Therapeutic Goods Administration - Public Consultation on ... · Therapeutic Goods Regulations 1990...

Public Consultation on the Proposed Amendments to the Poisons Standard

Notice under subsections 42ZCZL of the Therapeutic Goods Regulations 1990 (the Regulations)

A delegate of the Secretary to the Department of Health publishes herein all valid public

submissions made in response to the invitation for public submissions on the proposedamendments to the Poisons Standard. These submissions were considered by the Advisory Committee on Chemicals Scheduling (ACCS) #15 (November 2015 meeting).

In accordance with the requirements of subsection 42ZCZL of the Regulations these

submissions have had confidential information removed.

Material claimed to be commercial-in-confidence was considered against the guidelines for

the use and release of confidential information set out in Chapter 6 of the Scheduling

Policy Framework for Medicines and Chemicals (SPF, 2015), issued by the Australian

Health Ministers Advisory Council (AHMAC). The SPF is accessible at: https://www.tga.gov.au/publication/ahmac-scheduling-policy-framework-medicines-and-chemicals.

PROPOSED AMENDMENTS TO THE POISONS STANDARD (CHEMICALS)

JOINT ACCS/ ACMS MEETING- 9 OCTOBER 2015

Part 2, Section 1 (Labels) 1.5 (Exemptions) 8 Paints

The .. supports the amendment however we seek an implementation date of 1 January 2020. This will provide sufficient time for ou r indust ry to re-label products that ut i lise the current exemption .

The Secretary 29th

October 2015

Medicines and Poisons Scheduling

Office of Chemical Safety (MDP 88)

GPO Box 9848

CANBERRA ACT

2601

Dear Sir/Madam,

RE: Comments on proposed amendments referred by the Delegate for scheduling

advice for consideration by the Advisory Committee on Chemicals Scheduling

(ACCS) November 2015 meeting

would like to provide comments on the proposed

amendments referred by the Delegate to the Committee of Chemicals Scheduling (ACCS).

SCHEDULE 5

Isethionate (2-hydroxyethanesulfonic acid)

2-hydroxyethanesulfonic acid

2-hydroxyethanesulfonic acid is used in the manufacture of mild and high foaming anionic

surfactants and cleansing agents used in cosmetics. It is common that this parent acid is

used to form different isethionate salts.

The scheduling proposal for listing refers to a schedule 5 entry of isethionate (2-

hydroxyethanesulfonic acid). The proposal has not clarified which isethionate compounds

are affected. According to Part 1 section 2 of the Poisons Standard, reference to a substance

in a schedule includes its salts and derivatives unless otherwise stated. suggests that the

proposed schedule entry for isethionates be clarified and if scheduling is necessary, to

include an appropriate cut-off concentration if personal care products are affected.

Unique Australian requirements should not be set for ingredients in cosmetic products

unless a clear safety issue or unacceptable hazard or risk has been identified. The US

Cosmetic Ingredient Review (CIR) Expert Panel has reviewed the product use, formulation

and safety data of twelve isethionate salts, which mostly function as surfactants and

cleansing agents in cosmetic products. The Panel concluded that isethionate salts were safe

as cosmetic ingredients in the present practices of use and concentration, when formulated

to be non-irritating.

Summary

In summary, recommends that 2-hydroxyethanesulfonic acid remains unscheduled until

further clarification is made available to define what isethionate is recommended for

scheduling and the safety risks associated to propose a schedule 5 entry in the SUSMP.

Additionally, should the Committee and Delegate decide to proceed with the proposals,

current cosmetics in the market should not be impacted. Appropriate transition times

should be given to allow sponsors and manufacturers to implement the changes for new

products.

Yours faithfully,

Reply to Evaluation of Rat dilated renal pelvis

Date September 17, 2015

In the evaluation of the 2-generation study of Topramezone OCS has concluded

that dilated renal pelvis is a malformation that occurred at concentrations that were devoid of

significant maternal toxicity.

It is also stated that other HPPD inhibitors do not show similar effects, basing that on the

evaluation of Mesotrione, another HPPD inhibitor.

disagrees on several points with this evaluation.

