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Scheduling delegate's final decisions: ACCS, March 2015

Scheduling medicines and poisons

27 March 2015

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Part A - Final decisions on matters referred to an expert advisory committee (1.5-1.8)

1. Scheduling proposals referred to the November 2014 meeting of the Advisory Committee on Chemicals Scheduling (ACCS #12)

1.5 C. I. Acid black 29

Scheduling proposal

The delegate referred the following scheduling proposal for consideration by the ACCS:

  • To create a new entry for C. I. Acid Black 29 in Schedule 7.

The committee was asked to discuss and consider the resolutions with an implementation date of 1 June 2015/1 October 2015/1 February 2016.

In August 2014, NICNAS, under its IMAP programme, referred the following proposal to be considered by the delegate:

  • To create a new entry for C. I. Acid Black 29 in Schedule 7, consistently with other benzidine-based dyes.

The reasons for the request were:

  • Systemic long-term effects including carcinogenicity, reproductive toxicity and developmental toxicity.
  • Benzidine based-dyes have been shown to be metabolised to benzidine, a known human carcinogen.
Delegate's reasons for referring this to the committee

The delegate's reason for referring this scheduling proposal to the ACCS was that, the NICNAS IMAP program has reviewed a number of diazotized benzidine derivatives likely to be a component of dyes and stains. The toxicological profile of these benzidine-based azo dyes is consistent with the Scheduling Policy Framework's (SPF) criteria for listing in Schedule 7 (based on their mutagenicity and carcinogenicity profile and ability to be metabolised to benzidine, a known human carcinogen). The scheduling recommendations from the November ACCS meeting resulted in eleven benzidine-based azo dyes being listed in Schedule 7. Further advice of the ACCS was requested to determine whether CI Acid Black 29 should be added to the current Schedule 7 entry for BENZIDINE-BASED AZO DYES.

The delegate asked the ACCS the following questions:

  • The NICNAS IMAP report contains no direct toxicological information on CI Acid Black 29. Its toxicological profile is based on read-across from related dyes and the assumption that it, too, is metabolised in vivo to benzidine. Is there sufficient evidence to conclude that it represents the same hazard profile as other benzidine-based azo dyes listed in Schedule 7, and therefore warrants inclusion in that entry?
  • Should CI Acid Black 29 (and its CAS number) be simply added to the list of dyes currently captured by the generic Schedule 7 entry for BENZIDINE-BASED AZO DYES, or should it be listed under a separate schedule entry?
  • What weight should be given to the disclosure in the NICNAS IMAP report that these dyes are being phased out internationally and that there may be no current uses in Australia, other than the possibility that CI Black 29 might be present in imported textiles and fabrics?
Substance summary

Please refer to the NICNAS IMAP human health Tier II assessment report for C. I. Acid Black 29. This report is publicly available on the NICNAS website: Human health tier II assessment for C. I. Acid Black 29.

Scheduling status

C.I. Black 29 is not specifically scheduled.

Eleven benzidine-based azo dyes are listed in Schedule 7.

Schedule 7

BENZIDINE-BASED AZO DYES being:

  • 2,2'-[[1,1'-biphenyl]-4,4'-diylbis(azo)]bis[N-(4-chlorophenyl)-3-oxobutanamide], CAS No. 94249-03-3
  • Acid Red 85 (Acid Fast Red A).1,3-Naphthalenedisulfonic acid, 7-hydroxy-8-[[4'-[[4-[[(4-methylphenyl)sulfonyl]oxy]phenyl]azo][1,1'-biphenyl]-4-yl]azo]-, disodium salt. CAS No. 3567-65-5
  • Direct Black 38. 2,7-Naphthalenedisulfonic acid, 4-amino-3-[[4'-[(2,4-diaminophenyl)azo][1,1'-biphenyl]-4-yl]azo]-5-hydroxy-6-(phenylazo)-, disodium salt. CAS No. 1937-37-7
  • Direct Blue 2. 2,7-Naphthalenedisulfonic acid, 5-amino-3-[[4'-[(7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo][1,1'-biphenyl]-4-yl]azo]-4-hydroxy-, trisodium salt. CAS No. 2429-73-4
  • Direct Blue 6. 2,7-Naphthalenedisulfonic acid, 3,3'-[[1,1'-biphenyl]-4,4'-diylbis(azo)]bis[5-amino-4-hydroxy-, tetrasodium salt. CAS No. 2602-46-2
  • Direct Brown 2. 5-[[4'-[(7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo][1,1'-biphenyl]-4-yl]azo]-2-hydroxy- benzoic acid disodium salt. CAS No. 2429-82-5
  • Direct Brown 95. Cuprate(2-), [5-[[4'-[[2,6-dihydroxy-3-[(2-hydroxy-5-sulfophenyl)azo]phenyl]azo][1,1'-biphenyl]-4-yl]azo]-2-hydroxybenzoato(4-)]-, disodium salt. CAS No. 16071-86-6
  • Direct Green 1. 2,7-Naphthalenedisulfonic acid, 4-amino-5-hydroxy-3-[[4'-[(4-hydroxyphenyl)azo][1,1'-biphenyl]-4-yl]azo]-6-(phenylazo)-, disodium salt. CAS No. 3626-28-6
  • Direct Green 6. 2,7-Naphthalenedisulfonic acid, 4-amino-5-hydroxy-6-[[4'-[(4-hydroxyphenyl)azo][1,1'-biphenyl]-4-yl]azo]-3-[(4-nitrophenyl)azo]-, disodium salt. CAS No. 4335-09-5
  • Direct Red 28 (Congo Red). 1-Naphthalenesulfonic acid, 3,3'-[[1,1'-biphenyl]-4,4'-diylbis(azo)]bis[4-amino-, disodium salt. CAS No. 573-58-0
  • Direct Red 37. 1,3-Naphthalenedisulfonic acid, 8-[[4'-[(4-ethoxyphenyl)azo][1,1'-biphenyl]-4-yl]azo]-7-hydroxy-, disodium salt. CAS No. 3530-19-6
Scheduling history

C.I. acid black 29 is not specifically scheduled.

The following is the scheduling history of benzedine-based azo dyes.

