (by all route of exposure) and local effects (skin corrosion and possibly serious eye damage).

Risk characterisation - Public risk characterisation

The available information indicates that the chemical is widely used in Australia as a preservative in cosmetic, personal care (including baby products), cleaning and laundry products. The chemical is reported to be used in cosmetic/domestic products overseas at concentrations up to 0.1% (HHDB).

Considering the range of domestic and cosmetic and personal care products that could contain the chemical, the main route of public exposure is expected to be through the skin and inhalation from products applied as aerosols.

In the absence of any regulatory controls, the characterised critical health effect (skin sensitisation) has the potential to pose an unreasonable risk to the public through the identified uses.

The risks could be mitigated by implementing concentration limits and restricting uses to rinse-off products.

Risk characterisation - Occupational risk characterisation

During product formulation, dermal, ocular and inhalation exposure of workers to the chemical may occur, particularly where manual or open processes are used. These may include transfer and blending activities, quality control analysis, and cleaning and maintaining of equipment. Worker exposure to the chemical at lower concentrations can also occur while using formulated products containing the chemical. The level and route of exposure will vary depending on the method of application and work practices employed.

Given the critical systemic long-term, acute and local health effects, the chemical could pose an unreasonable risk to workers unless adequate control measures to minimise dermal, ocular and inhalation exposure to the chemical are implemented. The chemical should be appropriately classified and labelled to ensure that a person conducting a business or undertaking (PCBU) at a workplace (such as an employer), has adequate information to determine appropriate controls.

International regulations

The use of MCI/MI (CAS No. 55965-84-9), a 3:1 mixture of methylchloroisothiazolinone (MCI) and methylisothiazolinone (MI) is currently regulated in the EU with a maximum authorised mixture concentration of 0.0015% (SCCS, 2009).

MCI/MI is currently permitted at levels =0.0015% (15 µg/mL or 15 ppm) in rinse-off products and =0.00075% (7.5 µg/mL or 7.5 ppm) in leave-on products (Health Canada, 2011).

The Expert Panel of the Cosmetic Ingredient Review (CIR) recommended a concentration of 15 ppm MCI/MI (76.7% MCI and 23.3% MI) for cosmetic rinse-off products and =7.5 ppm in cosmetic leave-on products (CIR, 1992).

The following exposure standards are identified (Galleria Chemica):

  • An exposure limit - TWA of 0.2 mg/m3 and STEL of 0.4 mg/m3 was identified in Switzerland.
Scheduling status

Methylchloroisothiazolinone (MCI) is not specifically scheduled.

Scheduling history

Methylchloroisothiazolinone (MCI) has not been previously considered for scheduling.

Methylisothiazolinone, another similar chemical, is being re-considered for scheduling. In July 2014, the 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 delegates noted the committee's recommendation and public submissions and noted that the sensitising potential is the key driver for any scheduling action. The delegates decided to defer further consideration of scheduling methylisothiazolinone pending the publication of the final US CIR decision.

Pre-meeting public submissions

Four public submissions were received. Most submissions pointed to the current international standards in place for MCI/MI mix, such as it is permitted at 15 ppm or less for rinse-off products or 7.5 ppm or less for leave-on products. MCI/MI mix was requested to be exempt from scheduling in industry products such as paints, adhesives, sealants, at 15 ppm or less; this is what is currently in use.

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.

Edited versions of these submissions are available at Public submissions on scheduling matters.

Summary of ACCS/ACMS advice to the delegates

The committee recommended methylchloroisothiazolinone be considered a derivative of methylisothiazolinone and be cross referenced with 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

As with methylisothiazolinone (MIT), the key issue driving the need to regulate methylchloroisothiazolinone (MCIT) by scheduling is its sensitisation potential. The two substances were considered together by the ACCS/ACMS and this interim decision should be read in conjunction with that for MIT. The delegates accepted the advice from the ACCS/ACMS that MCIT should be listed in Schedule 6, with exemption cut-offs comparable to MIT. The delegates also noted that MCIT is not used as a preservative by itself, but usually in combination with MIT. Accordingly, the delegates determined that the cut-offs applied to MCIT should refer to the combined concentrations.

The delegates noted that the industry request for a cut-off of 7.5 ppm (0.00075 per cent) for leave-on products is not necessary, because of the general exemption (0.001 per cent) provided in Part 1 2(j) of the Poisons Standard.

Delegates' considerations

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 factors2;
  • Other relevant information.
Public submissions on the interim decision

Two submissions were received. Both submissions supported the delegates' interim decision. One submission proposed re-wording to Appendix F entry for MCI and noted that the proposed exemption cut-off of 0.0015% for products not intended to be applied to the skin may have been an editorial error, if consistency with the scheduling decision was the intent.

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:

  1. the wording of clause (b) to clarify that the proposed exemption cut-off should be 0.1% and that this only applies to products that are not intended to be applied directly to human skin;
  2. 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 delegates note that none of the three submissions raised objection to the proposed exemption cut-off of 0.0015% for methylchloroisothiazolinone (MCI). This is presumably because this concentration currently aligns with international regulations relating to MCI, or there is not much use of MCI in products sold in Australia (despite advice available to the ACCS that there is some use of MCI in some cosmetics and sunscreens).

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 MCI 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 0.0015% or less MCI in combination with MI) 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 MCI 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.

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 0.0015%. 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 0.0015% 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 dated is fixed by the date proposed for publication of the Poisons Standard.

Schedule entry
Schedule 6 - New Entry

METHYLCHLOROISOTHIAZOLINONE in leave-on cosmetic products or therapeutic goods intended for leave-on topical application, except in preparations containing 0.0015 per cent or less of methylchloroisothiazolinone and methylisothiazolinone in total.

Appendix F, Part 3 - New Entry
Poison Warning statements Safety direction
METHYLCHLOROISOTHIAZOLINONE 28 (over)(repeated) exposure may cause sensitisation

Implementation date: 1 June 2016.

Schedule 6 - Amend Entry

METHYLCHLOROISOTHIAZOLINONE except:

  1. in rinse-off cosmetic preparations or therapeutic goods intended for topical rinse-off application containing 0.0015 per cent or less of methylchloroisothiazolinone and methylisothiazolinone in total; or
  2. in other preparations that are not intended for direct application to the skin containing 0.1 per cent or less of methylchloroisothiazolinone and methylisothiazolinone in total.

Implementation date: 1 October 2017.


Footnotes

  1. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)

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