APP202804 – EDN

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SCIENCE MEMO

APP202804 – EDN

Substance database ID: 49330

July 2018

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Science memo for application to import or manufacture EDN for release (APP202804)

Executive Summary

EDN is a compressed gas containing the active ingredient ethanedinitrile at a concentration of 1000 g/kg, at a minimum purity of 95%.

The active ingredient is new to New Zealand. The applicant seeks to have EDN approved for use as a fumigant for insect pests, nematodes and fungi in timber logs for export.

The active substance ethanedinitrile is approved in Australia as a fumigant.

Ethanedinitrile toxicity is believed to be mediated through its hydrolytic breakdown to the cyanide ion (CN^-) (also called cyanide). The toxicological data for ethanedinitrile consist of some studies submitted by the applicant and some studies found in public literature, but is primarily based on toxicological studies from various surrogate compounds that also contain cyanide or release CN^- during their metabolism similar to ethanedinitrile. The total database of studies on these structural surrogates is extensive and robust and is considered sufficient to ascertain the toxicological hazard potential of ethanedinitrile and to characterise the potential risks to human health from its exposure.

The toxicological hazards of cyanides have been the subject of numerous reviews published by foreign governmental agencies including: the World Health Organisation (WHO), the United States (US) Department of Health and Human Services – Public Health Service – Agency for Toxic Substances and Disease Registry (ATSDR), the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), the US-National Research Council (NRC), the US-National Institute of Environmental Health Sciences – National Toxicology Program (NTP), and the Australian Pesticides and Veterinary Medicines Authority (APVMA). Unless

otherwise stated, all endpoint data summarised in this document were sourced from the relevant overseas reviews. We have accepted the conclusions of the overseas reviewers and have not assessed in detail all of the original reports presented in them.

We have assessed the risks to people and the environment in New Zealand from the use of EDN using the endpoint data available on ethanedinitrile and on the cyanide surrogates using standard risk assessment methodologies.

Potential exposure to ethanedinitrile from log fumigation under tarpaulins was modelled using weather data from the Port of Tauranga. All exposure levels derived from this modelling were well below the current and proposed WorkSafe exposure standard levels, 10 and 2 ppm respectively, for safe occupational exposures indicating Personal Protective Equipment (PPE) would not be required except for in certain circumstances.

Exposure estimations from fumigation of logs in fumigation chambers, shipping containers, and ship’s cargo holds were not provided so the risk associated with these types of use patterns was not determined nor evaluated.

Two exposure scenarios were considered to assess exposure risks to bystanders (general public) to ethanedinitrile. The first being of an acute nature such that might occur in accidental situations or in the context of single one-time or occasional exposure events, and another exposure scenario for the general

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public for exposure that might occur from a more chronic and continuous (24 hour) nature. The health risks to bystanders associated with acute occasional exposures were low, as the modelled exposure levels were well below an established threshold value for periods of up to 8 hours. Health risk concerns were higher for the modelled exposure levels that might occur on a chronic continuous basis as they were slightly above the established Tolerable Exposure Limit (TEL) at 100 metres, unless application method controls were

incorporated into the fumigation process.

Risks to the environment from use of EDN are considered negligible with the proposed controls in place.

Following fumigation of timber log stacks using tarpaulin, as indicated by the exposure modelling,

ethanedinitrile rapidly dissipates in the atmosphere once the tarpaulin is removed. As such, as a result of the very low air concentrations expected, it is considered that any direct exposure that may occur to non-target plants, aquatic organisms, terrestrial vertebrates (birds) and terrestrial invertebrates would be of negligible effect with the proposed controls in place.

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1. Background

1. This application is to manufacture and/or import the substance EDN, containing 1000 g/kg ethanedinitrile (also known as cyanogen) at a minimum purity of 95%.

2. EDN is intended to be used as a fumigant for the control of insect pests, nematodes, and fungi infesting timber and logs.

3. EDN is a liquefied gas under pressure in 73L cylinders containing the active ingredient ethanedinitrile.

The active ingredient is new to New Zealand.

4. The active ingredient and substance are approved in Australia under the names Sterigas 1000^TM

fumigant and EDN Fumigas® for the fumigation of logs and crops (pre-plant treatment of strawberries), respectively.

5. The active ingredient is ethanedinitrile which breaks down by hydrolysis into the toxic metabolite cyanide ion (CN^-).

6. Ethanedinitrile and the cyanide ion (CN^-) have been the subject of reviews by: the World Health

Organization (WHO), the United States (US) Department of Health and Human Services – Public Health Service – Agency for Toxic Substances and Disease Registry (ATSDR), the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), the US- National Research Council (NRC), the US-National Institutes of Environmental Health Sciences – National Toxicology Program (NTP), and the Australian Pesticides and Veterinary Medicines Authority (APVMA).

7. We have accepted the conclusions of the overseas reviewers and have not assessed in detail all of the original reports presented in them.

8. While the applicant did provide some toxicology and ecotoxicology test data on ethanedinitrile, unless otherwise stated, all endpoint data summarised in this document were sourced from the relevant overseas reviews and the studies utilised were deemed to be of sufficient quality for assessing each endpoint. For full details of testing undertaken, reference should be made to the relevant sections of the overseas reviews.

9. We have assessed the risks to people and the environment in New Zealand from the use of the substance as a log fumigant using the endpoint data available and generally accepted procedures adopted by regulatory authorities worldwide for assessing risks to human health and the environment.

Full details of the risk assessments can be found in Appendices H and I.