In April 2014, the delegate, based on ACCS advice, made a decision to list 11 benzidine-based dyes in Schedule 7. The delegate indicated that inclusion of benzidine-based dyes in Appendix C is not the most appropriate way of regulating the use of these substances. While there are stringent existing controls under Model Work Health and Safety legislation, and industry advises that they have been largely phased out of many uses, the delegate also noted that some of the dyes may have use in laboratory and analytical reagents, but that their carcinogenic potential, via conversion to benzidine (a known human carcinogen), indicates they should not be used in products available in the domestic market.

Pre-meeting public submissions

No public submissions were received.

Summary of ACCS advice to the delegate

The committee recommended that the current Schedule 7 BENZIDINE-BASED AZO DYES entry be amended to include C. I. Acid black 29.

The committee supported the implementation date of 1 June 2015.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (c) the toxicity of a substance.

The reasons for the recommendation comprised the following:

  • Concerns about the potential carcinogenic and reproductive affects.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • SPF scheduling factors;
  • Other relevant information.
Delegate's interim decision

The delegate notes that a number of benzidine-based azo dyes were listed in Schedule 7 as an outcome of advice from the February 2014 meeting of the ACCS. The listed dyes warrant stringent controls because of their carcinogenic potential via conversion to benzidine (a known human carcinogen). The delegate therefore accepts ACCS advice that CI Acid Black 29 shares the carcinogenic potential of the already listed benzidine-based azo dyes and that it should be added to the list of such dyes in the current Schedule 7 listing.

The delegate agrees with the implementation date 1 June 2015.

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; and (c) the toxicity of a substance.

Public submissions on the interim decision

No public submissions were received.

Delegate's final decision

The delegate confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

The delegate has confirmed the proposed implementation date of 1 June 2015.

Schedule entry
Schedule 7 - Amendment

BENZIDINE-BASED AZO DYES being:

  • 2,2'-[[1,1'-biphenyl]-4,4'-diylbis(azo)]bis[N-(4-chlorophenyl)-3-oxobutanamide], CAS No. 94249-03-3
  • Acid Red 85 (Acid Fast Red A). 1,3-Naphthalenedisulfonic acid, 7-hydroxy-8-[[4'-[[4-[[(4-methylphenyl)sulfonyl]oxy]phenyl]azo][1,1'-biphenyl]-4-yl]azo]-, disodium salt. CAS No. 3567-65-5
  • C. I. ACID BLACK 29. CAS No. 12217-14-0
  • Direct Black 38. 2,7-Naphthalenedisulfonic acid, 4-amino-3-[[4'-[(2,4-diaminophenyl)azo][1,1'-biphenyl]-4-yl]azo]-5-hydroxy-6-(phenylazo)-, disodium salt. CAS No. 1937-37-7
  • Direct Blue 2. 2,7-Naphthalenedisulfonic acid, 5-amino-3-[[4'-[(7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo][1,1'-biphenyl]-4-yl]azo]-4-hydroxy-, trisodium salt. CAS No. 2429-73-4
  • Direct Blue 6. 2,7-Naphthalenedisulfonic acid, 3,3'-[[1,1'-biphenyl]-4,4'-diylbis(azo)]bis[5-amino-4-hydroxy-, tetrasodium salt. CAS No. 2602-46-2
  • Direct Brown 2. 5-[[4'-[(7-amino-1-hydroxy-3-sulfo-2-naphthalenyl)azo][1,1'-biphenyl]-4-yl]azo]-2-hydroxy- benzoic acid disodium salt. CAS No. 2429-82-5
  • Direct Brown 95. Cuprate(2-), [5-[[4'-[[2,6-dihydroxy-3-[(2-hydroxy-5-sulfophenyl)azo]phenyl]azo][1,1'-biphenyl]-4-yl]azo]-2-hydroxybenzoato(4-)]-, disodium salt. CAS No. 16071-86-6
  • Direct Green 1. 2,7-Naphthalenedisulfonic acid, 4-amino-5-hydroxy-3-[[4'-[(4-hydroxyphenyl)azo][1,1'-biphenyl]-4-yl]azo]-6-(phenylazo)-, disodium salt. CAS No. 3626-28-6
  • Direct Green 6. 2,7-Naphthalenedisulfonic acid, 4-amino-5-hydroxy-6-[[4'-[(4-hydroxyphenyl)azo][1,1'-biphenyl]-4-yl]azo]-3-[(4-nitrophenyl)azo]-, disodium salt. CAS No. 4335-09-5
  • Direct Red 28 (Congo Red). 1-Naphthalenesulfonic acid, 3,3'-[[1,1'-biphenyl]-4,4'-diylbis(azo)]bis[4-amino-, disodium salt. CAS No. 573-58-0
  • Direct Red 37. 1,3-Naphthalenedisulfonic acid, 8-[[4'-[(4-ethoxyphenyl)azo][1,1'-biphenyl]-4-yl]azo]-7-hydroxy-, disodium salt. CAS No. 3530-19-6

1.6 Fenpyrazamine

Scheduling proposal

The delegate referred the following scheduling proposal for consideration by the ACCS:

  • To create a Schedule 5 entry for fenpyrazamine.

The committee was asked to discuss and consider the resolutions with an implementation date of 1 June 2015/1 October 2015/1 February 2016.

In August 2014, the Office of Chemicals Safety (OCS), based on an application made to the Australian Pesticides and Veterinary Authority (APVMA), referred the following proposal to be considered by the delegate:

  • A proposal to create a new Schedule 5 entry for fenpyrazamine.

The reasons for the request were that the chemical:

  • has low oral toxicity in rats (LD50 >2000 mg/kg bw, no deaths);
  • has low dermal toxicity in rats (LD50 >2000 mg/kg bw, no deaths);
  • has low inhalational toxicity in rats (LC50 >4840 mg/m3, no deaths, although the study was of reduced regulatory value based on exceedance of the mass median aerodynamic diameter (MMAD));
  • is not a skin or eye irritant in rabbits; and
  • is not a skin sensitiser in guinea pigs.

The toxicity profile of the preparation containing 400 g/L of fenpyrazamine was similar to the technical grade active constituent (TGAC), except for the inhalational toxicity. The inhalational toxicity value of the preparation containing 400 g/L of fenpyrazamine is >5612 mg/m3, no deaths; and the TGAC's inhalational toxicity value is >4840 mg/m3, no deaths.

