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Part B - Final decisions on matters not referred to an expert advisory committee
4. Delegate-only decisions on agricultural and veterinary chemicals
4.2 N,N-Dimethyloctanamide and N,N dimethyldecanamide
Delegate's final decision
Final decision:
The delegate's final decision is to create new Schedule 6 entries for N,N-dimethyloctanamide and N,N dimethyldecanamide. as follows:
Schedule 6 - New Entries
N,N-DIMETHYLOCTANAMIDE.
N,N-DIMETHYLDECANAMIDE.
Implementation date: 1 June 2019
Reasons:
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate include:
- the risks and benefits of the use of a substance:
- Benefit: use in Agvet products.
- Risks: there is uncertainty around the human exposure risk.
- the purposes for which a substance is to be used and the extent of use of a substance:
- N,N-dimethyldecanamide and mixtures of N,N-dimethyloctanamide and N,N-dimethyldecanamide have been identified in recent formulations of agricultural chemical products in Australia.
- Uses include as solvents in emulsifiable concentrate type agricultural chemical products, as well as coating, industrial cleaning, and processing aids.
- the toxicity of a substance:
- Based on the available toxicity data, a Schedule 6 entry is considered appropriate due to severe skin and eye irritation and acute toxicological endpoints.
- the dosage, formulation, labelling, packaging and presentation of a substance:
- Nil.
- the potential for abuse of a substance:
- Nil.
- any other matters that the Secretary considers necessary to protect public health:
- N,N-dimethyldecanamide, and mixtures of N,N-dimethyloctanamide and N,N-dimethyldecanamide have not previously been considered for scheduling.
Applicant's scheduling proposal and reasons for proposal
In November 2017, the Australian Pesticides and Veterinary Medicines Authority (APVMA) submitted a proposal to create new Schedule 6 entries for "N,N-dimethyloctanamide, N,N-dimethyldecanamide; and mixtures thereof" in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) - the Poisons Standard.
The applicant's proposed amendments to the Poisons Standard are:
Schedule 6 - New Entry
FATTY ACID DIMETHYLAMIDE MIXTURES.
The applicant's reasons for the request are:
- N,N-dimethyldecanamide, and mixtures of N,N-dimethyloctanamide and N,N-dimethyldecanamide have been identified in pesticides products.
- The available toxicological data for N,N-dimethyldecanamide, and mixtures of N,N-dimethyloctanamide and N,N-dimethyldecanamide show that they are severe eye and skin irritants.
Current scheduling status
N,N-dimethyloctanamide, N,N-dimethyldecanamide; and mixtures thereof, are not scheduled.
Scheduling history
N,N-dimethyloctanamide, N,N-dimethyldecanamide are not currently scheduled and has not been previously considered for scheduling. Therefore a scheduling history is not available.
The analogue dimethylacetamide (DMAC) is in Schedule 5 and Schedule 6 of the Poisons Standard.
In February 1997, the National Drugs and Poisons Schedule Committee (NDPSC) considered an application to list DMAC in the SUSMP due to its use in veterinary and agricultural products. DMAC is well absorbed through skin, gastrointestinal tract and lungs. Toxicological studies of DMAC mainly showed eye irritancy, hepatotoxicity, as well as some gestational and developmental toxicity at high exposures. The committee delayed a decision to seek public consultation on the matter and at the May 1997 meeting. Due to no responses made to the gazette notice, the committee decided to include DMAC in Schedule 6 with a cut-off of 20% or less to Schedule 5.
Australian regulations
N,N-dimethyloctanamide and N,N-dimethyldecanamide are listed with no additional information in the Inventory Multi-tiered Assessment and Prioritisation (IMAP) framework to accelerate the assessment of existing chemicals on the Australian Inventory of Chemical Substances (AICS).
N,N-dimethyloctanamide and N,N-dimethyldecanamide are not listed in Safe Work Australia Hazardous Chemical Information System (HCIS).
N,N-dimethyloctanamide and N,N-dimethyldecanamide do not appear to be in any products on the Australian Register of Therapeutic Goods (ARTG).
N,N-dimethyloctanamide and N,N-dimethyldecanamide do not appear in the current Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017.
International regulations
- USA: N,N-dimethyldecanamide and mixtures of N,N-dimethyloctanamide and N,N-dimethyldecanamide are approved for use in the USA as ingredients in agricultural products.
- EU: N,N-dimethyloctanamide is registered with REACH. Based on the classification provided by companies to ECHA, GHS hazard statements have been established in Europe for registrations in REACH of N,N-dimethyldecanamide, and mixtures of N,N-dimethyloctanamide and N,N-dimethyldecanamide.