OCS classified dilated renal pelvis as a malformation. This is against global standards in which

dilated renal pelvis is defined as a variation, but not a malformation (please the the DevTox

database: DevTox.Nomenclature: Selection of diagnoses). The DevTox Project was initiated by

the German Federal Ministry of Food, Agriculture and Consumer Protection (BMELV) and the

Federal Ministry of the Environment, Nature Conservation and Nuclear Safety (BMU) under the

auspices of the International Programme on Chemical Safety (IPCS).Secondary. The updated

harmonized nomenclature for developmental toxicology, based on the revised IFTS terminology

(Makris et al. 2009): More than 2.500 images show examples for external, skeletal, soft tissue

and maternal-fetal anomalies [last update October 2012].

In the original MOA framework for tyrosine mediated toxicity we have already pointed out that

dilated renal pelvis is highly associated with tyrosine mediated toxicity. OCS pointed out that this

is not the case, referring to Mesotrione.

has researched other recent global registration documents for HPPD-Inhibitors.

Actually the 2-generation study of Mesotrione shows increased macroscopic and microscopic

hydronephrosis in the pups (EPA; Mesotrione Registration Toxicology Disciplinary Chapter

2001). According to the DevTox-Database hydronephrosis and dilated renal pelvis are synonyms

for the same findings (see screenshot from the DevTox database below)

Dilated renal pelvis is also reported for the HPPD-Inhibitor Tembotrione in the rat in both the F1

and F2 generation(DAR 2008). The same holds true for the rat multigeneration study of with

Sulcotrione where the finding was observed in all generations (Sulcotrione DAR; 2006).

On the contrary the mouse did not demonstrate any effect on renal hydronephrosis with any of

the compounds mentioned above.

The presence of the effect in all multigeneration studies of HPPD-Inhibitors with the absence of

this effect in the mouse which does not develop such high tyrosine concentrations indicates that

dilated renal pelvis is associated to the highly elevated tyrosine levels in the rat.

In a recent evaluation of Bicylcopyrone, another HPPD-inhibitor, US EPA confirmed previous

evaluations that tyrosinemia in animals results in ocular, developmental, liver and kidney effects

(EPA, Bicyclopyrone Mesotrione Registration Toxicology Disciplinary Chapter D421265; 2015).

Tyrosinemia should also be considered to represent significant maternal stress/toxicity. This has

been confirmed in the review process by different global authorities around the globe, including

EU member states, EPA and Japan. Therefore, the statement that dilated renal pelvis occurred at

a dose devoid of maternal toxicity is not correct.

In summary, the finding of dilated renal pelvis occurs at maternal toxic concentrations, should be

considered a variation and not a malformation and is secondary to tyrosinemia.

Consequently dilated renal pelvis, like all other tyrosine dependent effects should be regarded as

not human relevant. Therefore, they should not be used for the derivation of reference values and

the NOAEL from the developmental rabbit studies should be used instead.

14 October 2015

CoJmn:utt~~e on Chemicals Scheduling c/o Chemicals Scheduling Secretariat Therapeutic Goods Administration PO Box 100 Woden, ACT, 2606

Email: [email protected]

Public Comment submissions to November 2015 meeting ofthe Advisory Committee on Chemicals Scheduling (ACCS)

We refer to the pre-November 2015 ACCS Meeting notice inviting public submissions with respect to celtain substances, addressing a matter raised in s.52E of the Therapeutic Goods Act 1989.

to provide infmmation for ACCS consideration for the ma.ttei·sfSlLibstances adctressedin the attached submission.

oppmtumty for :fi.uther submissiOn, if appropriate.

Should the cmmnittee require any additional this stage please do not hesitate to contact me on

Y oms sincerely,

Page 1 ct5

Advisory Committee on Chemicals Scheduling Meeting: 17-19 November 2015

Agenda Item Amisulbrom- The scheduling proposal is to create a new Schedule 6 entry for amisulbrom.

~notes the cmTent proposal to classify arnisulbrom as a new en1Iy in

Public submissions that address matters mentioned in section 52E of the Therapeutic Goods Act 1989 have been invited.

S52E (1) (a) the risks and benefits associated with the use of a substance

The cormnittee may take into account the risks and benefits associated with the use of a substance Section 52E (1) (a).

One of the great benefits of this new molecule is its con1I1bution to resistance management. Amisulbrom is a sulfonarnide derivative and has been developed for the conu·ol of Oomycete pathogens. Ainisulbrom con1Ids plant pathogens through the inhibition of mitochomh1al respiration. It belongs to a new group lmown as the quinone inside inhibitors (Qil) and is classified as a member of Group 21 lmder the FRAC code. Cyazofarnid is the only other member of this group. The Qil compounds do not exhibit cross resistance to the quinone outside inhibitor (Qol) compmmds which is an impoltant distinction.