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1.1 Regulatory status

Table 1: Regulatory status in New Zealand and overseas

Mixture name Regulatory history in New Zealand International regulatory history¹ (Australia, Canada, Europe, Japan, USA)

EDN New substance (not previously approved)

Approved with controls in Australia for the fumigation of timber (Sterigas 1000^TM

fumigant) and strawberries (EDN Fumigas®);

APVMA Product number P60096

2. Hazardous properties

10. The hazard classifications proposed for the active ingredient and substance are outlined in Table 2 and discussed in more detail below.

Table 2: Proposed classification for active and substance

Hazard endpoint Ethanedinitrile EDN

Flammable gas 2.1.1A 2.1.1A

Acute toxicity (inhalation) 6.1B 6.1B

Aquatic ecotoxicity 9.1A 9.1A

Physical/chemical hazard classifications (classes 1-5)

Flammability, gases (hazard class 2)

11. The lower explosive limit (LEL) reported by the applicant for ethanedinitrile is 6.45% by volume in air.

This meets one of the classification criteria in the Hazardous Substances (Classification) Notice 2017, Schedule 2, Clause 2 for 2.1.1A (Flammable gas, high hazard), that the LEL be below 13%.

Toxicity hazard classifications (class 6)

12. Ethanedinitrile is of relatively high acute toxicity to mammals and should be classified 6.1B for acute inhalation toxicity. No evidence of dermal toxicity or dermal irritation was observed in acute exposure studies to the gas. Cyanide and cyanide compounds are not known to induce contact sensitisation.

Ethanedinitrile is not classified as an eye irritant even though it induces an “irritation” sensation

1 It is noted that while ethanedinitrile is not approved for use in Malaysia it is accepted as a treatment for wood imported into Malaysia.

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response to the eyes (and throat) in humans at ~16 ppm. The mechanism of this effect is through the direct stimulation of sensory nerves as opposed to direct tissue damage which is the basis for a 6.4 eye irritation classification. A sensory irritation response can represent a valuable method of detecting an elevated concentration of ethanedinitrile as the gas is odourless until ~250 ppm. (Note: This sensory response is NOT meant to be used in lieu of reliable electronic monitoring devices in a workplace for its detection.) Results of genotoxicity studies conducted on ethanedinitrile were positive but deemed to likely be false positives associated with cellular toxicity due to CN^- formation. Cyanide compounds are not considered to be genotoxic, carcinogenic, or reproductive/developmental toxicants.

Ecotoxicity hazard classifications (class 9)

Aquatic toxicity (hazard class 9.1)

13. Ethanedinitrile is very ecotoxic in the aquatic environment and triggers a 9.1A HSNO hazard classification. This classification is based on read-across test data from sodium cyanide (as per the Simon (2011) and Wenzel (2011) studies summarised in Tables 54 and 55, Appendix J). The applicant also proposes that ethanedinitrile has a 9.1A hazard classification.

Soil toxicity (hazard class 9.2)

14. The applicant proposes that ethanedinitrile is not toxic in the soil environment. The EPA disagrees with this proposal since no reliable test data are available to make that conclusion. Furthermore,

ethanedinitrile is approved for use as a soil fumigant (in the product EDN Fumigas®) in Australia by the Australian Pesticides and Veterinary Medicines Authority (APVMA). As such, it is considered highly likely that ethanedinitrile is toxic in the soil environment, and a 9.2 hazard classification is likely to apply.

The ecotoxicity of ethanedinitrile in the soil environment could not be determined in this instance however, due to a lack of test data.

Terrestrial vertebrate toxicity (hazard class 9.3)

15. The applicant proposes that a hazard classification for ecotoxicity to terrestrial vertebrates is not applicable (“NA”) since ethanedinitrile is a gas and oral exposure is not a relevant route of exposure.

Since hazard class 9.3 is only concerned with toxicity to terrestrial vertebrates via the oral route of exposure, the EPA is in agreement with the applicant’s conclusion, and accepts that a 9.3 hazard classification is not applicable to ethanedinitrile.

Terrestrial invertebrate toxicity (hazard class 9.4)

16. Finally, the applicant proposes that a hazard classification for ecotoxicity to bees and other terrestrial invertebrates is also not applicable (“NA”). The EPA disagrees with this conclusion since no reliable test data are available to make that conclusion. In addition, it seems conceivable that it could be possible to expose bees to ethanedinitrile. As such, the EPA disagrees with the applicant’s proposal and considers instead that ecotoxicity to terrestrial invertebrates could not be determined (“ND”). It is considered highly

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likely however that ethanedinitrile is toxic to bees and other terrestrial invertebrates based on its conversion to CN^-, and is likely to trigger a 9.4 hazard classification if the test data existed.

3. Risk assessment context

17. We consider there is potential for significant exposure to people and/or the environment during the use phase of the lifecycle of EDN. We have therefore undertaken quantitative risk assessments to assess the likely exposures to the substance under the use conditions proposed by the applicant.

18. During the importation, manufacture, transportation, storage and disposal of EDN we consider that the proposed controls and other legislative requirements will sufficiently mitigate risks to a negligible level.

This assessment takes into account the existing HSNO requirements around packaging, identification and disposal of hazardous substances. In addition, the Land Transport Rule 45001, Civil Aviation Act 1990, Maritime Transport Act 1994 and New Zealand’s health and safety at work requirements all have provisions for the safe management of hazardous substances.