The OCS evaluation report noted that in the current context of the toxicological profile of fenpyrazamine, the OCS has based its Schedule 5 recommendation primarily on the SPF Schedule 5 factor "the substance has a low health hazard", but that the delegate may wish to consider whether the toxicological profile of fenpyrazamine was of sufficiently low health hazard, and whether there was sufficient public benefit, for a positive listing in Appendix B. Noting the uncertainty surrounding some of the findings in the two-year rat chronic/carcinogenicity study, from a cautionary principle approach, a Schedule 5 listing may be more appropriate.

Delegate's reasons for referring this to the committee

The delegate's reason for referring this scheduling proposal to the ACCS was that the scheduling application was sufficiently complex to require advice from the ACCS.

The delegate asked the ACCS the following questions.

  • To what extent is the toxicological profile of fenpyrazamine similar to other pyrazole fungicides (penflufen sedaxane), whose primary listing is currently in Schedule 5?
  • Despite the OCS conclusion, based on Mode of Action (MoA) analysis, that the carcinogenic response (high dose hepatocellular carcinomas and other tumours; no evidence of genotoxicity) seen in the 2-year rat study is unlikely to be relevant to humans, does the ACCS support the OCS recommendation that fenpyrazamine be listed in Schedule 5?
  • Alternatively, does the overall low toxicity profile suggest that listing in Appendix B may be appropriate?
Substance summary

Fenpyrazamine is a non-systemic fungicide belonging to the pyrizole chemical family. Although the compound is classified as non-systemic, limited translocation in plants was observed. Fenpyrazamine shows its fungicidal activity through inhibition of germ tube elongation and mycelium elongation. The exact biochemical mechanism of the fungicidal activity is not clarified1.

image of a chemical structure of Fenpyrazamine
Figure 1. Structure of Fenpyrazamine

Acute toxicity

The acute toxicity end-points for this chemical are listed in the below table.

Toxicity Species Fenpyrazamine SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rat > 2000 (no deaths) Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rat > 2000 (no deaths) Low toxicity
Acute inhalational toxicity LC50 (mg/m3/4h) Rat > 4840 (no deaths) Low toxicity
Skin irritation Rabbits Non-irritant
Eye irritation Rabbits Non-irritant
Skin sensitisation (Guinea Pig Maximisation Test) Guinea pig Non-sensitiser

The acute toxicity end-points a preparation containing 400 g/L of fenpyrazamine listed in the below table.

Toxicity Species Preparations containing 400g/L of fenpyrazamine SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rat > 2000 (no deaths) Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rat > 2000 (no deaths) Low toxicity
Acute inhalational toxicity LC50 (mg/m3/4h) Rat > 5612 (no deaths) Low toxicity
Skin irritation Rabbits Non-irritant
Eye irritation Rabbits Non-irritant
Skin sensitisation (Buehler method) Guinea pig Non-sensitiser
Repeated dose toxicity

In repeat-dose toxicity studies, the most sensitive species was the rat, with some common toxicology endpoints in all species (test substance related and dose dependent reduction in food consumption, lower body weight and decreased body weight gain), and an increase in the organ weight, incidence and severity of histopathological changes (hepatocellular hypertrophy as well as reduced fatty turnover) in the liver. The liver as a main target organ is consistent with the findings in toxicokinetics, i.e. rapid and extensive absorption, metabolism and excretion of the test substance, and the liver retaining the highest radiolabel levels throughout the toxicokinetics studies (up to day 7 post dosing). The most sensitive species in repeat-dose toxicity studies was the rat, with the lowest no observed effect level (NOEL) in this species being 12.72/15.64 mg/kg bw/day (300 ppm), established in the 2-year chronic toxicity and carcinogenicity study.

In addition to the liver, the thyroid was another target organ identified in rats, but not in mice or dogs. Similar to the liver changes, a treatment dose-dependent and temporally related increase in thyroid weight and the incidence of histopathological changes (follicular hypertrophy and/or hyperplasia) were detected in long term repeat dose studies in rats (in particular the 2-year combined chronic and carcinogenicity study and the two-generation reproduction study).

Mutagenicity

Salmonella typhimurium exposed to up to the limit dose of 5000 &microg;g/plate of the substance was not mutagenic in the bacterial reverse mutation assay with and without S9 metabolic activation.

Genotoxicity

Fenpyrazamine was not genotoxic in several in vitro and in vivo studies.

Carcinogenicity

There was no evidence of carcinogenic potential in a 78-week carcinogenicity study in mice by dietary administration up to and including the highest dose tested of 349/551 mg/kg bw/day (4000 ppm) for males/females, respectively.

In a 2-year carcinogenicity study in rats, increased neoplasia incidence only occurred at the highest dose tested of 2400 ppm (106.76/130.25 mg/kg bw/d for male/female), and consisted of hepatocellular carcinoma (4%), thyroid follicular carcinoma (6%), testes Leydig cell tumour (8%) and skin/subcutis keratoacanthoma (14%) in males; and uterine adenocarcinoma (4%) in females. While thyroid follicular carcinoma was at the upper historical control limit, and Leydig cell tumour, skin/subcutis keratoacanthoma and uterine adenocarcinoma were within historical control values, hepatocellular carcinoma was above concurrent and historical controls. In discussing this finding, the applicant has indicated that:

"The incidence of hepatocellular carcinoma in high dose [2400 ppm] males (4%) was only slightly higher than the maximum historic control rate of 2.8% in male rats. In the absence of any increase in altered foci or pre-neoplastic lesions in the livers of treated male rats it is difficult to conclude that the slight increase in the incidence of hepatocellular carcinoma above that of historical control rates represents a true carcinogenic effect"; and

"The lack of an increase observed for precursor events in the genesis of hepatocellular carcinoma, such as foci of cellular alternation and neoplastic nodules in treated animals, does not support a role for fenpyrazamine in tumour induction".

