Interim Decisions & Reasons for Decisions by Delegates of the Secretary to the Department of Health and Ageing
APRIL 2012 INVITATION FOR FURTHER SUBMISSIONS
Notice under subsection 42ZCZP of the Therapeutic Goods Regulations 1990
A delegate of the Secretary to the Department of Health and Ageing hereby gives notice of delegates’ interim decisions under subsection 42ZCZP of the Therapeutic Goods Regulations 1990 (the Regulations).
This notice provides the interim decisions of delegates, the reasons for those decisions and invites further submissions from the applicant and parties who made a valid submission in response to the original invitation for submissions (published on 14December2011 at www.tga.gov.au/newsroom/consult-scheduling-acms-1110.htm). Edited versions of these submissions are available at www.tga.gov.au/industry/scheduling-submissions.htm.
Further submissions must be relevant to the proposed amendment, must address a matter mentioned in section 52E of the Therapeutic Goods Act 1989 and be received by the closing date (10 May 2012).
Further submissions from parties other than those who made a valid submission in response to the original invitation or the applicant, or those received after the closing date, need not be considered by the delegate.
Please note that all valid submissions received on or before the closing date will be published following removal of confidential information. It is up to the person making the submission to highlight any information which they wish to be considered as confidential. Material claimed to be commercial-in-confidence will be considered against the guidelines for the use and release of confidential information set out in Chapter 6 of the Scheduling Policy Framework (SPF), issued by the National Coordinating Committee on Therapeutic Goods. The SPF is accessible at www.tga.gov.au/industry/scheduling-spf.htm.
Persons making submissions are strongly encouraged to lodge submissions in electronic format (word or unsecured PDF preferred) via the email address provided below. Submissions, preferably in electronic format, should be made to:
Medicines and Poisons Scheduling Secretariat (MDP88)
GPO Box 9848
CANBERRA ACT 2601
e-mail Facsimile 02-6289 2650
The closing date for further submissions is 10 May 2012
Delegate’s reasons for interim decision
February 2012 135
TABLE OF CONTENTS
GLOSSARY 2
Interim Decisions on proposals REFERRED TO AN ADVISORY COMMITTEE 7
1. February 2012 meeting of the Advisory committee on Chemicals Scheduling (ACCS) – ACCS#4 7
1.1 cyflufenamid 7
1.2 diethylphthalate and dimethylphthalate 20
1.3 Flonicamid 33
1.4 formaldehyde and paraformaldehyde 42
1.5 zinc borate, boric acid and borax 50
2. February 2012 meeting of the Advisory committee on MEDICINES Scheduling (ACMS) – ACMS#5 63
2.1 Proposed changes to Part 4 of the SUSMP (The Schedules) 63
2.1.1 Adrenaline 63
2.1.2 Ciclopirox 68
2.1.3 Ibuprofen 77
2.1.4 Loperamide 87
2.1.5 Loratadine 92
2.1.6 Pantoprazole 109
2.1.7 Paracetamol 121
2.2 Proposed changes to part 5 of the susmp 131
2.2.1 Boceprevir 131
2.2.2 Teleprevir 133
GLOSSARY
ABBREVIATION NAME
AAN Australian Approved Name
AC Active Constituent
ACCC Australian Competition and Consumer Commission
ACCM Advisory Committee on Complementary Medicines (formerly Complementary Medicine Evaluation Committee [CMEC])
ACNPM Advisory Committee on Non-Prescription Medicines (formerly Medicines Evaluation Committee [MEC])
ACPM Advisory Committee on Prescription Medicines (formerly Australian Drug Evaluation Committee [ADEC])
ACSM Advisory Committee on the Safety of Medicines (formerly Adverse Drug Reactions Advisory Committee [ADRAC])
ADEC Australian Drug Evaluation Committee (now Advisory Committee on Prescription Medicines [ACPM])
ADI Acceptable Daily Intake
ADRAC Adverse Drug Reactions Advisory Committee (now Advisory Committee on the Safety of Medicines [ACSM])
AHMAC Australian Health Ministers' Advisory Council
APVMA Australian Pesticides and Veterinary Medicines Authority
AQIS Australian Quarantine and Inspection Service
ARfD Acute Reference Dose
ASCC Australian Safety and Compensation Council
ASMI Australian Self-Medication Industry
ARTG Australian Register of Therapeutic Goods
CAS Chemical Abstract Service
CHC Complementary Healthcare Council of Australia
CMEC Complementary Medicine Evaluation Committee (now Advisory Committee on Complementary Medicines [ACCM])
CMI Consumer Medicine Information
COAG Councils Of Australian Governments
CRC Child-Resistant Closure
CTFAA Cosmetic, Toiletry & Fragrance Association of Australia
ECRP Existing Chemicals Review Program
EPA Environment Protection Authority
ERMA Environmental Risk Management Authority (NZ)
FAISD First Aid Instructions and Safety Directions
FDA Food and Drug Administration (US)
FOI Freedom of Information Act 1982
FSANZ Food Standards Australia New Zealand
GHS Globally Harmonised System for Classification and Labelling of Chemicals.