- The same GHS hazard statements apply to both N,N-dimethyldecanamide, and mixtures of N,N-dimethyloctanamide and N,N-dimethyldecanamide - H315: causes skin irritation; H319: causes serious eye irritation
Substance summary
| Property | N,N-dimethyloctanamide and N,N-dimethyldecanamide |
|---|---|
| Chemical structures |
171.28 g/mol
199.33 g/mol |
| Molecular formulas | C10H21NO and C12H25NO |
| CAS names | N,N-dimethyloctanamide and N,N-dimethyldecanamide |
| CAS numbers | 1118-92-9 and 14433-76-2 |
| IUPAC and/or common and/or other names |
IUPAC: N,N-dimethyloctanamide and N,N-dimethyldecanamide Alternative names of N,N-dimethyloctanamide include: N,N-dimethylcaprylamide; and octanamide, N,N-dimethyl Alternative names of N,N-dimethyldecanamide include: N,N-dimethylcapramide; decanamide, N,N-dimethyl; N,N-dimethyldecanoamide; and N,N-dimethyldecan-1-amide Commercial names of N,N-dimethyloctanamide and N,N-dimethyldecanamide mixtures include "Hallcomid® M-8-10", and "Agnique KE 3658" |
| Toxicity | Species | Hallcomid-M-8-10 | SPF (2015) Classification[1] |
|---|---|---|---|
| Acute oral toxicity LD50 (mg/kg bw) | Rat | 1250 or 1770 | 6 |
| Acute dermal toxicity LD50 (mg/kg bw) | Rat | 400 < LD50 > 2000 | 6 |
| Acute inhalational toxicity LC50 (mg/m3/4h) | Rat | > 3550 | - |
| Skin irritation | Rabbit | Severe irritant | 6 |
| Eye irritation | Rabbit | Severe irritant | 6 |
| Skin sensitisation (Buehler) | Guinea pig | Not sensitising | - |
The APVMA has identified N,N-dimethyldecanamide and mixtures of N,N-dimethyloctanamide and N,N-dimethyldecanamide in recent formulations of agricultural chemical products. These fatty acid dimethylamide compounds are used as solvents in emulsifiable concentrate type agricultural chemical products. Other uses of these compounds may include coating, industrial cleaning, and processing aids.
The APVMA has sourced publically available toxicological data on N,N-dimethyldecanamide, N,N-dimethyloctanamide, and mixes of N,N-dimethyloctanamide and N,N-dimethyldecanamide. The main available studies were conducted on the commercial product "Hallcomid M-8-10", which contains 40-70% N,N-dimethyloctanamide (w/w) and 30-60% N,N-dimethyldecanamide (w/w). The US EPA website was the main source of information (e.g.: US EPA 2003b: Dossier and Robust summaries for CAS N°: 1118-92-9 (pdf,4.58Mb).
Both N,N-dimethyldecanamide and N,N-dimethyloctanamide; and commercial mixtures of these constituents appear to have similar toxicity.
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
Acute toxicity based on US EPA reports
In rat, Hallcomid M-8-10 has low acute oral and inhalational toxicity but moderate acute dermal toxicity.
Skin and eye irritation
Hallcomid M-8-10 is a severe skin irritant in rabbits.
Hallcomid M-8-10 is considered to be a severe eye irritant in rabbits (irreversible corneal opacity). On animal welfare grounds observations were terminated 4 days after instillation of the test material. If observations had been allowed to progress, a corrosive effect may have been observed.
Sensitization
Hallcomid M-8-10 was not a skin sensitiser in Guinea pig (Buehler test, induction with 5% test material in 80% ethanol, challenge with 2.5% test material in acetone).
Repeat-dose toxicity based on US EPA reports
In a 5-day inhalation toxicity study, rats were exposed to aerosolised Hallcomid M-8-10 for 6 hours/day (nose/head only) and observed for two weeks post-exposure. Autopsies were performed after killing the animals either on Day 7, or on Day 22. The NOAEL was ~111 mg/m3, based on clinical signs of toxicity (laboured breathing, bradypnea, wheezing, reduced mobility, reddened nose and serous nasal discharge), decreased body temperatures, and histopathological findings in the respiratory tract in both sexes (increased incidence of (i) goblet cell hyperplasia in the nasal mucosa of females on days 7 and 22, (ii) subpleural round-cell infiltration of the lungs in males, and (iii) marginal emphysema of the lungs) at the highest dose of ~521 mg/m3.
In a 6 weeks oral gavage toxicity study in dogs, which significance was likely impaired by infection, the NOAEL was 100 mg/kg bw/d, based on transient behavioural changes (lateral position, disturbed coordination, and prone position) observed in some animals after dosing at 1000 mg/kg bw/d.