The OCS notes that the marginal increase identified occurred at the high dose (2400 ppm) only, without incidence/frequency at lower doses, and that hepatocellular adenoma frequency was identical to concurrent controls. Additionally, pre-neoplastic lesions (e.g. hyperplasia) were not noted in the histopathology, and no changes in the period to onset were identified (noting that hepatocellular carcinoma was only identified at terminal sacrifice, and animals presenting with hepatocellular carcinoma survived to final termination). On available data (noting mechanistic data and/or a mode of action (MOA) framework consideration of the observed effects were not provided), the OCS considers that on weight of evidence the test material is unlikely to have induced the hepatocellular carcinomas observed in the 2-year rat study, and that fenpyrazamine is unlikely to be carcinogenic.

Reproduction and developmental toxicity

In the two-generation reproduction study in rats, fenpyrazamine caused an increased incidence of post implantation loss, postnatal loss and lower pup weight for F1 and F2 pups/litters at ≥1000 ppm (72.5 mg/kg bw/d), doses where parental toxicity in P and F1 adult animals was observed (increased organ weight and histopathological changes occurred in the liver and thyroid).

Developmental studies in rats revealed various visceral and skeletal variations including abnormal lobation and supernumerary lobe in the liver, left sided umbilical artery, skull zygomatic arch fusion, and costal cartilages asymmetrically aligned at sternum >125 mg/kg bw/d. Maternal toxicity at 125 mg/kg bw/d was present as only a slightly (but occasionally statistically significantly) lower accumulated body weight gain. Comparable NOELs were seen in the reproduction study (20.3 mg/kg bw/d minimum) and the developmental study (30 mg/kg bw/d) in rats.

In rabbits, implantation loss and abortion/premature delivery was a finding consistently observed in the dose range finding study and the formal study at ≥50 mg/kg bw/d, with a dose-dependent pattern. However, overall, fenpyrazamine did not cause external, visceral and skeletal malformations or variations of toxicological significance in the presented studies, and it is considered that fenpyrazamine is not a reproductive or a developmental toxicant.

Observations in humans

No information was provided.

Public exposure

The product is not intended to be applied by domestic users.

Application of the product by air blast may lead to unintended bystander exposure via chemical spray drift. This may be in the form of a single random exposure or repeat exposures of residents who reside adjacent to areas being treated with the product. Parameters for assessing bystander exposure have not been finalised by the APVMA.

The most likely route of public exposure to these products is through consumption of residues in food. Assessment of the exposure of the Australian population to residues of agricultural and veterinary chemicals in food crops and target animals is performed by the Australian Pesticides and Veterinary Medicines Authority (APVMA), with the support of, and using procedures and databases provided by, Food Standards Australia New Zealand (FSANZ).

International regulations

No information was provided. The Scheduling Secretariat has found the following:

In February 2013, the US Environmental Protection Agency (EPA) granted unconditional registration of fenpyrazamine. The uses for the substance are almond, small fruit vine climbing subgroup, head and leaf lettuce, low growing berry subgroup, blueberry subgroup, cranberry subgroup, ginseng, pistachio and ornamentals.

In July 2012, the European Union (EU) approved the use of fenpyrazamine with an effective date for this decision of 1 January 2013.

Scheduling status

Fenpyrazamine is not specifically scheduled.

Scheduling history

Fenpyrazamine has not been previously considered for scheduling; therefore, scheduling history is not available.

Fenpyrazamine belongs to the pyrazole chemical group. Pyrazole substances, such as penflufen and sedaxane, are listed in Schedule 5.

In October 2012, the delegate, based on the Advisory Committee on Chemicals Scheduling (ACCS) advice, decided to list penflufen in Schedule 5.

In May 2012, the delegate made a delegate only decision to list sedaxane in Schedule 5 based on its low toxicity profile.

Fenpyrazamine presents its fungicidal activity through inhibition of germ tube elongation and mycelium elongation. A similar fungicidal mode of acting chemical namely fenhexamid was listed in Appendix B (for agricultural uses) in 1999.

Pre-meeting public submissions

No submissions were received.

Summary of ACCS advice to the delegate

The committee recommended that preparations containing more than 40 per cent of fenpyrazamine be listed in Schedule 5 as a new entry.

The committee supported the implementation date of 1 June 2015.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (c) the toxicity of a substance.

The reasons for the recommendation comprised the following:

  • Overall toxicity profile of the substance is consistent with listing in Schedule 5.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • SPF scheduling factors;
  • Other relevant information.
Delegate's interim decision

The delegate accepts ACCS advice that a new entry in Schedule 5 be created for fenpyrazamine, with a cut-off to exempt at 40 per cent. The low acute and chronic toxicity of fenpyrazamine and its overall toxicity profile is consistent with the Scheduling Policy Framework criteria for listing in Schedule 5. While there were some findings of carcinogenic potential in the long-term rat study, the lack of any supportive precursor events leading to carcinoma formation, in addition to there being no findings of carcinogenicity in a mouse study, tend to discount the significance of human carcinogenic potential as a matter for scheduling consideration. The delegate agrees with the ACCS that listing in Schedule 5 provides for warning levels and access controls more appropriate than if the chemical is listed in Appendix B. Furthermore, an appropriate set of First Aid and Safety Directions are recommended to the APVMA to be applied to the exempt product.

The delegate agrees with the implementation date 1 June 2015.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (c) the toxicity of a substance.

Public submissions on the interim decision

No public submissions were received.

Delegate's final decision

The delegate confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

The delegate has confirmed the proposed implementation date of 1 June 2015.

Schedule entry
Schedule 5 - New entry

FENPYRAZAMINE except in preparations containing 40 per cent or less of fenpyrazamine

1.7 Fluopyram

Scheduling proposal

The delegate referred the following scheduling proposal for consideration by the ACCS:

  • To create a new Schedule 5 entry for fluopyram with appropriate low concentration cut-off to exempt from scheduling.

The committee was asked to discuss and consider the resolutions with an implementation date of 1 June 2015/1 October 2015/1 February 2016.

In August 2014, OCS, based on an application to the APVMA, requested that the delegate consider a proposal to include preparations containing 500 g/L or more of fluopyram in Schedule 5.