4. Human health risk assessment

19. For the application method of fumigation under a tarpaulin, the predicted worker exposures to ethanedinitrile on the downwind side of the log pile source are below both the current (10 ppm) and proposed (2 ppm) New Zealand Workplace Exposure Standard (WES) limits at a minimum buffer zone of 10 m for a single log pile source, or at a 20 m distance when multiple log piles have been fumigated (10 m concentrations were not modelled for multiple log piles) (Graham, 2018). This exposure estimate for workers is a modelled estimate of a 95^th percentile exposure at various distances from either a single 750 m³ log pile source or 20 m from a multiple (30) log pile source at a time period of either 1 or 24 hours after tarpaulin removal at the conclusion of a fumigation process. Although the estimated

ethanedinitrile concentrations at the 10 or 20 m distances are below the proposed WES, it is based on a mixing gradient starting at the source (log pile) where the ethanedinitrile concentration is estimated to be anywhere from ~200 to ~9,500 ppm (extreme variation is due to exposure modelling assumptions noted in the report, Graham, 2018). Therefore, appropriate respiratory PPE should be required when working within 10 m of a single fumigated log source or 20 m of multiple log pile sources to ensure risks of adverse health effects are mitigated.

20. No data were provided to assess the potential exposures from emissions from the use of EDN in fumigation chambers, shipping container, or ship’s cargo holds. Without knowledge of the potential exposures, safe buffer zone distances, appropriate PPE and monitoring practices cannot be set to ensure exposure to workers is minimised to safe levels.

21. Risk associated with ethanedinitrile exposure to bystanders or the general public was evaluated under two different types of exposure scenarios. The first being a short-term (very acute and transient) exposure lasting anywhere from 10 minutes (min) to 8 hours (hr); and the second scenario for repeated

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exposures over a longer term. This latter scenario would apply to people who may be residing in close proximity to a fumigation facility in which exposure durations could be of a more continuous nature.

22. For the short-term exposure risks, the modelled exposure levels were compared to the acute exposure guideline values (AEGLs) established for ethanedinitrile by the NRC designed to protect the general population of varying sensitivities. Under this exposure scenario, the risks to bystanders are considered negligible as the highest modelled exposure level (ie, the 24 hr exposure average 20 m from a multiple log fumigation process that included all the modelling uncertainty adjustments) is only 0.858 ppm and the AEGL threshold value of concern ranges from 2.5 ppm (10 min exposure) to 1 ppm (8 hr exposure).

23. For longer term exposure risks, the modelled exposure levels were evaluated in the context of the EPA staff-derived TEL of 0.034 ppm for ethanedinitrile. Under this exposure scenario, risks to bystanders are negligible from a single source log pile at a distance of 60 m as the estimated exposure level after all the uncertainty adjustments are included is 0.030 ppm. Risk to bystanders where there is a multiple log pile exposure source are ~8X above the TEL even at a distance of 120 m as the modelled exposure levels after all the uncertainty adjustment factors are included is 0.266 ppm. In order to bring exposure down to an acceptable level, controls would need to be set.

24. EDN contains two impurities of toxicological concern: hydrogen cyanide (CAS 74-90-8) 0.5% and carbon dioxide (CAS 124-38-9) 2.0%. Although these gases are highly toxic, the risk they present is of low significance given the higher concentration and high acute toxicity of the ethanedinitrile active.

5. Environmental risk assessment summary

25. Ethanedinitrile is expected to dissipate rapidly within the atmosphere once the tarpaulin is removed from the log stacks and ventilated, based on the exposure modelling.

26. Based on the proposed use pattern it is considered that there is no direct exposure pathway to plants, aquatic organisms or terrestrial invertebrates.

27. Due to a lack of direct exposure to aquatic organisms or direct contamination of surface water, direct risks to aquatic organisms are considered to be negligible.

28. Terrestrial vertebrates and invertebrates, particularly threatened or non-threatened native species, are unlikely to be found in the surroundings of a port where ethanedinitrile will be vented. Since the likelihood of exposure is low, the direct risks to non-target terrestrial invertebrates are considered to be negligible. However, there are concerns regarding the risks to terrestrial vertebrates (birds) when ethanedinitrile is vented. The EPA proposes to apply a control to only allow fumigations to occur where water bird colonies are not known to exist in order to minimise risks to bird species from inhalation of this substance. Furthermore, a permission control would enable the EPA to manage potential risk to birds as the EPA could request a site specific risk assessment to be provided by the users, including the location of, and species present of, nearby bird colonies and their distance to the treatment site, and how potential risks will be managed.

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29. Based on the use patterns outlined in the application, we consider risks to the environment to be negligible provided that the use is restricted to fumigation of logs at port locations. It should be noted that if the applicant wishes to apply for additional uses in the future (for example soil fumigation), the applicant would be required to provide additional environmental fate and ecotoxicology information in order for the risks from those uses to be evaluated.

6. Proposed controls

30. The EPA staff consider that the prescribed controls would manage a number of the identified risks to humans and the environment. However, it is recommended that the following requirements or controls are added in a Safe Work Instrument or under Section 77 and Section 77A of the HSNO Act to adequately manage the risks to human health and the environment:

Proposed additional requirements that fall under WorkSafe’s jurisdiction

 PPE should be worn by workers when they are within 10 m of a single log stack or within 20 m of a process in which multiple log stacks are being fumigated.

 The concentration of EDN under the tarpaulin should be ≤700 ppm prior to the removal of the tarpaulin from a fumigated log pile.

Proposed additional controls that fall under HSNO

 The following limit is set for toxicologically relevant impurities in the active ingredient ethanedinitrile used to manufacture this substance: Hydrogen cyanide: 1% v/v maximum

 The maximum application rate of this substance is 150 g of substance/m³

 EDN must not be applied into or onto water.