GIT Gastro-intestinal tract
GP General Practitioner
HCN Health Communication Network
HCP Health Care Provider
INN International Non-proprietary Name
ISO International Standards Organization
LC50 The concentration of a substance that produces death in 50% of a population of experimental organisms. Usually expressed as mg per litre (mg/L) as a concentration in air.
LD50 The concentration of a substance that produces death in 50% of a population of experimental organisms. Usually expressed as milligrams per kilogram (mg/kg) of body weight.
LOAEL Lowest Observed Adverse Effect Level
LOEL Lowest Observed Effect Level
MCC Medicines Classification Committee (NZ)
MEC Medicines Evaluation Committee (now Advisory Committee on Non-Prescription Medicines [ACNPM])
MOH Ministry of Health (NZ)
NCCTG National Coordinating Committee of Therapeutic Goods
NDPSC National Drugs and Poisons Schedule Committee
NHMRC National Health and Medical Research Council
NICNAS National Industrial Chemicals Notification & Assessment Scheme
NOAEC No Observed Adverse Effect Concentration
NOAEL No Observed Adverse Effect Level
NOEL No Observable Effect Level
NOHSC National Occupational Health & Safety Commission
OCM Office of Complementary Medicines
OCSEH Office of Chemical Safety and Environmental Health
ODA Office of Devices Authorisation
OMA Office of Medicines Authorisation (was Office of Prescription and Non-prescription Medicines)
OOS Out of Session
OTC Over-the-Counter
PACIA Plastics And Chemicals Industries Association
PAR Prescription Animal Remedy
PBAC Pharmaceutical Benefits Advisory Committee
PEC Priority Existing Chemical
PGA Pharmaceutical Guild of Australia
PHARM Pharmaceutical Health and Rational Use of Medicines
PI Product Information
PIC Poisons Information Centre
PSA Pharmaceutical Society of Australia
QCPP Quality Care Pharmacy Program
QUM Quality Use of Medicines
RFI Restricted Flow Insert
SCCNFP Scientific Committee on Cosmetic and Non-Food Products
SCCP Scientific Committee on Consumer Products
STANZHA States and Territories and New Zealand Health Authorities
SUSDP Standard for the Uniform Scheduling of Drugs and Poisons
SUSMP Standard for the Uniform Scheduling of Medicines and Poisons
SVT First aid for the solvent prevails
TCM Traditional Chinese Medicine
TGA Therapeutic Goods Administration
TGC Therapeutic Goods Committee
TGO Therapeutic Goods Order
TTHWP Trans-Tasman Harmonisation Working Party
TTMRA Trans-Tasman Mutual Recognition Agreement
WHO World Health Organization
WP Working Party
WS Warning statement
Interim Decisions on proposals REFERRED TO AN ADVISORY COMMITTEE
1. February 2012 meeting of the Advisory committee on Chemicals Scheduling (ACCS) – ACCS#4
1.1 cyflufenamid
DELEGATE’S REFERRAL TO EXPERT ADVISORY COMMITTEE
Cyflufenamid – seeking advice on a proposal to capture in Schedule 6.
EXPERT ADVISORY COMMITTEE RECOMMENDATION
The Committee recommended that a new Schedule 6 entry be created for cyflufenamid with a cut-off to Schedule 5 for preparations containing 5 per cent or less of cyflufenamid. The Committee also recommended an implementation date of no more than 6 months after delegate’s final decision (i.e. 1 September 2012).