The reasons for the request were that the chemical:

  • has low acute oral toxicity in female rats (LD50 >2000 mg/kg bw with no deaths or clinical signs of toxicity);
  • has low acute dermal toxicity in male and female rats (LD50 >2000 mg/kg bw with no deaths or clinical signs of toxicity);
  • has low acute inhalational toxicity in male and female rats (4-hr LC50 >5.1 mg/L the maximum obtainable concentration with no deaths);
  • is not a skin irritant in rabbits;
  • is not an eye irritant in rabbits; and
  • is not a skin sensitiser in mice (LLNA).

The OCS evaluation report noted that the carcinogenic potential of the substance is of concern. Thyroid tumours were seen in male mice only and these were not considered relevant to humans. However, liver tumours were seen in female rats only, and while it is likely the mode of action (MOA) for these fluopyram induced liver tumours is similar to that developed for phenobarbital (which is not considered relevant to humans), there were data indicating AhR activation, which is not regarded as playing a role in phenobarbital's carcinogenic MOA. Therefore, further information is required on the association of fluopyram exposure and AhR activation and, in the absence of such data, the observed liver tumours could not be entirely discounted as being relevant to humans.

The assessment was originally undertaken as a Global Joint Review (GJR).

Germany considered the liver but not the thyroid tumours relevant for humans and classified fluopyram as a category 2 carcinogen (H351) according to the Globally Harmonised System for Classification and Labelling of Chemicals (GHS).

The US EPA considered the data insufficient to support the proposed carcinogenic MOA, resulting in possible irrelevance for humans of both tumour types. A prime deficiency was a lack of dose-response concordance with key precursor events and tumour incidence. Fluopyram was classified as "Likely to be Carcinogenic to Humans" based on tumours in two species and two sexes, and a linear low dose extrapolation model applied to animal data was recommended for quantitative estimation of human risk. Canada came to the same conclusion as the US EPA. US EPA based their risk estimate on the rat liver tumours but Canada on the mouse thyroid tumours (GJR).

At the national review stage, OCS concurred with Germany's interpretation of the tumour findings, and retained this position after the national evaluation. Like Germany, OCS considered fluopyram a category 2 carcinogen under the GHS (and a category 3 carcinogen under the NOHSC Approved Criteria for Classifying Hazardous Substances (NOHSC, 2004)).

Delegate's reasons for referring this to the committee

The OCS scheduling recommendation is clear and has been supported by the applicant. However, the delegate decided to seek the advice of the ACCS, noting the discord between some of the regulatory agencies involved in the global evaluation of fluopyram in relation to the interpretation of the carcinogenic responses in male mice and female rats.

The Delegate asked the ACCS the following questions.
  • Noting the different conclusions drawn by the US EPA, EU German rapporteur, Health Canada and JMPR in relation to the interpretation of the evidence relating to the Mode of Action (MoA) for the thyroid cancers seen in male mice and the hepatocellular adenomas seen in female rats at high doses, does the ACCS concur with the OCS assessment that the MoA evidence is sufficient to conclude that the tumours are of little or no relevance for human risk assessment, or have a clear threshold?
  • Does the ACCS support the OCS recommendation that fluorpyram be listed in Schedule 5? Is the proposed Schedule 5 listing compatible with the OCS classification of fluopyram as a hazardous substance according to NOHSC Approved Criteria for Classifying Hazardous Substances (NOHSC, 2004), with the following risk phrases: Xn; R40 Limited evidence of a carcinogenic effect
  • Does the ACCS agree that the product containing 50% fluopyram can be exempted from scheduling?
Substance summary

Fluopyram is a broad-spectrum fungicide with preventive, systemic and curative properties. It can be applied to plant foliage using ground, air-blast or aerial spray equipment. Fluopyram represents a new group of fungicide called pyridinyl ethylbenzimides that are succinate dehydrogenase inhibitors (SDHI) within the fungal mitochondrial chain, thus blocking electron transport2.

image of a chemical structure of Fluopyram
Figure 2. Structure of Fluopyram

Acute toxicity

The acute toxicity end-points for this chemical are listed in the below table.

Toxicity Species Fluopyram SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rat > 2000 Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rat > 2000 Low toxicity
Acute inhalational toxicity LC50 (mg/m3/4h) Rat > 5112 Low toxicity
Skin irritation Rabbit Non-irritant
Eye irritation Rabbit Non-irritant
Skin sensitisation (local lymph node assay) Mouse Non-sensitiser

The acute toxicity end-points for preparations containing 500 g/L of fluopyram are listed in the below table.

Toxicity Species Preparation containing 500 g/l of fluopyram SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rat ≥ 5000 Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rat > 2000 Low toxicity
Acute inhalational toxicity LC50 (mg/m3/4h) Rat > 2091 Moderate to high toxicity
Skin irritation Rabbit Non-irritant
Eye irritation Rabbit Non-irritant
Skin sensitisation (local lymph node assay) Mouse Non-sensitiser
Repeat-dose toxicity

In short-term and sub-chronic oral toxicity studies, the liver proved to be the main target organ in rats, mice and dogs. Hepatotoxicity became apparent by a dose-related increase in organ weight, alterations of clinical chemical parameters and histopathological findings such as centrilobular hypertrophy or periportal or midzonal vacuolation or macrovacuolation. In general, the adverse effects of fluopyram were more pronounced in rodents than in dogs. The lowest relevant no observed adverse effect level (NOAEL) was 12.5 mg/kg bw/d from the 90-day feeding study in rats, based on liver and kidney effects (organ weight increase, clinical chemistry and histopathological findings (hyaline droplet nephropathy in the kidney)) at the next higher dose level of 60.5 mg/kg bw/d.

In chronic oral studies, the liver and kidneys remained the main target organs with an increase in organ weight that was sometimes accompanied by gross pathological findings; however, in mice, follicular cell hyperplasia in the thyroid gland was observed as well.

In a rat short-term dermal study, increased cholesterol, increased prothrombin time and increased liver weights associated with hepatocellular hypertrophy were seen at 1000 mg/kg bw/d. A NOAEL of 300 mg/kg bw/d was established based on these findings.

Genotoxicity and Mutagenicity

Fluopyram was tested in a minimum battery of standard genotoxicity and mutagenicity tests in vitro and in vivo. These studies demonstrate that fluopyram has no genotoxic potential. There was no indication of gene mutation either in the presence or absence of metabolic activation in both the bacterial reverse mutation and mammalian gene mutation tests. The in vitro chromosome aberration test and the in vivo mouse micronucleus test were both negative and, thus, a clastogenic potential may be excluded.