Diseases in agt1cultme can develop resistance quickly if the same chemis1Iy is used multiple times in succession without the use of other che1nis1Iy. This new molecule lends its self to mixtures with existing chemis1I1es which will delay the development of resistance (as two modes of action are being used in a combined spray). This will promote the longevity of other chemis1I1es as well as b1mg new cheinis1Iy to the "tool box" for disease management in ag~.·iculture .

S52E (1) (b) the purposes for which a substance is to be used and the extent of use of a substance

The cormnittee may take into account the pmposes for which a substance is to be used and the extent of use of a substance Section 52E (1) (b).

This product fi.mctions to con1Id oomycetes and is a mitochondi1al respiration inhibitor and belongs to a new class of che1nis1Iy, the sulfamoyl-1I1azoles.-have conducted research for use patterns as a protectant fi.mgi.cide in g~.·apes and brassica ~e crops for downy mildew, and for white blister in brassica vegetable crops. The brassica vegetable crops include broccoli, cauliflower, head cabbage and Bmssels sprouts.

The proposed end use product contains 32g!L runisulbrom (and 1I1basic copper sulphate- a different mode of action) and is proposed for use at 2llha in brassica vegetable crops and 250mll1 OOL in g~.·apes, which u·anslates to 64g a.i.lha and 80g a.i.lha arnisulbrom per application, respectively. The proposed label res1I1cts the use in grapes to a maximmn of three applications per crop, and in brassica vegetable crops to a maximmn of fom applications per crop (with no more

Page2ct5

than two consecutive applications). The restriction on the mnnber of applications is to conse1v e the efficacy of this chemistry and prevent resistance developing.

S52E (1) (c) the toxicity of a substance The cormnittee may take into account the toxicity of a substance Section 52E (1) (c).

The Office of Chemical Safety ( OCS) have evaluated amisulbrom and proposed a cautious approach and recommended a schedule 6 entiy into SUSMP. The repmt evaluates eve1y aspect of toxicology and the rationale for the schedule 6 entiy is distilled down to a concem on eye toxicology and carcinogenicity. Whilst we understand the cautious approach taken by OCS, we would like to add to the dialogue.

The Scheduling Policy Framework (Chapter 3) defines a schedule 5 to include products with eye initation of slight to moderate. A schedule 6 includes products with eye initation rated as severe.

The NOHSC criterion for invoking a R41 risk pln·ase is "severe ocular lesions": • mean scores comea opacity ~3 or iris lesions > 1. 5 - condition not met • two or more animals comea opacity ~3 or iris lesions =2 - condition not met • ocular lesions still present at the end of the obse1vation time - condition not met • ineversible colouration of the eyes - condition not met

The NOHSC criterion for invoking a R36 risk pln·ase (hTitating to eyes) is "significant ocular lesions":

• mean scores comea opacity >2 z <3; or iris lesions > 1 z <1.5; redness ~2.5; oedema ~2 -condition not met

• two or more animals comea opacity >2 z <3; or iris lesions > 1 z <2; redness ~2.5; oedema ~2 - condition not met

Under GHS the criterion for invoking a Categmy 1 (hazard statement H318 Causes serious eye damage), used by OCS as justification for the eye toxicology recommendation:

Page3ct5

• in at least one animal effects on the comea, iris or conjlmctiva that are not expected to reverse or have not reversed within an obse1vation · of 21 condition not

• m tested animals a positive response of comeal opacity ~3 and/or iritis > 1.5 -condition not met

Under GHS the criterion for invoking a Categmy 2 (hazard statement H319 Causes serious eye initation, or H320 Causes eye initation) have the potential to induce reversible initation; and in 2 of 3 animals:

• comeal opacity ~1 - condition not met • iritis ~1 - condition not met • conjunctival redness ~2 - condition not met

· · oedema · ~2 - condition not met

The OCS repmt was written based on the data and infonnation submitted to the APVMA in April 2014. The processes at the APVMA do not allow for subsequent data to be submitted lmder an evaluation (unless it is detrimental or conflicts with data presented). Data. can be presented for a subsequent application,-- rese1ves this option for a future time depending on the outcome of this applica~

Regarding the end use product: The tribasic copper sulphate component of the fmmulation requires that the end use product labelling bears a schedule 6 heading, so the dete1mination of amisulbrom in schedule 5 or 6 is immaterial to the end use product.