BACKGROUND
Cyflufenamid belongs to the amidoxime group of fungicides with activity against all strains of cereal powdery mildew including those resistant to demethylation inhibitor, strobilurin-type and benzimidazole-type fungicides. The mode of action of cyflufenamid was unknown.
The IUPAC name for cyflufenamid is (Z)-N-[α-(cyclopropylmethoxyimino)-2,3-difluoro-6-(trifluoromethyl)benzyl]-2-phenylacetamide and the structure is:
XXXXX submitted data to the APVMA seeking approval of the active ingredient cyflufenamid and registration of a new fungicide product, XXXXX. The product was proposed to be used in cucurbits and grapes as a protectant fungicide against powdery mildew.
The Office of Chemical Safety (OCS) Risk Assessment Technical Report on XXXXX APVMA submission included a scheduling recommendation for cyflufenamid. A delegate agreed that this was a matter for a scheduling consideration and that advice from the ACCS was required.
SCHEDULING STATUS
Cyflufenamid was not specifically scheduled. There were no entries that would capture cyflufenamid as a derivative, nor any group entry that would capture cyflufenamid.
INITIAL SUBMISSIONS
The OCS Report recommended that, based on the toxicity profile, cyflufenamid be listed in Schedule 6 with no cut-off. Other evaluator’s conclusions included:
· The ADI for cyflufenamid was established at 0.03 mg/kg bw/d based on a NOEL of 4.14 mg/kg bw/d in a 52-wk dietary study in dogs, by applying a 0.7* times oral absorption correction factor and a 100-fold safety factor, to account for inter- and intra-species variation. The NOEL was based on elevated alkaline phosphatase (ALP) levels in both sexes and adrenal vacuolation and hypertrophy in females.
· The ARfD for cyflufenamid was established at 0.07 mg/kg bw, based on the maternal and foetal NOEL of 10 mg/kg bw/d in a rabbit developmental study, applying a 0.7 times oral absorption correction factor and using a 100-fold safety factor to account for potential intra- and inter-species variation. The NOEL was based on decreased body weight gain and food consumption in dams and minor skeletal variations/abnormalities in foetuses.
*The evaluator later indicated that there should not be an absorption correction factor on the ADI.
Toxicology
Absorption, distribution, metabolism and excretion in mammalsRate and extent of oral absorption / Rapid absorption. Tmax = 1–4 h; a minimum of 70% of oral low dose (10mg/kgbw) absorbed in rats.
Dermal absorption
(triple-pack methodology) / 1% (5% emulsion-in-water [EW] formulation) human
8% (0.25 g/L dilution of cyflufenamid) human
16% (0.0156 g/L dilution of cyflufenamid) human
Distribution / Extensive in rats. Highest detected concentrations in kidney, muscle, fat, liver, GI tract.
Potential for accumulation / No evidence for accumulation in rats. > 80% elimination in excreta by 24 h after final dose in repeat-dose (14 d) experiment, with essentially complete elimination in excreta 168 h after final dose. Residual dose in rat carcass < 1%.
Rate and extent of excretion / Rapidly excreted in rat; > 95% eliminated in excreta by 48 h after single dose. Higher urinary excretion of radiolabel in males compared to females.
Metabolism / Extensive; numerous metabolites in urine, faeces and bile. Processes involved include hydrolysis, amidine reduction, deamination, di-hydroxylation/methoxy conversion, mono-hydroxylation, cleavage of cyclopropylmethoxy moiety and glucuronide conjugate, cyclisation and isomerisation.
Toxicologically significant compounds (animals, plants and environment) / Cyflufenamid (NF-149); 149-F, 149-F1, 149-F6, 149-F-3-OH-4-OH-B, 149-F-3-OH-B and 149-F-4-OH-B, 149-F4B and associated glucuronide conjugate, 149-F12 and 149-E-FB. Impurities CPMOH and CPCA in cyflufenamid TGAC.
Toxicologically relevant compounds for residue
definition / Cyflufenamid (NF-149); 149-F, 149-F1, 149-F6, 149-F11, 149-(E)-FB.
Acute toxicity
Rat oral LD50 / > 5000 (mg/kg bw)
Mouse worst oral LD50 / > 5000 (mg/kg bw)
Rat dermal LD50 / > 2000 (mg/kg bw)
Rat inhalation 4-hr LC50 / > 4760 (mg/m3)
Skin irritation / Not irritating
Eye irritation / Slight irritant
Skin sensitization / Not sensitising (Guinea pig)
Short-term toxicity
Target/critical effect / Liver (organ weight changes, clinical chemistry changes, histopathological change [hypertrophy]) across species (rats, mice and dogs).