Carcinogenicity

In a rat 2-year dietary study, the only treatment related carcinogenic finding was an increased incidence of combined hepatocellular adenoma and carcinoma in females at the top dose of 89 mg/kg bw/d (11/59 animals including 3 animals with carcinoma, compared to 2/60 in controls). No such finding was seen in males, noting that the top dose level of 750 ppm was reduced to 375 mg/kg bw/d from week 85 onwards due to the high mortality seen at 750 ppm, to give an overall study phase dose estimated to be 29 mg/kg bw/d.

In a mouse 18-month dietary study, the only treatment related carcinogenic finding was an increased incidence of follicular cell adenoma in males at the top dose level of 105 mg/kg bw/d (7/50 animals compared to 1/50 in controls). No such finding was seen in females at up to and including 129 mg/kg bw/d.

However, there was available evidence that rodents are much more susceptible to thyroid tumours than humans, and that the greater sensitivity of (particularly) male rodents to perturbations of the pituitary-thyroid axis by xenobiotics or physiologic alterations compared to humans is the result of:

  • Higher circulating levels of TSH in rodents (>25 times) than humans;
  • Shorter plasma half-life of T4 in rodents (12-24 hours) than in humans (5-9 days); and
  • Serum T4 binding with high specificity to thyroxine-binding globulin (TBG) in humans which is absent in rodents. TBG has binding affinities 3-5 orders of magnitude greater than albumin or pre-albumin. This means the higher unbound T4 is very susceptible to physiological events, like induced UDPGT, that enhance its clearance from blood.

Furthermore, by analogy with other agents (i.e. phenobarbital) known to induce thyroid tumours in rodents by CAR/PXR associated increases in Phase II enzymes metabolising free T4 (as proposed for fluopyram), but not causing tumours in humans even after many years of therapeutic use, the MOA deduced for fluopyram rodent thyroid tumours is not considered relevant to humans.

Fluopyram was therefore considered as carcinogenic, as the observed liver tumours in female rats could not be entirely discounted as being relevant to humans.

Reproduction and developmental toxicity

There were no treatment related effects on reproductive performance in a dietary 2-generation rat study up to and including dose levels producing parental toxicity.

In a rat oral (gavage) developmental toxicity study, maternal bodyweight gain at 450 mg/kg bw/d remained static during gestation days (GD) 6-8 of treatment, resulting in an overall decrease in body weight gain of 16%. A similar but lower level effect was at 150 mg/kg bw/d with an overall body weight gain reduction of 6%. Food consumption at 450 mg/kg bw/d was decreased between 13 and 15% between GD 6 and 14. Developmental toxicity was observed at 450 mg/kg bw/d in terms of slightly lower fetal body weight (5%), and a slightly increased incidence of two visceral ('thymic remnant present' and 'ureter convoluted and/or dilated') and two skeletal minor variations ('at least one thoracic centrum split/split cartilage' and 'at least one thoracic centrum dumbbell and/or bipartite/normal cartilage'). The observed fetal findings at 450 mg/kg bw/d were considered a secondary non-specific of the observed marked maternal toxicity as shown by an overall decrease in body weight gain of 16%.

In a rabbit oral developmental toxicity study, at 75 mg/kg bw/d only very slight increases in maternal body weight gain were seen between GD 14-18 and GD 18-22, that resulted in an overall decrease in body weight gain of 35% between GD 6-29. These findings at 75 mg/kg bw/d were associated with decreases in food consumption between 24 and 34% for all intervals between GD 14-26. Developmental toxicity was observed at 75 mg/kg bw/d in terms of a 11% decrease in fetal body weight and a slight increase in the incidence of very small fetuses (classified as 'runts'). The observed fetal findings at 450 mg/kg bw/d were considered a secondary non-specific of the observed marked maternal toxicity as shown by an overall decrease in body weight gain of 35%.

Therefore, fluopyram was not considered a developmental toxicant in rats and rabbits.

Observation in humans

No information was provided.

Public exposure

Luna Privilege Fungicide is not intended for domestic use and therefore accidental exposure is not expected.

International regulations

No information was provided. The Scheduling Secretariat found the following information.

In February 2012, the US Environmental Protection Authority (EPA) registered the use of fluopyram on apples, banana, dry beans, cherries, peanuts, pistachios, potatoes, strawberries, sugar beets, tree nuts, watermelons and wine grapes to control a variety of diseases. Moreover, the degree of regulation by the US EPA indicates that fluopyram is classified as "Likely to be Carcinogenic to Humans".

The 2010 Joint FAO/WHO Meeting on Pesticide Residues (JMPR) indicated that the International Estimated Daily Intakes (IEDI) of fluopyram for the 13 Global Environment Monitoring System (GEMS)/Food regional diets, based on estimated supervised trial median residue (STMRs), were 1 to 6% of the maximum ADI of 0.01 mg/kg bw. The Meeting concluded that the long-term intake of residues of fluopyram from uses that have been considered by the JMPR is unlikely to present a public health concern. The International Estimated Short-term Intake (IESTI) varied from 0 to 4% of the ARfD (0.5 mg/kg bw) for the general population and 0 to 10% for children. The Meeting concluded that the short-term intake of residues of fluopyram from uses considered by the Meeting is unlikely to present a public health concern.

Scheduling status

Fluopyram is not specifically scheduled.

Fluopyram is a member of the chemical class namely pyridylethylamides. It is also identified as a member of the benzamide and pyridine class of fungicides.

Diflubenzuron (a benzmide class of substance) is listed in Schedule 5.

Pyridine fungicides, namely pyrifenox (Schedule 5), fluazinum (Schedule 6) and boscalid (Appendix B) are listed in the Poisons Standard.

Scheduling history

Fluopyram has not been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

No submissions were received.

Summary of ACCS advice to the delegate

The committee recommended an entry in Schedule 5 for preparations containing more than 50 per cent of fluopyram.

The committee supported the implementation date of 1 June 2015.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (c) the toxicity of a substance.