 A use and a label control stating “Atmospheric conditions should be monitored and

ethanedinitrile should not be vented under very low wind speed conditions (less than 5 km/h) or under inversion conditions.”

 Fumigations conducted at port locations must be undertaken only at locations where water bird colonies are not known to exist.

 A permission control, which would enable the EPA to request a site specific risk assessment from the users, including the location of, and species present of, nearby bird colonies and their distance to the treatment site, and how potential risks will be managed.

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Appendix A: Proposed controls

Physical hazards controls

Standard controls associated with a highly flammable gas will be applied.

Toxicity controls

Exposure thresholds

Ethanedinitrile has been used as an industrial gas internationally for many years and accordingly has had workplace exposure standards (WES) developed to support its safe use (Table 3). In addition, because the toxic metabolite cyanide ion (CN^-) can be found in many environmental sources (air, food, water) there have been health-based exposure thresholds developed for the cyanide ion (CN^-) to minimise the risks associated with its exposure under various long-term exposure scenarios (Table 4) and short-term exposure scenarios (Table 5).

EPA staff have reviewed the acute and chronic health based exposure guidance values established by overseas regulators for ethanedinitrile and the cyanide ion (CN^-) and have also developed a tolerable

exposure limit (TEL) based on laboratory studies conducted on ethanedinitrile. The TEL developed by staff is comparable to various long-term exposure thresholds established for CN^-.

Workplace exposure thresholds

Table 3: Current international workplace exposure standards for ethanedinitrile

Jurisdiction or Advisory Body 8-Hour Limit Value (ppm) Short-term Limit Value¹ (ppm)

Australia 10

Austria 10 50

Belgium 10

Canada 10

Denmark 10 20

Finland 10²

France 2 10

Germany 5 10

Ireland 10

New Zealand 10³

Singapore 10

South Korea 10

Spain 10

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Switzerland 5 10

USA – National Institute of Occupational Safety and Health (NIOSH)

10

USA – American Conference of Governmental Industrial Hygienist (ACGIH)

5²

UK 10⁴

1.) 15 minutes average value; 2.) Ceiling limit value;3.) Currently undergoing a review with a proposal to lower to 2 ppm. 4.) The UK Advisory Committee on Toxic Substances has expressed concern that health may not be adequately protected because of doubts that the limit was not soundly-based. This OEL was included in the published UK 2002 list and its 2003 supplement, but are omitted from the published 2005 list.

General Population (bystander) thresholds for cyanide ion (CN^-) or ethanedinitrile

Regulatory agencies around the globe have established various long-term exposure threshold levels to the cyanide ion in the environment due to its ubiquitous nature (Table 4).

Table 4: Long-term exposure thresholds for ethanedinitrile or CN

^{- 1}

in air, food, and water

Air Food Water

TEL²: 0.034 ppm (0.072 mg ethanedinitrile /m³, ~0.036 CN^-/m³, 0.0205 mg

ethanedinitrile/kg bw/day, or ~0.01 mg CN^- /kg bw/day )(NZ-EPA)

RfC³ = 0.00083 mg CN^-/m³(0.00039 ppm)(US EPA)

 TDI⁴ = 0.045 mg CN^-/kg bw/day; (~0.09 mg/kg ethanedinitrile)(WHO)

 PMTI⁵ = 0.02 mg CN^-/kg bw/day (~0.04 mg/kg ethanedinitrile) (JECFA)

 MRL⁶intermediate = 0.05 mg CN^- /kg bw/day (~0.1 mg

ethanedinitrile/kg bw/day)(oral intake of up to 1 yr; ATDSR)

 ARfD⁷ = 0.09 mg CN^-/kg bw/day (~0.18 mg ethanedinitrile /kg bw/day)(JECFA/WHO)

 DWSNZ = 0.08 mg CN^-/L (~0.005 mg ethanedinitrile/kg bw/day)

 Australian drinking water guideline: 0.08 mg CN^-/L

 MCL⁸ = 0.2 mg CN^-/l; US EPA, Canada) (~0.01 mg ethanedinitrile/kg bw/day)

1.) ~1 mg/kg of CN^- is equivalent to ~2 mg/kg of ethanedinitrile; CN^-Molecular Weight (MW) = 26.03 g/mol, ethanedinitrile MW = 52.03 g/mol

2.) TEL (Tolerable Exposure Limit): Is a concentration of a substance in an environmental medium as set in accordance with regulation 24 of the Hazardous Substances (Classes 6, 8 and 9 Controls) regulations 2001. This value represents a concentration for which humans could be exposed to on a chronic basis.

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3.) RfC (reference concentration): An estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime.

4.) TDI (Tolerable Daily Intake): is an estimate of the amount of a substance in air, food or drinking water that can be taken in daily over a lifetime without appreciable health risk.

5.) PMTI (provisional max. tolerated intake): The endpoint established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) used for contaminants with no cumulative properties. Its value represents permissible human exposure as a result of the natural occurrence of the substance in food and in drinking-water.

6.) MRL (minimal risk level): Is an estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk of adverse non-cancer health effects over a specified duration of exposure. The above threshold was established for exposures from 15-365 days.

7.) ARfD (acute reference dose): Is defined as an estimate of a substance in food or drinking water, expressed on body weight basis that can be ingested over a short period of time, usually during one meal or one day, without appreciable health risk to the consumer on the basis of all known facts at the time.

8.) MCL (maximum contamination level): The highest level of a contaminant in drinking water. MCLs ensure that drinking water does not pose either a short-term or long-term health risk.