Brain (reversible vacuolation, myelin oedema and thinness in myelin membranes) at high doses (1500 ppm) in dogs.
Thymus (involution/atrophy) at high doses (1500 ppm) in dogs.
Lowest relevant oral NOEL / 6.5/7.5 mg/kg bw/d (males/females) 13-wk dog study.
Based on organ weight and histopathology changes in liver, clinical pathology alternations at higher doses in dogs.
Lowest relevant dermal NOEL / 1000 mg/kg bw/d (4-wk rat study) the highest dose tested.
Genotoxicity / Non-mutagenic/genotoxic in vitro with and without ±S9, and did not cause genotoxicity or DNA damage in vivo.
Long-term toxicity and carcinogenicity
Target/critical effect / Histopathological changes in kidney (male) and liver (female) in rat.
Reduced body weight gain, liver weight increase and histopathological change in liver, heart and lungs in mouse.
Adrenal vacuolation and hypertrophy (females) and elevated ALP levels (both sexes) in dogs.
Lowest relevant NOEL / 4.14/4.41 mg/kg bw/d (males/females) in dog (1 yr).
62.8/75.5 mg/kg bw/d (males/females) in mouse (78 wk).
4.4/5.5 mg/kg bw/d (males/females) in rat (2 yr).
Carcinogenicity / Thyroid adenoma/carcinoma in male rats at highest dose tested, but of limited relevance to humans. Pancreatic islet cell carcinoma in female mice at highest dose but noting the absence of a clear sequential progression (e.g. over-stimulation leading to hyperplasia through to neoplasm), this marginal finding in one sex is considered likely incidental and not treatment-related.
Hepatocellular adenomas in male mice at highest dose. However, compared to the historical control range the observed slight increase in benign liver tumours in males only at the top dose level was seen at a dose level that produced a 25.1% decrease in body weight gain over the study period. Consequently, the observed incidence of benign liver tumours in one sex only were of limited relevance as they were only observed above the historical control range at a dose level substantially exceeding the maximum tolerated dose (MTD).
Reproductive toxicity
Reproduction target/critical effect / Reproductive parameters unaffected by treatment. Evidence of treatment-related toxicity (increased liver and thyroid weights, decreased body weight gain) observed in both generations.
Lowest relevant reproductive NOEL / Parental NOEL: 250 ppm (18.0/19.9 mg/kg bw/d).
Offspring NOEL: 250 ppm (18.0/19.9 mg/kg bw/d).
Fertility NOEL: 800 ppm (57.4/65.7 mg/kg bw/d).
Developmental toxicity
Developmental target/critical effect / Maternal: Decreased food consumption, increased liver weights, decreased body weight gain. Foetal: Increased frequency of minor skeletal variations/abnormalities and delayed ossification above control frequencies.
Lowest relevant developmental NOEL (mg/kg bw/d) / Maternal (rat): 100, Foetal (rat): 1000 (limit dose), Maternal (rabbit): 10,
Foetal (rabbit): 10,
Neurotoxicity / No effects. Not neurotoxic in subchronic neurotoxicity study in rats.
Summary / NOEL
(mg/kg bw/d) / Study / Comments
ADI (0.03 mg/kg bw/d) / 4.14 / 1-yr dog study (adrenal vacuolation and hypertrophy in females) / 0.7 oral absorption correction factor, 100-fold safety factor for inter-/intra-species variation.
ARfD (0.07 mg/kg bw) / 10 / Rabbit developmental toxicity study (increased skeletal variations/delayed ossification) / 0.7 oral absorption correction factor, 100-fold safety factor for inter-/intra-species variation.
NOEL for OHS Risk Assessment
(4.55 mg/kg bw) / 6.5 / 13-wk dog toxicity study (organ weight/histopathology changes in liver, clinical pathology changes) / 0.7 oral absorption correction factor, 100-fold safety factor for inter-/intra-species variation and for brain vacuolation observed at high doses (> 65 mg/kg bw/d) that was reversible 26-wk after cessation of treatment.
Vacuolation