The reasons for the recommendation comprised the following:

  • Evidence of a carcinogenic effect at high doses for which the mode of action has not been fully established.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • SPF scheduling factors;
  • Other relevant information.
Delegate's interim decision

The delegate accepts ACCS advice that a new entry in Schedule 5 be created for fluopyram, with a cut-off to exempt at 50 per cent. The low acute and chronic toxicity of fluopyram, and its overall toxicity profile is consistent with the Scheduling Policy Framework criteria for listing in Schedule 5. The apparent differences in interpretation of the carcinogenicity findings between the three agencies that collaborated in the joint global review was noted. The purported mode of action (MoA) evidence at high levels of exposure tended to discount the significance of human carcinogenic potential as a matter for scheduling consideration for at least the observed thyroid tumours. The proposed MoA for the hepatocellular tumours was not considered to be so conclusive. The delegate agrees with the ACCS that listing in Schedule 5 provides for appropriate warning levels and access controls. Furthermore, an appropriate set of First Aid and Safety Directions are recommended to the APVMA to be applied to the exempt product.

The delegate agrees with the implementation date 1 June 2015.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: c) the toxicity of a substance.

Public submissions on the interim decision

No public submissions were received.

Delegate's final decision

The delegate confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

The delegate has confirmed the proposed implementation date of 1 June 2015.

Schedule entry
Schedule 5 - New entry

FLUOPYRAM except in preparations containing 50 per cent or less of fluopyram.

1.8 Methyl ethyl ketone oxime or 2-Butanone, oxime

Scheduling proposal

The delegate referred the following scheduling proposal for consideration by the ACCS:

  • To amend the current Schedule 6 methyl ethyl ketone oxime entry to exempt from scheduling for silicone adhesive and sealant preparations containing 2.5% or less of methyl ethyl ketone oxime.

The committee was asked to discuss and consider the resolutions with an implementation date of 1 June 2015/1 October 2015/1 February 2016.

In May 2014, the delegate received an application to consider a proposal to amend the current Schedule 6 methyl ethyl ketone oxime (MEKO) entry to exempt from scheduling for silicone adhesive and sealant preparations containing 2.5% or less of MEKO.

The reasons for the request were:

  • silicone adhesives and sealant preparations contain oximosilane cross-linkers and the corresponding hydrolysis product namely 2-butanone oxime (also known as MEKO).
  • MEKO, in general, has irritation and skin sensitisation potential. Silicone adhesive and sealant preparations containing up to 7.1% of MEKO (in sum of free and hydrolysable MEKO), however, are not considered to be hazardous.

Delegate's reasons for referring this to the committee

The delegate's reason for referring this scheduling proposal to the ACCS was that, this matter was initially referred via a NICNAS IMAP report and considered at the November 2013 meeting of the ACCS. At that time, the ACCS recommended listing in Schedule 6, with an exemption cut-off of 1%. A product sponsor has now requested reconsideration of the exemption cut-off for a specific range of products (silicone adhesives and sealants). The SPF suggests that the Delegate seek advice from the ACCS in relation to any re-scheduling application. The delegate noted that the application had been made using an appropriate format, and that supplementary toxicity studies had been provided in support of the submission.

The delegate sought the following specific advice from the ACCS:

  • In accepting ACCS advice that methyl ethyl ketoxime be listed in Schedule 6, the delegate noted that the critical toxicological endpoints driving this categorisation (severe eye irritancy and sensitisation potential) are consistent with SPF factors for listing in Schedule 6, with the public health risk sufficiently ameliorated for products containing less than 1% to be exempted from scheduling.
  • The delegate noted that the ACCS considered the sensitising potential of preparations similar to those the subject of this re-scheduling request. An extract from the records of the November ACCS 2013 meeting reflects this consideration:
  • "The Committee considered an appropriate low level cut-off to exempt from scheduling for methyl ethyl ketone oxime. It is anticipated that it would be used as an anti-skinning agent in the formulation of alkyd paints, varnishes, stains and coatings for domestic use and found at concentrations up to 1 per cent. The chemical will also be used as minor components in some silicone sealants (up to 5 per cent). It was noted that animals exposed to 3 per cent of methyl ethyl ketone oxime resulted in significant skin sensitisation. The Committee noted that preparations containing the substance would not be deliberately applied on to the skin therefore the risk at 1 per cent or less is tolerable rather than negligible. Members considered that a low concentration exemption cut-off at 1 per cent or less of methyl ethyl ketone oxime to exempt from scheduling would be appropriate."
  • The skin sensitisation studies in the NICNAS IMAP report that lead to this conclusion were conducted with pure methyl ethyl ketoxime, at concentrations ranging from 3% to 50%.
  • Noting that the applicant has submitted skin sensitisation studies that demonstrate no sensitisation potential for two products containing oximosilane cross-linked silicone, with some residual methyl ethyl ketoxime, does the ACCS support raising the exemption cut-off to 2.5% for this specific type of product?
  • Does the ACCS support adoption of exemption clauses similar to those proposed in the application:

Schedule 6: METHYL ETHYL KETONE OXIME, except:

  1. In viscous silicone adhesives or viscous silicone sealants containing 2.5 per cent or less of free methyl ethyl ketone oxime
  2. In other preparations containing 1 per cent of less of methyl ethyl ketone oxime.

Substance summary

MEKO is part of the chemical grouping discrete organics and the chemical sub-grouping oximes, or more specifically, ketoximes.

The most prevalent use of MEKO is as an anti-skinning agent in the formulation of alkyd paints3, primers, varnishes and stains, to prevent oxidative drying and the formation of hard, gelatinous films on the surface of the paint product in the container. The majority of these uses were in the manufacture of alkyd paint products for both industrial and consumer applications. The substance is also present as a formulant in several pesticide products, namely wood preservatives and antifouling marine paints. In addition, it is a minor component of some sealants and adhesives and, to a lesser degree, of some fillers and artists' paint and printing materials.

MEKO is also used as a corrosion inhibitor in industrial boilers and water treatment systems and as a blocking agent in the manufacturing process of urethane polymers4.

image of a chemical structure of MEKO
Figure 3. Structure of MEKO

Acute toxicity

The applicant provided skin irritation, eye irritation and skin sensitisation toxicity studies. In September 2013, NICNAS, under its IMAP programme, requested the delegate consider listing MEKO in Schedule 6. NICNAS provided an evaluation report and scheduling recommendation on MEKO.