The US National Research Council (NRC) through its Committee on Toxicology formulated guidance on the use of procedures and methodologies to develop AEGLs for high-priority, acutely toxic chemicals. The AEGLs represent threshold exposure limits for the general public below which adverse health effects are not likely to occur. This includes susceptible subpopulations such as infants, children, elderly, persons with asthma, and those with other illnesses. Three levels (AEGL-1, -2, and -3) have been established for five exposure periods (10 min, 30 min, 1, 4, and 8 hr) and are distinguished by varying degrees of severity of toxic effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and severity of the effects described for each corresponding AEGL.

The three AEGLs are defined as follows:

 AEGL-1 is the airborne concentration of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic non-sensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.

 AEGL-2 is the airborne concentration of a substance above which the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.

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 AEGL-3 is the airborne concentration of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening adverse health effects or death.

The NRC Committee developed AEGLs on ethanedinitrile which EPA staff believe are applicable for use in assessing health risk from EDN fumigation and ethanedinitrile exposure to general population bystanders who may be exposed for similar periods of time (https://www.epa.gov/aegl/cyanogen-results-aegl-program).

These AEGL values developed for ethanedinitrile are presented in Table 5 below.

Table 5: Short-term exposure thresholds for ethanedinitrile in air: Acute Exposure Guideline Levels (AEGL) for Selected Airborne Chemicals

Ethanedinitrile (ppm)

Periods of time 10 min 30 min 60 min 4 hr 8 hr

AEGL-1 2.5 2.5 2.0 1.3 1.0

AEGL-2 50 17 8.3 4.3 4.3

AEGL-3 150 50 25 13 13

Other toxicity controls

PPE should be worn by workers when they are within 10 m of a single log stack or within 20 m of a process in which multiple log stacks are being fumigated.

The concentration of gas under the tarpaulin should be ~700 ppm or lower prior to the removal of a tarpaulin from a fumigated log pile.

An active monitoring programme should be employed in the workplace. This could be achieved through personal air monitoring devices worn by workers as well as devices in the immediate vicinity around EDN gas tanks to ensure their integrity. An active monitoring programme should also be utilised to ensure bystander exposures are below the TEL.

The following limit is proposed for the toxicologically relevant impurity in the technical grade active ingredient ethanedinitrile:

 Hydrogen cyanide: <1% (v/v)

Ecotoxicity controls

Maximum application rate

A maximum application rate is proposed to be set for EDN, as shown in Table 6.

Table 6: Active ingredient(s) maximum application rates

Active component Maximum application rate

Ethanedinitrile 150 g/m³

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Other ecotoxicity controls

 EDN must not be applied into or onto water.

 A use and a label control stating “Atmospheric conditions should be monitored and

ethanedinitrile should not be vented under very low wind speed conditions (less than 5 km/h) or under inversion conditions.”

 Fumigations conducted at port locations must be undertaken only at locations where water bird colonies are not known to exist.

 A permission control, which would enable the EPA to request a site specific risk assessment from the users, including the location of, and species present of, nearby bird colonies and their distance to the treatment site, and how potential risks will be managed.

Table 7: List of components requiring identification

Label SDS

ethanedinitrile Ethanedinitrile

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Appendix B: Identity of the active ingredient, use pattern and mode of action

Identity of the active ingredient and metabolites

APP202804 is the second application made under Part 5 of the Hazardous Substances and New Organisms (HSNO) Act 1996 for the import of ethanedinitrile. A previous application (ERMA200203) was submitted and was subsequently withdrawn by the applicant. General data on the active ingredient on ethanedinitrile are provided in Table 8.

Table 8: Identification of the active substance ethanedinitrile

IUPAC name Oxalonitrile (Ethanedinitrile, Cyanogen)

CA name Ethanedinitrile

Molecular formula C2N2

CAS Number 460-19-5

Molecular weight 52.036

Structural formula N ≡ C – C ≡ N

Purity Min. 95% w/w

Significant

impurities/additives

hydrogen cyanide (CAS 74-90-8):

0.5% (v/v); carbon dioxide (CAS 124-38-9): 2.0% (v/v)

Use pattern and mode of action

Use pattern

The applicant seeks approval for the use of EDN, which contains the active ethanedinitrile at a concentration of 1000 g/kg. EDN is proposed as a fumigant for the control of a wide range of wood insects, nematodes and fungi in timber logs to be exported out of New Zealand.

EDN will be imported in the form of a liquefied gas under pressure in 73L cylinders. The applicant seeks to have EDN approved for application as a fumigant under tarpaulins, in fumigation chambers (or similar structures) on shore, in shipping containers, and in ships’ holds.

Application will be at the rate of 150 g/m³, with one application over a 24 hour period. More details on the intended uses for EDN are given in Table 9.

Mode of action

Ethanedinitrile is a fumigant for controlling wood insects in harvested timber. Ethanedinitrile can be hydrolysed to form the cyanide ion (CN^-). CN^- binds to the iron atom of cytochrome c oxidase, an enzyme found in mitochondria in all cells. The binding of cyanide to this cytochrome prevents transport of electrons

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from cytochrome c oxidase to oxygen. This prevents the cells’ use of oxygen leading to a “cellular asphyxiation” and death of the cell.

