You are here

Scheduling delegate's final decisions: ACCS/ACMS, April 2014

Scheduling medicines and poisons

14 April 2014

Book pagination

Part A - Final decisions on matters referred to an expert advisory committee (ACCS) - 1.1-1.5

1. Scheduling proposals referred to the November 2013 meeting of the Advisory Committee on Chemicals Scheduling (ACCS) - ACCS # 9

1.1 Aminopyralid

Scheduling proposal

On 23 August 2013, Office of Chemical Safety (OCS) requested that the delegate consider a proposal to amend the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) to include aminopyralid, present as the triisopropanolamine (TIPA) salt in Schedule 5. The testing provided by the applicant was not conducted by using 100 per cent aminopyralid TIPA and therefore, the OCS considers there is insufficient information to support a recommendation for a Schedule 5 entry for aminopyralid TIPA as a separate active constituent from aminopyralid to the scheduling delegate.

The applicant also proposed an alternative, which is to include the product in Schedule 5. Since scheduling is compound specific rather than product specific, it is not possible to include the applied product in Schedule 5 directly.

The product contains aminopyralid and is therefore currently classified as a Schedule 6 poison. Based on the acute toxicology profile of the product as demonstrated by the acute toxicity testing supplied by the applicant and given that there is a low hazard from repeated use, this classification is not considered appropriate.

The OCS recommends a new Schedule 5 entry for aminopyralid. This amended entry would result in a Schedule 5 classification for the product.

The delegate considered the proposal for referring this scheduling proposal to the Advisory Committee on Chemicals Scheduling (ACCS) was that, in accordance with section 4.2 of the Scheduling Policy Framework1 (SPF, 2010), advice is required to be obtained from an expert advisory committee for all rescheduling proposals.

The delegate sought for the following specific advice from the ACCS:

  • Does the ACCS support the scheduling proposal to amend the current Schedule 6 entry for aminopyralid to provide a cut-off to Schedule 5 at 0.5 per cent for the product under consideration in the OCS report?
  • Noting that the Schedule 6 entry for aminopyralid appears to be primarily driven by its severe eye irritancy, rather than other aspects of its toxicity profile (which appear to be consistent with Appendix B), does the ACCS consider that a further review of aminopyralid scheduling is warranted?

Noting that the toxicity profile of picloram, the other active component of the product, is possibly more consistent with SPF factors for Schedule 5 than Appendix B, and that the Appendix B status for picloram was conferred in 1987, is there any basis for review of the schedule entry for picloram? There are 89 products containing picloram on PUBCRIS2, although many of them may not be impacted by a scheduling change because of multiple active ingredients.

Substance details

The product contains the active constituents, aminopyralid and picloram which are structurally related to compounds such as triclopyr, fluroxypyr and 2,4-D. Aminopyralid causes epinasty (curled leaves) followed by necrosis.

The product is intended for use by direct application to control woody weeds, wild tobacco trees, rhizomatous plants, wandering jew and herbaceous weeds.

Aminopyralid is a synthetic auxin and picloram is an auxin mimic.

Acute toxicity

The summary of acute toxicity studies is shown in the table below.

End-point of acute toxicity Aminopyralid Picloram Product SPF*
Acute oral toxicity LD50 (mg/kg bw) >5000 3536 (Female) >5000 Low toxicity
Acute dermal toxicity LD50 (mg/kg bw) >5000 >2000 >5000 Low toxicity
Acute inhalational toxicity LC50 (mg/kg bw/4h) >5500 >1630 >5080 Low toxicity/moderate to high toxicity
Skin irritation Non-irritant Slight irritant Non-irritant
Eye irritation Severe irritant Slight - moderate irritant Slight irritant
Respiratory irritation No data No data No data
Skin sensitisation Non-sensitiser Sensitiser Non-sensitiser

*Scheduling Policy Framework for Medicines and Chemicals (2010)

Repeat-dose toxicity

Effects on various organs were observed in oral repeat-dose studies using aminopyralid or aminopyralid TIPA. In the case of the liver, there was an increase in hepatocyte size with altered cytoplasmic staining and decreased liver glycogen at 1000 mg/kg bw/d in mice. Higher relative liver weights, associated in some cases with very slight hypertrophy of centrilobular to midzonal hepatocytes, were observed at 967 mg/kg bw/d in male dogs and at 1038 mg/kg bw/d in females. A dermal repeat-dose study found slight chronic focal inflammation of the liver in male rats at 500 mg/kg bw/d.

The caecum was affected in a number of rat studies. Increased caecum size and/or weight was observed in four studies in rats, at dose levels between 500 mg/kg bw/d and 1000 mg/kg bw/d. In two of these studies, increased caecum weights were associated with very slight hyperplasia of the caecal mucosal epithelium of the rats at 1000 mg/kg bw/d.

In dogs, effects on the stomach included a slight, diffuse hyperplasia and hypertrophy of the mucosal epithelium of the stomach at 1070 mg/kg bw/d in males and at 929 mg/kg bw/d in females. Another study found diffuse thickening of the stomach mucosa, slight diffuse mucosal hyperplasia and hypertrophy, slight chronic mucosal inflammation and slight lymphoid hyperplasia of the stomach mucosa, in male and females at 967 mg/kg bw/d and 1038 mg/kg bw/d, respectively.