The acute toxicity end-points for the chemical are listed in the below table.

Toxicity Species Methyl ethyl ketone oxime SPF Classification
Acute Oral LD50 (mg/kg bw) Not provided Not provided Unable to assess
Acute Dermal LD50 (mg/kg bw) Not provided Not provided Unable to assess
Acute Inhalational LC50 (mg/m3/4h) Not provided Not provided Unable to assess
Skin irritation Rabbits Non-irritant
Eye irritation Rabbits Slight irritant
Skin sensitisation (Closed patch Test) Guinea pig Non-sensitiser
Repeat-dose toxicity

No information was provided.

Mutagenicity, genotoxicity and reproduction and developmental toxicity

No information was provided.

Observations in humans

No information was provided.

Public exposure

No information was provided.

The Secretariat obtained the following information from Health Canada's report on 2-butanone, oxime (butanone oxime)5.

With regard to consumer products, butanone oxime is most prevalent in alkyd paints, stains, varnishes and coatings. Butanone oxime is also present in a few sealants, adhesives and fillers that are used mainly by industry, but which may also be available to the general population for home maintenance and do-it-yourself applications. Accordingly, use of alkyd paint containing butanone oxime was the primary scenario used to characterize exposure from products.

A limited number of studies report concentrations of butanone oxime during manufacture and use of products such as alkyd paints. A US study of consumer exposure to butanone oxime predicted a maximum concentration of butanone oxime in indoor air of 18 mg/m3 based on the use of alkyd paint containing 0.293% w/w butanone oxime, the highest level of butanone oxime that was present in the products tested. A limited unpublished study measured butanone oxime concentrations of up to 9.9 ppm (30 mg/m3) during a simulation using an indoor painting scenario with an alkyd paint containing approximately 0.2% butanone oxime.

There were no identified data on absorption of butanone oxime following inhalation exposure. While dermal absorption have been reported to range between 13% and 29% in a study conducted in rats, the estimates of internal exposure were derived using 100% uptake for inhalation and dermal absorption.

Based on the available information, the most likely route of exposure to butanone oxime for the general population is from inhalation during use of alkyd paints and coatings.. However, in light of the limited data available on concentrations in environmental media, confidence in this estimate is very low.

International regulations

No information was provided.

The Secretariat has obtained the following.

No current use of butanone oxime in cosmetics has been notified in Canada6.

The use of butanone oxime in cosmetics is prohibited in Denmark and in the United Kingdom (in accordance with an amendment to Directive 76/768/EEC of the European Commission (European Commission 2004)9

The NICNAS's IMAP report notes the following restrictions apply:

  • Association of Southeast Asian Nations (ASEAN) Cosmetic Directive Annex II Part 1: List of substances which must not form part of the composition of cosmetic products; and
  • New Zealand Cosmetic Products Group Standard. Schedule 4: Components Cosmetic Products Must Not Contain.
Scheduling status

Methyl ethyl ketone oxime is listed in Schedule 6 and Appendix E.

Schedule 6

METHYL ETHYL KETONE OXIME except in preparations containing 1 per cent or less of methyl ethyl ketone oxime.

Appendix E
Poisons Standard statements
Methyl ethyl ketone oxime

A - For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once).

E1 - If in eyes washout immediately with water.

S1 - If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water.

Other similar substances, such as methyl ethyl ketone and methyl ethyl ketone peroxide are included in Schedule 5 and Appendices E and F.

Schedule 5

METHYL ETHYL KETONE except in preparations containing 25 per cent or less of designated solvents.

Schedule 5

METHYL ETHYL KETONE PEROXIDE.

Scheduling history

In April 2014, the chemicals scheduling delegate, based on the advice from the ACCS, decided to include preparations containing more than 1% MEKO is Schedule 6. The delegate also decided to create an Appendix E entry for MEKO.

Pre-meeting public submissions

No submissions were received.

Summary of ACCS advice to the delegate

The committee recommended that the current Schedule 6 methyl ethyl ketone oxime entry be amended to exempt from scheduling viscous silicone adhesives or viscous silicone sealants containing 2.5% or less of methyl ethyl ketone oxime.

The committee supported the implementation date of 1 June 2015.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the recommendation comprised the following:

  • The form of the presentation of this material mitigates the acute irritation and skin sensitisation effects at the relevant concentration.
Delegate's considerations
  • The delegate considered the following in regards to this proposal:
  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • SPF scheduling factors;
  • Other relevant information.
Delegate's interim decision

The delegate accepts the advice from the ACCS and agrees to add the proposed exemption clause to the current Schedule 6 entry for methyl ethyl ketone oxime. The additional information provided by a sponsor of silicone sealant products containing methyl ethyl ketone oxime shows that the risks or skin irritancy/sensitization are sufficiently ameliorated at concentrations up to 2.5%.

The delegate agrees with the implementation date 1 June 2015.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (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; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

Schedule entry
Schedule 6 - Amendment

METHYL ETHYL KETONE OXIME except:

  1. in viscous silicone adhesives or viscous silicone sealants containing 2.5% or less of methyl ethyl ketone oxime; or
  2. in other preparations containing 1 per cent or less of methyl ethyl ketone oxime.

Footnotes

  1. Reasoned opinion on the modification of the existing MRLs for fenpyrazamine in apricots, cherries, peaches and plums. European Food Safety Authority. Accessed on 1 September 2014. Available at [http://www.efsa.europa.eu/en/efsajournal/pub/3619]
  2. Fluopyram. New Active Ingredient Review April 2012, Minnesota Department of Agriculture. Accessed 26 August 2014
  3. Burka, 1999 Methyl Ethyl Ketoxime (CAS No. 96-29-7) Administered in Drinking Water to F344/N Rats and B6C3F Mice. U.S. Department of Health and Human Services Public Health Service National Institutes of Health.
  4. 2-Butanone, oxime (Butanone oxime) Environment Canada, Health Canada.
  5. 2-Butanone, oxime (Butanone oxime) Health Canada.
  6. 2-Butanone, oxime (Butanone oxime) Environment Canada, Health Canada.
  7. Commission Directive 2004/93/EC of 21 September 2004.

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