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Table 9: List of intended uses for EDN

Crop and/or situation (a)

Use pattern (b)

Pests or group of pests controlled (c)

Mixture Application Application rate per treatment

Remarks Type (d- (l)

f)

Conc of ai (g)

Method and kind (h-i)

Growth stage &

season (j)

Number Min max (k)

Interval between applications – days

(minimum)

g/m³ min max

water L/ha min max

g/m³ max

Timber logs fumigation under sheet

N/A

Insect pests and pathogens on timber and logs

Gas

1000 g/kg (min 950 g/kg)

Directly applying EDN from the cylinder

Post-

harvest N/A N/A 150 N/A N/A

24 hours treatment period equal to or above 10°C Timber logs

fumigation in shipping container

N/A

Gas

1000 g/kg (min 950 g/kg)

Post-

24 hours treatment equal to or above 10°C Timber logs

fumigation chamber or similar structures

N/A

Gas

1000 g/kg (min 950 g/kg)

Post-

24 hours treatment period equal to or above 10°C Timber logs

fumigation in ships’

hold

N/A

Gas

1000 g/kg (min 950 g/kg)

Post-

24 hours treatment period equal to or

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a Where relevant, the use situation should be described (e.g. fumigation of soil) b Outdoor or field use (F), glasshouse application (G) or indoor application (I).

c e.g. biting and sucking insects, soil borne insects, foliar fungi, weeds d e.g. wettable powder (WP), emulsifiable concentrate (EC), granule (GR)

e CropLife international, 2008. Technical Monograph no 2, 6th edition. Catalogue of pesticide formulation types and international coding system f All abbreviations used must be explained

g g/kg or g/l or others

h Method, e.g. high volume spraying, low volume spraying, spreading, dusting, drench, aerial, etc ,

i Kind, e.g. overall, broadcast, aerial spraying, row, individual plant, between the plant - type of equipment used must be indicated. If spraying include droplet size spectrum

j growth stage at last treatment (BBCH Monograph, Growth Stages of Plants, 1997, Blackwell (ISBN 3-8263-3152-4), including where relevant, information on season at time of application k Indicate the minimum and maximum number of application possible under practical conditions of use

l Remarks may include: Extent of use/econo: c importance/restrictions

above 10°C

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Appendix C: Hazard classification of ethanedinitrile

The hazard classification of ethanedinitrile is listed in Table 10.

Table 10: Applicant and EPA Staff classification of ethanedinitrile

Hazard Class/Subclass

Mixture classification by:

Method of classification

Remarks Applicant EPA

Staff

Mixture data Read across Mixture rules

Class 1 Explosiveness NA No

Class 2 Flammability 2.1.1 A 2.1.1A

The lower explosive limit (LEL) reported by the applicant is 6.45% by volume in air. This meets the requirement that it is below 13%, one of the classification criteria in the Hazardous Substances (Classification) Notice 2017, Schedule 2, and Clause 2 for 2.1.1A (Flammable gas, high hazard).

Class 3 & 4 Flammability NA NA The substance is a gas.

Class 5 Oxidisers/Organic

Peroxides No NA

The substance is a reducing agent rather than an oxidiser.

Subclass 8.1 Metallic

corrosiveness No ND

Subclass 6.1 Acute toxicity

(oral) NA NA

The substance is a gas and oral exposure is not a relevant route of exposure.

(dermal) No No

LD50 = >~10,000 ppm;

Rabbits exposed to

~10,000 ppm

ethanedinitrile for 8 hrs showed no evidence of toxicity indicating material is not dermally absorbed in significant amounts.

(inhalation) 6.1B 6.1B LC50 = ~136 ppm

Subclass 6.1 Aspiration hazard No NA The substance is a gas.

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Staff

Subclass 6.3/8.2 Skin

irritancy/corrosion No No

Rabbits exposed to

~10,000 ppm

ethanedinitrile for 8 hrs showed no evidence of dermal irritation

Subclass 6.4/8.3 Eye

irritancy/corrosion No ND

Although irritation of the eyes was observed in humans after a 6-8 min.

exposure to 16 ppm ethanedinitrile, it was a sensory or neurological effect and not due to tissue damage. Sensory irritation is not a classifiable effect.

Subclass 6.5A Respiratory

sensitisation No ND

This effect is very unlikely as respiratory sensitisation was not observed in a chronic inhalation study with ethanedinitrile

Subclass 6.5B Contact

sensitisation No No

Material is a gas and does not appear to penetrate the dermis. Sensitisation is also not a property associated with CN^-or CN^- generating compounds.

Subclass 6.6 Mutagenicity No No

Positive results from some studies on ethanedinitrile were deemed as false positives due to cytotoxicity. CN^-, and cyanide compounds as a class, are not considered to be genotoxicants.

Subclass 6.7 Carcinogenicity No No

Results of a study on acetonitrile, a CN^-

generating compound, did not show evidence of tumour formation. CN^-, and CN^- generating

compounds as a class, are

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Staff

not considered to be carcinogenic.

Subclass 6.8 Reproductive/

developmental toxicity No No

CN^-, and CN^- generating compounds as a class, are not considered to be reproductive toxicants.

Subclass 6.8 Reproductive/

developmental toxicity (via lactation)

No ND

This risk is believed to be minimal as CN^-, and CN^- generating compounds as a class, are not considered to be reproductive

toxicants and lactation would not be a significant pathway of excretion.

Subclass 6.9 Target organ

systemic toxicity (oral) No NA

Ethanedinitrile is a gas and oral exposure is not a relevant route of exposure.

systemic toxicity (dermal) No NA

Ethanedinitrile is a gas and as such, is not dermally absorbed in significant amounts.

systemic toxicity (inhalation) No No

No specific target organ was identified in two 6 month inhalation studies with ethanedinitrile.