No kidney pathology was observed. However there were reductions in urine pH and decreased urine protein and ketones at 1000 mg/kg bw/d in rats. In another rat study, there was increased urine volume, with decreased urine specific gravity, pH, protein and ketones at 1000 mg/kg bw/d. A study using aminopyralid TIPA found increased urine volume and decreased urine specific gravity at 1000 mg/kg bw/d in rats.

Neurotoxicity

A chronic neurotoxicity study found occurrences of sinusoidal dilatation within the pars distalis of the pituitary gland in male and female rats at dose levels of 1000 mg/kg bw/d.

Genotoxicity

A range of genotoxicity studies were performed with aminopyralid and aminopyralid TIPA. The only effect was a weak clastogenic response in rat lymphocyte cultures treated continuously with aminopyralid for 24 hours without activation by S9.

Reproduction and developmental toxicity

A reproductive study in rats found no effects of aminopyralid in terms of reproductive or neonatal toxicity at 1000 mg/kg bw/d, the highest dose level tested. A variety of developmental studies using aminopyralid or aminopyralid TIPA found no effects on foetal development, with the possible exception that certain skeletal variations were more common in foetuses from rats treated with aminopyralid TIPA, although there were no dose-response effects.

A neurotoxic effect, viz. incoordinated gait, was first observed in developmental studies on aminopyralid involving rabbits. A study using aminopyralid TIPA found three cases of transient incoordination, associated with repetitive chewing behaviour in two of the three cases, among 26 rabbits at a dose level of 150 mg/kg bw/d. A no observed effect level (NOEL) for maternal effects was established at 50 mg/kg bw/d of aminopyralid TIPA (equivalent to 26 mg/kg bw/d of aminopyralid).

Scheduling status

Aminopyralid is currently listed in Schedule 6.

Scheduling history

Aminopyralid was first considered by the NDPSC at their June 2005 meeting as a new active constituent.

The committee considered an application for the registration of a herbicide product, an emulsion, oil in water, formulation containing 10 g/L of the new active ingredient aminopyralid, present as the triisopropanolamine (TIPA) salt. As part of this application for the registration of the herbicide product, approval was also sought for the new active constituent aminopyralid.

The committee noted the following points raised by the OCS evaluation report for consideration.

  • Aminopyralid has low oral toxicity in rats with an LD50 > 5000 mg/kg (relative to body mass) in males and females. It has a low dermal toxicity (LD50 > 5000 mg/kg) in male and female rats and low inhalation toxicity (LC50 > 5500 mg/m3) in male and female rats. It is non-irritating to rabbit skin and non-sensitising to guinea pig skin. Aminopyralid is, however, a severe eye irritant in rabbits.
  • Oral repeat dose studies produced a range of effects, but common effects at lower doses were increased caecum size and weight, increased urine volume, decreased urine specific gravity, decreased urine pH.
  • No carcinogenic effects were observed.
  • No reproductive, neonatal, foetotoxic or teratogenic effects were observed.
  • The only genotoxic effect was a weak clastogenic response in rat lymphocyte cultures treated with aminopyralid for 24 h without activation by S9. A range of other studies were negative: Salmonella-Escherichia coli/mammalian-microsome reverse mutation assay; Chinese hamster ovary cell/hypoxanthine-guanine-phosphoribosyl transferase (CHO/HGPRT) forward mutation assay; mouse bone marrow micronucleus test; (with product containing 41.3 per cent aminopyralid TIPA in aqueous solution) Salmonella-Escherichia coli/mammalian-microsome reverse mutation assay; in vitro chromosomal aberration assay utilising rat lymphocytes; Chinese hamster ovary cell/hypoxanthine-guanine-phosphoribosyl transferase (CHO/HGPRT) forward mutation assay; mouse bone marrow micronucleus test.
  • Transient incoordination was seen in pregnant rabbits at single doses of aminopyralid TIPA of 150 mg/kg.
  • Overall, the noteworthy toxicological effects of aminopyralid were severe eye irritancy and transient incoordination in pregnant rabbits shortly after dosing with 150 mg/kg (equivalent to 78 mg/kg aminopyralid). Given the potential for eye irritation, NDPSC in 2005 considered that aminopyralid be placed in Schedule 6.
  • An aqueous gel formulation containing 0.5% aminopyralid has a low oral LD50 of 5000 mg/kg in female rats, a low dermal toxicity with an LD50 > 5000 mg/kg in male and female rats, and low inhalation toxicity with an LC50 > 5260 mg/m3 in male and female rats. It is a moderate skin irritant in rabbits but not a skin sensitiser in guinea pigs. It is a severe eye irritant in rabbits.

The committee considered that the severe eye irritancy of an aqueous gel formulation may be related to the presence of aminopyralid, despite its relatively low concentration in this product. The other active ingredient in the formulation was only a slight eye irritant. However other excipients undoubtedly contributed to the severe eye irritancy of the formulation. The eye irritancy of aminopyralid was the principal toxicological finding for placing to it in Schedule 6. The company had not provided any data to support a cut-off to a lower schedule.

The NDPSC agreed that based on the assessment of toxicity and having regard to severe eye irritancy, aminopyralid be included in Schedule 6 of the SUSDP.

Public pre-meeting submissions

No public submissions were received for aminopyralid.

ACCS advice to the delegate

The committee recommends that the current Schedule 6 entry for aminopyralid be amended to provide a cut-off to Schedule 5 at 0.5 per cent with an implementation date of 1 June 2014.