Page 4 ct5

•position:

point in time, we would suppoli a schedule 5 entiy for amisulbrom, as we would also accept a schedule 6 entiy for amisulbrom as it would make little difference to the resultant scheduling of the end use product The scheduling decision needs to be made on the data presented and we believe that it could be argued that the data suppmts a schedule 5 entiy, but we accept that OCS has been cautious with their recommendation of a schedule 6. We would like to see the expedient scheduling of amisulbrom in order to conclude the application with the APVMA.

- rese1ves the right to revisit the scheduling of amisulbrom in the future if needed, i£'when ~ta is available and ifi'when rescheduling is commercially required.

S52E (1) (d) the dosage, formulation, labelling, packaging and presentation of a substance The cmmnittee may take into account the dosage, fonnulation, labelling, packaging and presentation of a substance Section 52E (1) (d).

Amisulbrom will be not offered directly for sale to the market. The end use product will be a mixture of32g/L amisulbrom and 180g/L ti1basic copper sulphate. The fonnulation type is a suspension concenn·ate (SC) and the product will be labelled and packaged according to the requirements of the APVMA for ag~1cultural che1nical products. A similar product in tenns of dosage of ti1basic copper sulphate (190g/L ti1basic copper sulphate), fmm~

k · d t ti ha b · the market place for many years~ ).

Page SetS

The Secretary Scheduling Secretariat GPO Box 9848 CANBERRA ACT 2601

Email : [email protected]

Dear Sir/Madam

Public Comment Submission to the November 2015 meeting of the Advisory Committee on Chemicals Scheduling (ACCS)

We refer to the notice published on 1 October 2015 inviting public submissions, with respect to certain substances, addressing a matter raised in s.52E of the Therapeutic Goods Act 1989.

wishes to provide information on:

• 1 ,5-Napthalenediol

• 1-Naphthalenol • 2,6-dimethoxy-3,5-pyridinediamine

• 2, 7 -Naphthalenediol • Azo dyes listed below that may release potentially carcinogenic aromatic amines by azo reduction:

· CAS numbers: 3564-09-8; 75627-17-7; 85186-64-7; and 85186-66-9

• C.l. Direct Orange 1 • lsethionate • Musk ambrette • Part 2, Section 1 (Labels), 1.5 (Exemptions), 8 Paints

• Phenol, 4-amino-3-nitro

• p-methylaminophenol

for consideration at the November 2015 meeting of the ACCS.

Please see the attached submission for details.

is an interested party and stakeholder with regard to the nominated substances and would appreciate being advised of the Committees' considerations and the Delegate's interim decision, with the opportunity for further submission, if appropriate.

We look forward to further advice from the ACCS and the Delegate. Should the Committee or the Delegate require any additional information from at this stage please do not hesitate to contact me on

_______________________________________________________________________________________________

Yours faithfully

[unsigned for electronic submission]

29 October 2015

ACCS meeting: November 2015

1,5-Napthalenediol

has no objections to aligning the scheduling controls for this substance with the EU.

notes that the substance can be used at up to 1% in in-use preparations for hair dye

preparations. We note that it is important to maintain the concept of in-use preparation as many of the dyes are intended to be mixed with an oxidising substance prior to use, which dilutes the concentration of the dye for in-use preparation.


1-Naphthalenol


notes that the substance can be used at up to 2% in in-use preparations for hair dye preparations. We note that it is important to maintain the concept of in-use preparation as many of the dyes are intended to be mixed with an oxidising substance prior to use, which dilutes the concentration of the dye for in-use preparation.


2,6-dimethoxy-3,5-pyridinediamine


notes that the substance can be used at up to 0.25% (as the hydrochloride) in in-use

preparations for hair dye preparations. We note that it is important to maintain the concept of in-use preparation as many of the dyes are intended to be mixed with an oxidising substance prior to use, which dilutes the concentration of the dye for in-use preparation.


2,7-Naphthalenediol


notes that the substance can be used at up to 1% in in-use preparations for hair dye preparations. We note that it is important to maintain the concept of in-use preparation as many of the dyes are intended to be mixed with an oxidising substance prior to use, which dilutes the concentration of the dye for in-use preparation.