Subclass 9.1 Aquatic

ecotoxicity 9.1A 9.1A

Read across from sodium cyanide study on algal growth inhibition (48-hr EC50 = 12.4 µg free CN^-/L)

Subclass 9.2 Soil ecotoxicity No ND No reliable test data were

submitted

Subclass 9.3 Terrestrial

vertebrate ecotoxicity NA NA

Hazard class 9.3 is only concerned with toxicity to terrestrial vertebrates via the oral route of exposure.

Since ethanedinitrile is a gas, this hazard class is considered not applicable

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Staff

as the oral route of exposure is not relevant.

Subclass 9.4 Terrestrial

invertebrate ecotoxicity NA ND No reliable test data was

submitted

NA: Not Applicable. For instance testing for a specific endpoint may be omitted if it is technically not possible to conduct the study as a consequence of the properties of the substance: e.g. very volatile, highly reactive or unstable substances cannot be used, mixing of the substance with water may cause danger of fire or explosion or the radio-labelling of the substance required in certain studies may not be possible.

ND: Not determined due to a lack of test data or unreliable test data.

No: Not classified based on actual relevant data available for the substance or all of its components. The data are conclusive and indicate the threshold for classification is not triggered.

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Appendix D: Physico-chemical properties of ethanedinitrile

The physico-chemical properties of ethanedinitrile are listed in Table 11.

Table 11: Physical and chemical properties of ethanedinitrile

Property Reference

Colour Colourless Application form

Physical state Gas Application form

Melting point -27.8°C Lide, D.R. CRC Handbook of Chemistry and Physics 88th Edition 2007-2008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 3- 124

Boiling Point -21.1°C Lide, D.R. CRC Handbook of Chemistry and Physics 88th Edition 2007-2008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 3- 124

Odour Threshold 500 mg/m³ (~235 ppm) Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986)

Vapour density 1.8 (Air = 1) National Fire Protection Guide. Fire Protection Guide on Hazardous Materials.

10th ed. Quincy, MA: National Fire Protection Association, 1991., p. 325M-29

Flash point NA Ethanedinitrile is a gas under normal

conditions, the flashpoint is therefore not defined

Flammability 6 – 32 vol.% in air APVMA approval summary Vapour pressure 520 kPa (21°C), 570 kPa

(25°C)

Application form

Water Solubility (20°C)

9.75 g/L Application form and Maxa, I.D.

Physiochemical properties of cyanogen (EDN). University of Chemistry and Technology, Prague. 2016.

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Appendix E: List of environmental fate endpoints

Unless otherwise stated, all environmental fate data for ethanedinitrile were sourced from the applicant or the Australian Government’s Department of Sustainability, Environment, Water, Population and Communities (DSEWPaC) environmental risk assessment for ethanedinitrile (2012) prepared for the Australian Pesticides and Veterinary Medicines Authority (APVMA).

Residues relevant to the environment

Based on the theoretical EQuilibrium Criterion (EQC) modelling provided by the applicant (as summarised in Appendix J), almost all ethanedinitrile (nearly 100%) remains in air, and only a minor amount is transported to water (0.000125%), soil or sediment (0.0048%). As such, the degradation and fate of ethanedinitrile in aquatic environments and soil environments, as described below, is likely to be of minor significance in comparison with degradation and dissipation in the atmosphere.

Ethanedinitrile is reactive and does not persist in the environment unchanged. The most common degradation pathway is the hydrolysis in the atmosphere to yield one molecule of hydrogen cyanide (HCN) and one molecule of cyanic acid (HOCN) as shown by the equation below.

N≡C-C≡N + H-O-H → H-O-C≡N + H-C≡N

In the presence of timber logs however, a study by Hall et al. (2016) demonstrated that fumigation of pine logs with ethanedinitrile in fumigation chambers either does not result in the production of

hydrogen cyanide or that the concentration of hydrogen cyanide produced is not detectable because it is so small that it is masked by the hydrogen cyanide concentration that is endogenous to the

ethanedinitrile.

Most of the ethanedinitrile applied is expected to be adsorbed into the timber logs during fumigation.

Hall et al. (2014) have shown in a laboratory trial that there is no desorption of ethanedinitrile after 1.5 hours aeration following log fumigation.

The applicant states that the amount of ethanedinitrile to be released to the environment should be significantly lower than the amount applied due to the tendency of ethanedinitrile molecules to be adsorbed within the treated commodity (ie, the timber logs). After removal of the tarpaulin, free ethanedinitrile is expected to spread rapidly in the atmosphere and be diluted in air so its concentration will be below the limit of detection.

In conclusion, in regard to the environment the only compound assessed was ethanedinitrile. It is noted that data regarding the rate at which ethanedinitrile forms its breakdown products in the environment was not available.

Degradation and fate of ethanedinitrile in aquatic environments

Information on the degradation and fate of ethanedinitrile in the aquatic environment is summarised in Table 12. Information on bioaccumulation potential is listed in Table 13.

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Table 12: Degradation and fate in aquatic environments

Test type Ethanedinitrile Reference

Ready biodegradation No test data submitted Aqueous photolysis half-

life (DT50)

Disregarded study (see Appendix K)

Ajwa, H. (2015). Photolysis of Cyanogen under UV light (without water). Performing laboratory:

Ajwa Analytical Laboratories, 1514 Moffett Street, Salinas, California 93905. Laboratory study ID: AAL 2015-13. Sponsor: Lučebni zăvody Draslovka a.s. Kolín, Havlíčkova 605, 280 99 Kolín, Czech Republic. Completed: May 22, 2015.