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

The reasons for the recommendation comprised the following:

  • Significantly reduced eye irritation.
  • Some scheduling control retained as the product is in the domestic market.
  • Water soluble gel formulation.
Delegate's interim decision

The delegate agrees with the advice of the ACCS that the current Schedule 6 entry be amended to allow an aqueous gel formulation containing 0.5% aminopyralid to be down-scheduled to Schedule 5. While the toxicity profile of the pure chemical is consistent with the SPF factors for listing in Schedule 6, the reduction in eye irritancy associated with the diluted preparation is consistent with SPF factors for Schedule 5. The new Schedule 5 entry is specific for preparations containing 0.5% or less of aminopyralid in an aqueous gel formulation.

The delegate agrees to an implementation date of 1 June 2014.

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

Submissions on interim decision

One public submission was received. The submission indicated that as the delegate's interim decision on aminopyralid had no impact on therapeutic goods, it had no further comments in relation to the delegate's interim decision on the substance.

Delegate's final decision

The delegate has confirmed 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 proposed an early implementation date of 1 June 2014 to facilitate marketing of the product when registered by the APVMA.

Top of page

Scheduling entry

Schedule 6 - reschedule

AMINOPYRALID except when included in Schedule 5.

Schedule 5 - new entry

AMINOPYRALID in water soluble gel formulations containing 0.5 per cent or less of aminopyralid.

1.2 Phosphonium, tributyloctyl-, chloride (1:1)

On 29 August 2013, the delegate received an application proposing the inclusion of phosphonium, tributyloctyl-, chloride (1:1) in Schedule 7. The Schedule 7 proposal was based on data which suggested that the substance has moderate to high acute oral toxicity and is corrosive having the potential to cause severe eye damage. In addition, the substance was classified as being toxic in contact with skin.

The delegate referred the scheduling proposal to the ACCS as phosphonium, tributyloctyl-, chloride (1:1) as data provided regarding the substances toxicological profile warrants scheduling.

While the toxicological profile appears to be consistent with the Scheduling Policy Framework1 (SPF, 2010) factors for listing in Schedule 7 (based on corrosivity and other acute toxicity), there is little (if any) potential for the general public to be exposed to the chemical or products containing it.

The delegate questioned the need for this chemical to be listed in any schedule of the SUSMP given the limitation of its use to industrial settings.

The delegate sought ACCS advice to confirm this opinion and asked that the committee considers the following:

  • Does the ACCS support the delegate's proposal that listing this chemical in any of the schedules of the SUSMP is unnecessary, given its presumed exclusive use in an industrial or manufacturing setting? In an industrial setting, it is presumed the Global Harmonized System or the National Occupational Health and Safety Commission labelling provisions would apply.
  • If not, does the ACCS support listing in Schedule 7? There appears to be some precedent for listing highly toxic industrial chemicals in S7 (e.g. vinyl chloride).
  • Is there a need to develop Appendix E, F and J statements?
Substance details

Phosphonium, tributyloctyl-, chloride (1:1) is an extractant for the removal of impurities during metal refining at ≤73 per cent concentration in aqueous solution.

End-point of acute toxicity Phosphonium, tributyloctyl-, chloride (1:1) SPF*
Acute oral toxicity LD50 (mg/kg bw) 50-300 Moderate to highly toxic
Skin irritation Corrosive

*Scheduling Policy Framework for Medicines and Chemicals (2010)

Due to the corrosive nature of the chemical, acute dermal, acute inhalation, and eye irritancy studies have not been conducted. However, for corrosive substances, the risk of severe damage to the eyes is considered implicit. In addition, the notifier has classified the chemical (at ≤ 73 per cent concentration in aqueous solution) as being toxic in contact with skin.

Repeat-dose toxicity

A repeat dose oral toxicity study (chemical at ≤73 per cent concentration in aqueous solution) established a NOEL of 5 mg/kg bw/day. Toxicological significant effects that were recorded at mid- and/or high dose (30 and 75 mg/kg bw/day) levels included increased salivation and noisy respiration. Reduced kidney, liver and thymus weights were also noted in males treated with 75 mg/kg bw/day. However, these results were not considered by the study authors to be of clinical significance as they were within historical ranges.

Statistically significant increases in haematocrit and haemoglobin were observed in all female treatment groups and there was a statistically significant increase in platelet levels in females treated with 75 mg/kg bw/day. The study authors noted that these results were within historical ranges and therefore considered them to be toxicologically insignificant. There were no noted effects for blood chemistry parameters.

Genotoxicity/mutagenicity

Bacterial reverse mutation and in vivo micronucleus studies on the notified chemical were negative.

Observations in humans

Not reported.

Occupational health and safety

The primary risks associated with worker exposure will be due to the corrosive and sensitising nature of the chemical (and the toxicity of the chemical via the dermal route). However, dermal and ocular exposure is expected to be minimised by the wearing of PPE. While the chemical is considered to be toxic via the oral route, ingestion is unlikely under the proposed use scenario. Exposure to the chemical via inhalation is not expected under the proposed use scenario.

Provided that control measures are in place to minimise worker exposure, the risk to the health of workers from use of the chemical is not considered to be unreasonable.

Public health

The chemical is intended for use in industrial settings by trained workers. When used in the proposed manner, the risk to public health from the chemical is not considered to be unreasonable.