Azo dyes (as listed) that may release potentially carcinogenic aromatic amines by azo reduction:

CAS numbers: 3564-09-8; 75627-17-7; 85186-64-7; and 85186-66-9 As noted in previous submissions for similar groups of substances, supports the approach of scheduling the specific chemicals as assessed by NICNAS through the IMAP process. If any decision is made to include these substances in the Poisons Standard, they should be addressed as a group of “azo compounds”, similar to the decision made for “benzidine based azo dyes” in Schedule 7 i.e. the scheduling control should be limited to the substances specifically identified under the entry. It should be noted that an Appendix C or Schedule 7 entry, without the inclusion of allowable cut-off limits, has the potential to be problematic. When considering the status of unscheduled ingredients where derivatives of these seven entries may be present as an impurity, substances could be inadvertently captured as an impurity at any concentration is covered by the Schedule 7 entry. The NICNAS IMAP report also stated that “trace levels of the aromatic amines used in dye production could be technologically inevitable”.


C.I. Direct Orange 1

has no objection to the inclusion of C.I. Direct Orange 1 (CAS number 54579-28-1) in the Schedule 7 Entry for BENZIDINE-BASED AZO DYES. This is consistent with the previously established approach of scheduling the specific chemicals under this entry as assessed by NICNAS through the IMAP process.


Isethionate (2-hydroxyethanesulfonic acid)

The US Cosmetic Ingredient Review (CIR) Expert Panel has reviewed the product use, formulation and safety data of twelve isethionate salts1, which mostly function as surfactants and cleansing agents in cosmetic products. The Panel concluded that isethionate salts were safe as cosmetic ingredients in the present practices of use and concentration, when formulated to be non-irritating. It has been our long held view that these surfactants do not require scheduling as the risks of using surfactants (skin irritation from defatting and eye irritation) are well known to consumers, and globally, surfactant ingredients in personal care and cosmetic products are not subject to restrictions. We note however that the ACCS has previously considered several surfactant substances including Ammonium Cocoyl Isethionate, which resulted in a new Schedule 6 entry; Ammonium cocoyl isethionate, except in cosmetic rinse-off preparations containing 30 per cent or

less and if containing more than 5 per cent of ammonium cocoyl isethionate when labelled with a

warning to the following effect:

IF IN EYES WASH OUT IMMEDIATELY WITH WATER If scheduling is deemed necessary, any new Schedule entry for isethionate should be in line with the scheduling of other surfactants, with exemption cut-offs that allow for use at low concentrations in rinse-off products.

.

1 http://www.cir-safety.org/sites/default/files/isethionate.pdf


Musk ambrette (Benzene, 1-(1,1-dimethylethyl)-2-methoxy-4-methyl-3,5-

dinitro-) As far as we are aware, none of our Members are marketing products containing musk ambrette.

notes that musk ambrette is listed in Annex II (substances banned in cosmetics) of the EU Cosmetics Regulation. Therefore, currently has no objections to the inclusion of musk ambrette in Schedule 10 to prohibit its use in cosmetic and domestic products.


Part 2, Section 1 (Labels)

1.5 (Exemptions) 8 Paints

notes that the intent of this proposal appears to be in removing ambiguity around the labelling exemptions for paints, and removing any exemption provisions that do not relate to workplace labelling requirements. As this may result in the need for changes to labelling of paint and tinter products, the time required to execute these changes should be acknowledged and accommodated when considering the implementation date. We have not been advised at this point in time of any negative impact this may have on our members and their operations, and as such, we have no objection to the proposed changes.


Phenol, 4-amino-3-nitro

notes that currently, there is a Schedule 6 entry for nitrophenols with no exemptions for

preparations containing small quantities of nitrophenols. It is our understanding that industry has been applying the current Schedule 6 entry for nitrophenols to phenol, 4-amino-3-nitro.

supports aligning the schedule entry of this substance with the EU i.e. removing scheduling controls for hair dye preparations containing small quantities of phenol, 2-amino-6-chloro-4-nitro. We note that in the EU the substance is allowed at up to 1.0% in ready to use preparations, with higher concentrations of up to 1.5% (when applied to hair) allowed for preparations that are intended to be diluted before application.


p-methylaminophenol


notes that the substance can be used at up to 0.68% (as sulphate) in in-use preparations for hair dye preparations. We note that it is important to maintain the concept of in-use preparation as many of the dyes are intended to be mixed with an oxidising substance prior to use, which dilutes the concentration of the dye for in-use preparation.

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