In a 90-day dietary toxicity study in rats, the NOAEL was ~137 mg/kg bw/d in males and ~895 mg/kg bw/d (the highest dose used in the study) in females, based on an increased incidence/severity of renal basophilic cortical tubules (which was reversible during a 28 days additional observation period) and deposition of protein casts in medullary tubules of kidneys in males at the highest dose of 788 mg/kg bw/d.
Mutagenicity and Genotoxicity
In an adequate range of in vitro assays conducted on bacteria and mammalian cells, there was no evidence that Hallcomid M-8-10 is mutagenic or genotoxic.
Reproduction and developmental toxicity
Hallcomid M-8-10 was administered to presumed pregnant rats by oral gavage at 0, 50, 150 or 450 mg/kg bw/d on GD6 to GD15. The maternal NOAEL was 150 mg/kg bw/d, with a LOAEL of 450 mg/kg bw/d based on ruffled fur, ventral recumbency, dyspnea, apathy, transient comatose, reduced bodyweight gain as a result of decreased food consumption. The embryo/foetal NOAEL was 150 mg/kg bw/d, with a LOAEL of 450 mg/kg bw/d based on increased post-implantation loss, decreased bodyweight and increased incidence of skeletal malformations (incomplete or non-ossification of the vertebrae and sternebrae). It was considered that the observed treatment related effects on reproductive and developmental parameters were likely due to maternal toxicity.
Hallcomid M-8-10 (in 0.5% cremophor) was administered to presumed pregnant rabbits by oral gavage at 0, 100, 300, or 1000 mg/kg bw/d on GD6-GD18. No treatment related signs of toxicity were observed and gross necropsies were all unremarkable. Reproductive parameters were unaffected by the treatment. Maternal food consumption and bodyweight gain of the highest dose group were slightly lower than controls. The maternal NOAEL was 300 mg/kg bw/d, with a LOAEL of 1000 mg/kg bw/d based on reduced bodyweight gain. The embryo/foetal NOAEL was 1000 mg/kg bw/d, the highest tested dose.
Considering both studies, Hallcomid M-8-10 (N,N-dimethyloctanamide and N,N-dimethyldecanamide) appears to be non teratogenic in rats or rabbits, and there was no indication that these compounds may affect reproductive parameters in the absence of maternal toxicity.
Toxicity of formulated products containing N,N-dimethyldecanamide and/or mixes of N,N-dimethyloctanamide and N,N-dimethyldecanamide
Acute toxicity studies were conducted with three formulated agricultural products containing either 52% N,N-dimethyldecanamide or 39-47% mixes of N,N-dimethyloctanamide and N,N-dimethyldecanamide. These studies indicate that the products have low acute oral, dermal and inhalational toxicity, and are slight skin irritants. One of these products is a skin sensitiser while the two other products are not skin sensitisers. These three products are all severe eye irritants.
Eye irritancy of the products was largely attributed to N,N-dimethyldecanamide, or mixes of N,N dimethyloctanamide and N,N-dimethyldecanamide present in the products' formulations, as (i) these compounds are known severe eye irritants and (ii) based on the known toxicity of other constituents, it appears unlikely that they contributed significantly to the eye irritancy of the formulated products.
Delegate's considerations
The delegate considered the following in regards to this proposal:
- Scheduling proposal
- Section 52E of the Therapeutic Goods Act 1989
- Scheduling Policy Framework (SPF 2018)
- Other relevant information
Delegate's final decision
The delegate's final decision to be implemented on 1 June 2019 is to create new Schedule 6 entries for N,N-dimethyloctanamide and N,N-dimethyldecanamide. as follows:
Schedule 6 - New Entries
N,N-DIMETHYLOCTANAMIDE.
N,N-DIMETHYLDECANAMIDE.
Reasons for the final decision:
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate include:
- the risks and benefits of the use of a substance:
- Benefit: use in Agvet products
- Risks: there is uncertainty around the human exposure risk
- the purposes for which a substance is to be used and the extent of use of a substance:
- N,N-dimethyldecanamide and mixtures of N,N-dimethyloctanamide and N,N dimethyldecanamide have been identified in recent formulations of agricultural chemical products in Australia.
- Uses include as solvents in emulsifiable concentrate type agricultural chemical products, as well as coating, industrial cleaning, and processing aids.
- the toxicity of a substance:
- Based on the available toxicity data, a Schedule 6 entry is considered appropriate due to severe skin and eye irritation and acute toxicological endpoints.
- the dosage, formulation, labelling, packaging and presentation of a substance:
- Nil.
- the potential for abuse of a substance:
- Nil.
- any other matters that the Secretary considers necessary to protect public health:
- N,N-dimethyldecanamide, and mixtures of N,N-dimethyloctanamide and N,N-dimethyldecanamide have not previously been considered for scheduling.
Footnotes
- See TGA website for SPF classification guideline - AHMAC - Scheduling policy framework for medicines and chemicals