Scheduling status

Phosphonium, tributyloctyl-, chloride (1:1) has not been specifically scheduled.

Scheduling history

Not applicable.

Public pre-meeting submissions

One public submission was received.

The submitter did not provide comments regarding the delegate's proposal and indicated that it will provide comments, if required, based on delegate's interim decision.

ACCS advice to the delegate

The ACCS recommended that phosphonium, tributyloctyl-, chloride (1:1) does not require a schedule listing.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: (a) the risks and benefits and (b) the purposes for which a substance is to be used and the extent of use of a substance. The reasons for the recommendation comprised the following:

  • Industrial chemicals are managed under occupational, packaging and transport legislation.
  • Solely industrial only. No domestic use flagged. No likelihood of public access.
Delegate's interim decision

The delegate accepts the advice of the ACCS that, given the proposed use patterns for phosphonium, tributyloctyl-, chloride (1:1) are mostly industrial with little potential for public exposures, listing in the Schedules of the SUSMP is not needed to protect public health. Industrial uses are adequately regulated under other legislation.

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 and c) the toxicity of the substance.

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;
  • Scheduling factors2;
  • Other relevant information.
Submissions on interim decision

One public submission was received. The submission indicated that as the delegate's interim decision on the substance had no impact on therapeutic goods, it had no further comments on the delegate's interim decision.

Delegate's final decision

The delegate notes the submissions received in response to publication of the interim decision and 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.

Top of page

1.3 Pyridine, 2-chloro-6- (trichloromethyl)

Scheduling proposal

On 16 September 2013, the delegate received an application proposing the inclusion of pyridine, 2-chloro-6-(trichloromethyl)- in Schedule 6 based on the following reasons as outlined in the Scheduling Policy Framework for Medicines and Chemicals (SPF, 2010):

  • Acute oral and dermal toxicity data indicate the chemical has moderate to high toxicity which may cause death or severe injury if taken internally or in contact with skin or eyes; this profile is consistent with Schedule 6 factors.
  • Skin irritation data indicate the chemical in either encapsulated or non-encapsulated form is a slight irritant which meets the factors for listing in Schedule 5.
  • Eye irritation data indicate the chemical in either encapsulated or non-encapsulated form is a slight to moderate irritant which meets the factors for listing in Schedule 5.
  • Skin sensitisation data indicate the chemical is a moderate skin sensitiser which meets the factors for listing in Schedule 6.
  • Carcinogenicity data indicate the chemical exhibits a moderate risk of producing irreversible toxicity which meets the factors for listing in Schedule 6.

Based on the data provided for the substance, the application also recommends including pyridine, 2-chloro-6-(trichloromethyl)- in Appendix F as the applicant believes that strong warnings and the use of distinctive packaging should apply to the substance.

The delegate sought the following specific advice from the ACCS:

  • Given the proposed use pattern for this chemical, as a nitrogen stabiliser component of fertilizers, with limited direct public exposure potential, is listing in the SUSMP appropriate?
  • If so, is the preferred chemical name for listing 2-chloro-6-(trichloromethyl)-pyridine or the marketing name nitrapyrin?
  • Is Schedule 6 the most appropriate listing, or does the ACCS consider that the potential for carcinogenicity warrants inclusion in Schedule 7?
  • Does the apparently lower acute toxicity profile of a micro-encapsulated (20 per cent) formulation warrant a scheduling exemption at this level?
  • Noting that the application suggests hazard labelling for potential sensitisation and carcinogenicity for mixtures >1 per cent, is any scheduling cut-off appropriate? [The application notes that ≥1per cent Conc. <10 per cent: H317, H351. Skin sensitisation (Category 1): H317 - May cause an allergic skin reaction and Carcinogenicity (Category 2): H351 - Suspected of causing cancer].
  • To what extent is there likely to be conflict between any labelling controls applied through scheduling and hazard labelling imposed under workplace labelling controls (GHS)?
  • Given that the agricultural application pattern is comparable to that for pesticides, but the chemical is apparently not eligible for registration by the APVMA, will mixer-loaders, appliers and bystanders be adequately informed of the potential risks by Appendix E & F statements? If so, what Appendix E & F statements does the ACCS recommend?
Substance details

The chemical (at ≤22 per cent concentration) is intended to be used as a nitrogen stabiliser for use on crops and pastures. The chemical acts by delaying nitrification of ammonia and urea nitrogen fertilisers through the inhibition of soil bacteria. The chemical will be introduced (and used) in a microencapsulated form (suspension capsules), which is designed to decrease the loss of the notified chemical through volatilisation during use. The capsules are within the respirable range (<10 μm).

Pyridine, 2-chloro-6-(trichloromethyl)- acts by delaying nitrification of ammonia and urea nitrogen fertiliser through the inhibition of soil bacteria. It will be mixed with other products (e.g. fertiliser or pesticides) and then applied to crops or pastures, most likely via low boom spray.

Figure 1. Structure of 2-chloro-6-(trichloromethyl)-pyridine

image of Figure 1. Structure of 2-chloro-6-(trichloromethyl)-pyridine

End-point of acute toxicity Pyridine, 2-chloro-6-(trichloromethyl)- SPF*
Acute Oral Toxicity LD50 (mg/kg bw) < 252 in guinea pigs, 1072 in rats Moderate to high toxicity
Acute Dermal Toxicity LD50 (mg/kg bw) 848 Moderate to high toxicity
Acute Inhalation Toxicity LD50 (mg/m3) Inconclusive Inconclusive
Skin irritation Slight irritant
Eye irritation Moderate irritant
Respiratory irritation Inconclusive
Skin sensitisation Sensitiser

*Scheduling Policy Framework for Medicines and Chemicals (2010)

Repeated dose toxicity

Oral

In a subchronic oral study, rats (10/sex/dose) were administered dietary doses of the notified chemical at 0, 10, 40 or 120 mg/kg bw/day. The no observed adverse effect level (NOAEL) was established as 10 mg/kg bw/day in this study, based on increased liver weights, nephrosis and tubule degeneration/regeneration in males treated at 40 mg/kg bw/day and above, and brown pigment in the convoluted tubule in females treated at 40 mg/kg bw/day and above.

In a subchronic oral study, mice were administered dietary doses of the notified chemical up to 800 mg/kg bw/day. Mortalities were observed in all 600 mg/kg bw/day (10 males and 10 females) and 800 mg/kg bw/day (10 females) groups. The females treated at 800 mg/kg bw/day died mostly within the first week of treatment. The males and females treated at 600 mg/kg bw/day died between one to two months of treatment. Male groups that completed 3 months treatment were administered 0, 200, 300 or 400 mg/kg bw/day (10/dose), and females were administered 0, 200 or 400 mg/kg bw/day (10/dose). There were numerous treatment related haematology changes in males and females treated at 400 mg/kg bw/day. Additionally there were increases in aspartate aminotransferase in males treated at 400 mg/kg bw/day, and increases in alanine aminotransferase in males and females treated at 400 mg/kg bw/day and in males treated at 300 mg/kg bw/day. There were dose related increases in liver weights in all treatment groups, accompanied by dose related hypertrophy. Other histopathological findings were in the liver and were observed at 300 mg/kg bw/day and above. Liver toxicity was evident from this study and a lowest observed effect level (LOAEL) was established as 200 mg/kg bw/day based on effects observed at the lowest dose.

Top of page

Dermal

In a 21-day dermal study, rabbits (5/sex/dose) were administered the notified chemical at 0, 100, 500 or 1 000 mg/kg bw/day. The NOAEL for systemic toxicity was 500 mg/kg bw/day based on increased liver weights at 1000 mg/kg bw/day. Slight to well defined erythema and oedema were observed in all treated groups, indicating dermal irritation.

Inhalation

The acute inhalation study tested a vapour concentration of ~0.03 mg/L. Based on the low concentration of the notified chemical tested in this study, a conclusion on the potential for acute inhalation toxicity (and relevant hazard classification) could not be drawn. However, it is noted that the notified chemical has an airborne exposure standard: TWA = 10 mg/m3, STEL = 20 mg/m3.

Mutagenicity/genotoxicity

Pyridine, 2-chloro-6-(trichloromethyl)-l is not considered to be mutagenic in vivo based on negative results in two separate bacterial reverse mutation tests, in an in vitro mammalian cell gene mutation test, in an in vivo unscheduled DNA synthesis study and in an in vivo micronucleus study in mice.

Carcinogenicity

Carcinogenic effects (in the liver, stomach, epididymis and Harderian gland) were noted in mice treated with pyridine, 2-chloro-6-(trichloromethyl)- at 125 and 250 mg/kg bw/day. In 2005, the notified chemical was classified by the US EPA as 'Likely to be carcinogenic to humans', The epididymal sarcomas that were observed in mice administered the notified chemical at 125 (2/50) and 250 mg/kg bw/day (4/50), but not in the concurrent control group, were originally considered to be treatment related by the US EPA and formed part of the basis for carcinogenicity classification. Epididymal tumours were also observed in another 2-year carcinogenicity study in mice treated with the notified chemical at 25-75 mg/kg bw/day (at 75 mg/kg bw/day; 1/50 Leydig cell tumour) and in control animals (2/50 Leydig cell tumour and 1/50 histiocytic sarcoma).

Samples from these studies were recently re-evaluated by a pathology working group by immunohistochemical staining. The tumours that were originally classified as Leydig cell tumours by the original study pathologists, were subsequently classified by the pathology working group as histiocytic sarcomas (i.e., 3/50 in controls and 1/50 in the 75 mg/kg bw/day group). Similarly, the working group confirmed that the epididymal sarcomas that were observed in the mice treated at 125 and 250 mg/kg bw/day were histiocytic sarcomas. The US EPA agreed with the findings of the working group, and considered that when the data from the two studies are combined, the occurrence of the epididymal histiocytic sarcomas was not related to the notified chemical (US EPA, 2012a).

Regarding the treatment-related increased incidences of liver tumours in mice administered the notified chemical at 125 and 250 mg/kg bw/day, mechanistic data (as discussed above) were submitted to the US EPA to support the proposed mode of action of tumour formation [i.e., induction through activation of the constitutive androstane nuclear receptor (CAR)]. The US EPA considered that cell proliferation and PROD induction data did not support the proposed mode of action for the induction of liver tumours and that the tumours cannot be excluded from being relevant for human cancer hazard assessment. However, it was considered that evidence for the reversibility of the key events had been provided, indicating that a threshold exists for the induction of the liver tumours (US EPA, 2012a).

Based on the available information, the notified chemical is recommended for hazard classification according to the Globally Harmonised System for the Classification and Labelling of Chemicals (GHS), as adopted for industrial chemicals in Australia, as a Category 2 carcinogen.

Developmental toxicity

Studies concluded that pyridine, 2-chloro-6-(trichloromethyl)- was not teratogenic under the conditions of the study, as foetal toxicity was only observed at maternally toxic doses.

Reproductive Toxicity

Studies concluded that pyridine, 2-chloro-6-(trichloromethyl)- was not a reproductive toxicant.

Scheduling status

Pyridine, 2-chloro-6-(trichloromethyl)- is not specifically scheduled.

Scheduling history

Not applicable

Public pre-meeting submissions

Two public submissions were received.

One submission noted that although the delegate's proposal did not appear to have any impact on therapeutic goods, the submission requested that the drafting of any scheduling amendment should be in such a way to avoid any unintended impact on therapeutic goods.

The other submitter did not provide comments regarding the delegate's proposal and indicated that it will provide comments, if required, based on delegate's interim decision.

ACCS advice to the delegate

The ACCS recommended that 2-chloro-6-(trichloromethyl)-pyridine be included in Schedule 6.

The ACCS recommended an implementation date of 1 June 2014.

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

The reasons for the recommendation comprised the following:

  • The risk is the potential toxicity to end users. The benefit is enhancing the efficacy of agricultural fertilizers.
  • Concern of the potential leakage of the commercial products getting to the domestic market.
  • Toxicity profile is consistent with S6 factors in SPF.
  • Microcapsule presentation reduces human exposure.
Delegate's interim decision

The delegate accepts the advice of the ACCS that a new listing in Schedule 6 be created for 2-chloro-6-(trichloromethyl)-pyridine, with no exemption cut-off. The toxicity profile of the chemical is consistent with SPF factors for listing in Schedule 6, with acute toxicity, skin/eye irritancy and sensitisation potential and some evidence of carcinogenic potential driving this classification. The delegate also notes ACCS advice that the microencapsulated formulation may ameliorate skin-eye irritancy potential to some extent, but this formulation approach does not warrant a lower schedule. The delegate also notes that the ACCS did not propose allocating First Aid, Warning Statements or Safety Directions via listing in Appendices E & F. The ACCS advice was that such label warnings would be addressed under GHS labelling code provisions.

The delegate agrees with the implementation date being 1 June 2014.

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

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;
  • Scheduling factors3;
  • Other relevant information.
Submissions on interim decision

One public submission was received. The submission indicated that as the delegate's interim decision would not have impact on therapeutic goods, it had no further comments on the delegate's interim decision.

Delegate's final decision

The delegate has confirmed 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.

Scheduling entry
SCHEDULE 6 - new entry

2-CHLORO-6-(TRICHLOROMETHYL)-PYRIDINE.

Top of page

1.4 Sulfites

Scheduling proposal

On 17 September 2013, NICNAS under the Inventory Multi-tiered Assessment Prioritisation (IMAP) Tier II human health assessment process, recommended that the delegate consider a proposal to include sulfites (salts of sulfurous and disulfurous acids) in Schedule 5 with potential lower concentration cut-off level.

The NICNAS IMAP report includes the following chemicals:

  • Sulfurous acid, monosodium salt
  • Disulfurous acid, disodium salt (1:2)
  • Disulfurous acid, disodium salt
  • Sulfurous acid, disodium salt
  • Sulfurous acid, dipotassium salt
  • Sulfurous acid, monoammonium salt
  • Sulfurous acid, diammonium salt
  • Disulfurous acid, dipotassium salt.

The NICNAS proposal for these substances is based on the following considerations:

  • The general public may be exposed to the chemical through oral, dermal and inhalation routes when using cosmetic/domestic products containing these chemicals.
  • New Zealand and the European Union (EU) have restricted the use of these chemicals in cosmetics. The EU also has restrictions on using sodium bisulfite (CAS no: 7631-90-5) in plastics with food contact use.
  • The characterised critical health effects (such as severe eye irritation and liberating toxic gas when in contact with acid) have the potential to pose an unreasonable risk under the uses identified. The risks could be mitigated by implementing concentration limits for certain uses to reduce exposure.
  • Sensitivity to sulfites is more likely to be related to exposure via food and beverages than to circumstances related to industrial use

The IMAP report stated that the EU Scientific Committee on Cosmetic products and Non Food Products (SCCNFP) concluded that sulfites (as free SO2) do not pose any unacceptable risk to human health when used in cosmetic formulations at the intended use concentrations (up to 0.67 per cent in oxidative hair dye products, up to 6.7 per cent in hair waving/straightening products, up to 0.45 per cent in self-tanning products for the face and up to 0.40 per cent in self-tanning products for the body).

The delegate considered the proposal for creating a new Schedule 5 for sulphites, i.e. salts of sulfurous and disulfurous acids, with appropriate amendments to the current Schedule 5 entry for sodium metabisulfite, to align with EU restrictions on the use of sulfites in cosmetics and to consider appropriate cut-offs to exemption from the proposed Schedule 5 entry.

Sodium metabisulfite is the only sulfite (salt of sulfurous or disulfurous acid) currently listed (Schedule 5) in the SUSMP with a cut-off to exempt at 10 per cent. The NICNAS IMAP report addresses the need to create a new Schedule 5 entry covering all the sulfites evaluated under the IMAP program, primarily to address the potential for inhalational irritancy associated with their use as preservatives in a variety of consumer products. The intent is to align Australian scheduling restrictions with those in EU Health and Consumers Cosmetic regulations (Annex III/99 and VI/9). Because of the potential impact on Australian industry associated with this scheduling proposal, the advice of the ACCS is required.

The delegate sought the following specific advice from the ACCS:

  • Does the ACCS support the need for new scheduling restrictions on consumer products containing sulfites as a preservative? Note that because of the general Appendix A exemption for food additives in food, this should not impact on those uses.
  • Can the ACCS propose a suitable cut-off to exempt from such an entry in Schedule 5 (noting that the current sodium metabisulfite entry has a 10 per cent cut-off)?
  • Is implementation of the NICNAS-proposed restrictions on use of sulfites in cosmetics best achieved through drafting a new specific entry in Appendix C, or should the proposed Schedule 5 entry provide a sufficient level of control? Does the ACCS support listing in Schedule 5 under the generic name sulfites, rather than the full list of names included in the NICNAS IMAP report?

Is there a need for Appendix E and F statements for sulfites when included in Schedule 5?

For sodium and potassium metabisulfite these statements are inconsistent in the current SUSMP. Appendix E First Aid statements for the potassium salt are A (only), while the sodium salt requires A and G3; the Appendix E warning statements for both the potassium and sodium salts are 5, 26, with safety directions 1,4, but for the sodium salt, they are only applicable to preparations containing 50 per cent or more. Use of SD 4 (avoid contact with skin) seems inappropriate if applicable to cosmetic products.

Substance details

Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) Human Health Tier II Assessment Report, which is available on from the NICNAS website.

Scheduling status

The above sulfites are not currently scheduled.

Sodium metabisulphite and potassium metabisulphite (both of which belongs to the group of sulfites) are scheduled as follows:

Top of page

Schedule 5

SODIUM METABISULPHITE when packed for domestic use except in preparations containing 10 per cent or less of sodium metabisulphite.

POTASSIUM METABISULPHITE when packed for domestic use except in preparations containing 10 per cent or less of potassium metabisulphite.

Scheduling history

A scheduling history for the sulfites is not available.

Public pre-meeting submissions

Three submissions were received.

One submission indicated that sulfites are naturally occurring in food and are also commonly added to food as preservatives. Sulphites are also used in medicines. The submission noted that sulphites in cosmetics can be considered in isolation without considering the prevalent nature of sulphites in foods, beverages and medicines. There are a significant number of individuals with sulfite allergies, serious reactions to sulfites are rare and ingredient labelling disclosure (required by the Australian Competition and Consumer Commission) should inform those individuals suffering from sulfite allergies. This submission did not support scheduling of sulfites.

Another indicated that some of the agenda items include broad substance such as 'sulfites' which a search of the TGA e-BS site shows are present in many different salts and derivatives and are also included in therapeutic goods.

The submission expressed concern that some therapeutic goods regulated by the TGA may inadvertently be affected by the proposed amendments and urges the ACCS to consider that:

  • Amendments to schedules for any of the chemicals should be carefully drafted and worded in such a way that therapeutic goods are excluded.
  • Care should be taken so that entries are as specific as possible so as not to affect all salts and derivatives (unless clearly intended), as some salts and derivatives of substances may be present in therapeutic goods.

The last submission did not provide comments regarding the delegate's proposal and indicated that it will provide comments, if required, based on delegate's interim decision.

ACCS advice to the delegate

The ACCS recommended that sulfites do not require a schedule listing and that the current scheduling of sodium metabisulphite remains appropriate.

Delegate's interim decision

The Delegate accepts the advice of the ACCS that there is no need to amend the current schedule 5 entries for sodium and potassium metabisulfites, with their current exemption levels at 10%, nor to create additional schedule entries for the other listed salts of sulfurous and disulfurous acids (or a more generic entry covering all salts of these acids). The delegate notes the intent of the NICNAS recommendation to limit the use of these SO2-generating preservatives in cosmetics and other consumer products, but it also notes the potential for a more generic schedule entry to inadvertently capture therapeutic goods that use sulphur dioxide (SO2) as a preservative. The delegate notes ACCS advice that there is insufficient evidence of public health concerns associated with long and widespread use of SO2-generating preservatives in cosmetics and other consumer products and that the use of the Schedules to regulate uses beyond existing controls over sodium and potassium metabisulfites is not warranted.

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 the 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 the substance.

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;
  • Scheduling factors4;
  • Other relevant information.
Submissions on interim decision

Two public submissions were received. Both submissions support the delegate's decision of not to amend the current Schedule 5 sodium and potassium metabisulfites entries.

Delegate's final decision

The delegate notes the submissions received in response to publication of the interim decision and 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.

Top of page

1.5 Benzidine-based azo dyes

Scheduling proposal

On 29 August 2013, NICNAS under the Inventory Multi-tiered Assessment Prioritisation (IMAP) process, requested that the delegate consider a proposal to include a group of 11 benzidine-based dyes in Appendix C. The basis for this recommendation is that benzidine-based dyes have the characteristic diazotized benzidine structure but differ with respect to the chemical groups attached at the diazo linkages. All the chemicals are expected to be metabolised in vivo to benzidine (CAS No. 92-87-5), a known human carcinogen. Critical health effects of these chemicals are carcinogenicity, developmental and reproductive toxicity. These chemicals have similar uses.

The delegate's reason for referring this scheduling proposal to the ACCS was that this (referral from the NICNAS IMAP program relates to a group of diazotized benzidine derivatives) chemical is likely to be a component of dyes and stains. NICNAS suggests that the toxicological profile of the chemical warrants scheduling. While the toxicological profile appears to be consistent with the Scheduling Policy Framework factors for listing in Schedule 7 (based on their mutagenicity and carcinogenicity profile and ability to be metabolised to benzidine, a known human carcinogen), listing in Appendix C is another option. The advice of the ACCS was requested to confirm this scheduling proposal.

The delegate sought the following specific advice from the ACCS:

  • Does the ACCS support listing of benzidine-based dyes in Schedule 7, or is a listing in Appendix C more appropriate? The implied objective of the NICNAS IMAP report is to effectively 'ban' the use of these benzidine-based dyes in Australia.
  • Since the NICNAS IMAP report lists eleven separate dyes in this grouping, is it necessary to list each chemical separately, or will a generic entry 'benzidine-based dyes' suffice?
  • There is no current listing of the known human carcinogen benzidine in any schedule (possibly because there are no commercial products containing this chemical. Is a listing for benzidine also warranted in Schedule 7 or Appendix C?
  • What is the potential regulatory impact of scheduling in the way proposed? Are there likely to be any products in retail or domestic use that could be affected?
  • Is there a need to develop specific Appendix E & F statements (and Appendix J if listed in S7)? If so, what does the ACCS suggest?
Substance details

Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) Human Health Tier II Assessment Report, which is available on from the NICNAS website.

Scheduling status

Benzidine-based substances are not specifically scheduled.

Scheduling history

Not applicable.

Public pre-meeting submissions

Two submissions were received.

The first submission did not support the proposal to include benzidine and its salts in Schedule 7. The submitter noted that benzidine and its salts are regulated in jurisdictions that have adopted the Model Work Health and Safety legislation, since it is a prohibited carcinogen. They also noted that it did not believe that benzidine or its salts are being used in any formulated chemical products in Australia. On this basis, and based on the hazard posed by the substance, it supports including benzidine and its salts (excluding derivatives) in Appendix C with a scheduling cut-off of 0.1 per cent to align with the Model Work Health and Safety Regulations. In addition, it did not support including all benzidine derived dyes in Appendix C. The submission raised concern that generic Appendix C Scheduling entry for all benzidine based dyes would have unintended consequences of banning currently useful substances, without properly considering the risks and benefits of each dye.

The second submission did not provide comments regarding the delegate's proposal and indicated that it will provide comments, if required, based on delegate's interim decision.

ACCS advice to the delegate

The ACCS recommended that benzidine-based dyes for domestic used be included in Schedule 7.

The committee also recommended an implementation date of 1 June 2014.

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; and (c) the toxicity of a substance.

The reasons for the recommendation comprised the following:

  • These are useful chemicals but, because they are metabolised to a known human carcinogen (benzidine), access for domestic use needs to be restricted.
  • Concerns about carcinogenicity.
Delegate's interim decision

The delegate accepts ACCS advice that inclusion of benzidine-based dyes in Appendix C is not the most appropriate way of regulating the use of these substances. It is 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. 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 accepts ACCS advice that the specific dyes assessed in the NICNAS IMAP report should be listed in Schedule 7, based on their carcinogenic potential.

A nomenclature issue is raised by this scheduling proposal. It is not feasible to list the chemicals assessed as a group in the NICNAS without further specification of their individual names. Accordingly, the delegate proposes to create a generic entry for BENZIDINE-BASED DYES in Schedule 7, with additional sub-listing of the chemical names, dyestuff common names and descriptors, and possibly CAS numbers. The nomenclature issues should be further addressed during the consultation phase of this interim decision.

The delegate agrees to the implementation date of 1 June 2014.

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 and (c) the toxicity of a substance.

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;
  • Scheduling factors5;
  • Other relevant information.
Submissions on interim decision

Two submissions were received.

One submission supported the delegate's interim decision. The submission indicated that the EU Cosmetics Regulation refer this substance as benzidine-based azo dyes and requested that an alignment of terminology with the EU may be helpful for industry.

The other submission indicated that as the delegate's interim decision on benzidine-based dyes had no impact on therapeutic goods, it had no further comments regarding the delegate's interim decision on this substance.

Delegate's final decision

The delegate notes the submissions received in response to publication of the interim decision and confirms the interim decision, with a slightly modified listing nomenclature, as no evidence has been received to alter the substance of the interim decision. However, noting a comment about the utility of aligning the nomenclature used in schedule listing with EU Regulations, the delegate has decided to modify the name used in the Schedule 7 listing by adding the word 'AZO'. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

The name used in the primary schedule listing has been slightly modified to reflect that these are benzidine-based azo dyes.

Scheduling entry
Schedule 7 - new entry

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

Top of page


Footnotes

  1. Scheduling Policy Framework for Medicines and Chemicals (2010)
  2. Scheduling Policy Framework for Medicines and Chemicals (2010)
  3. Scheduling Policy Framework for Medicines and Chemicals (2010)
  4. Scheduling Policy Framework for Medicines and Chemicals (2010)
  5. Scheduling Policy Framework for Medicines and Chemicals (2010)

Book pagination