Degradation in aerobic water/sediment (DT50)

No test data submitted

Water solubility at 25°C 9.75 g/L Application form and Maxa, I.D. Physiochemical properties of cyanogen (EDN). University of Chemistry and Technology, Prague. 2016.

Hydrolysis half-life in the dark (DT50)

Disregarded study (see Appendix J)

Ajwa, H. (2015). Effect of pH on hydrolysis of cyanogen in the dark. Performing laboratory:

Ajwa Analytical Laboratories, 1514 Moffett Street, Salinas, California 93905. Laboratory study ID: AAL 2015-12-A. Sponsor: Lučebni zăvody Draslovka a.s. Kolín, Havlíčkova 605, 280 99 Kolín, Czech Republic. Completed: May 22, 2015.

Hydrolysis half-life under UV light (DT50)

Disregarded study (see Appendix J)

Ajwa, H. (2015). Effect of pH on hydrolysis of cyanogen under UV light. Performing

laboratory: Ajwa Analytical Laboratories, 1514 Moffett Street, Salinas, California 93905.

Laboratory study ID: AAL 2015-12-B. Sponsor:

Lučebni zăvody Draslovka a.s. Kolín,

Havlíčkova 605, 280 99 Kolín, Czech Republic.

Completed: May 22, 2015.

Table 13: Bioaccumulation potential

Partition coefficient octanol/water [Log Pow]

0.07 Australian Government Department of

Sustainability, Environment, Water, Population and Communities (DSEWPaC). The application specific environmental risk assessment for ethanedinitrile in Sterigas 1000 Fumigant. 20 August 2012.

Bioconcentration factor 3.16 (estimated from log KOW)

Australian Government Department of Sustainability, Environment, Water, Population and Communities (DSEWPaC). The application specific environmental risk assessment for

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ethanedinitrile in Sterigas 1000 Fumigant. 20 August 2012.

Degradation and fate of ethanedinitrile and its metabolites in soil

Information on the degradation and fate of ethanedinitrile and its metabolites in the soil environment is summarised in Table 14.

Table 14: Degradation and fate in soil

Aerobic half-life in soil

(DT50lab) No test data submitted

Anaerobic degradation in

soil (DT50lab) No test data submitted Aerobic half-life in soil

(DT50field) No test data submitted

Soil photolysis half-life

(DT50) No test data submitted

Sorption to soil (Koc) 8.3 (estimated)

Australian Government Department of

Sustainability, Environment, Water, Population and Communities (DSEWPaC). The application specific environmental risk assessment for ethanedinitrile in Sterigas 1000 Fumigant. 20 August 2012.

General conclusion about environmental fate

Ethanedinitrile is expected to adsorb to the timber logs during fumigation. Free ethanedinitrile is expected to spread rapidly in the atmosphere and be diluted in air.

Despite a lack of test data, and limitations in data quality, the environmental fate data gaps in regard to the fate of ethanedinitrile in soil and water are not considered to be significant based on the use patterns outlined in the GAP table (fumigation under tarpaulins, shipping container, fumigation chamber or similar structures and in a ship’s hold). Furthermore, exposure to aquatic and soil environments is expected to be minimal, if any.

Although there is no exposure pathway for aquatic or terrestrial organisms, based on the bioconcentration factor as well as rapid metabolism and degradation in biological systems, ethanedinitrile is not expected to bioaccumulate.

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Appendix F: Mammalian toxicology

Ethanedinitrile contains two cyanide functional groups that can be hydrolysed to form hydrogen cyanide (HCN) and cyanic acid (HOCN). The latter compound is also a detoxification product of the cyanide ion (CN^-) and is significantly less toxic than cyanide. Accordingly, its hazards have not been considered in this assessment. Cyanide toxicity occurs when the cyanide ion binds to the iron atoms of cytochrome c oxidase, an enzyme found in mitochondria in all cells. The binding of cyanide to this cytochrome prevents transport of electrons from cytochrome c oxidase to oxygen. This prevents the cells’ ability to use oxygen leading to a “cellular asphyxiation” and cell death. This mode of action can lead to a shutdown of vital organs and rapid death after an exposure to a high concentration of CN^-. Highly metabolically active organs such as the central nervous system and heart are particularly sensitive to its acutely toxic effects.

CN^- is primarily (~80%) detoxified in the body through the formation, and elimination in the urine, of thiocyanate. CN^- may also become detoxified through formation of cyanic acid (the other breakdown product of ethanedinitrile) which then converts to CO2 and is eliminated through the lungs. The thiocyanate metabolite is a competitive inhibitor of iodide absorption in the thyroid gland and can cause a decreased output of thyroxin hormone from the thyroid. Re-adjustment to the original output of thyroxin requires an increase in thyroid mass (volume) brought about by increased secretion of thyroid stimulating hormone by the pituitary gland.

The toxicodynamics of CN^- poisoning in animals are complex and are determined by a number of factors. These include the dose amount and the rate of delivery of CN^-, and the rate and total capacity for detoxification (thiocyanate formation) and the rate of elimination of thiocyanate. In acute poisoning scenarios there is a very steep dose-response curve when the rate of delivery of CN^- exceeds the detoxification capacity resulting in overt acute toxicity. Whereas in chronic exposure scenarios, or where the rate of delivery is maintained within the detoxification capacity limits, acute CN^- toxicity can be avoided. Consequently, it is possible to achieve a higher cumulative dose of cyanide when

exposure is over a longer period than if it is delivered in a single exposure. This phenomenon is apparent in several of the mammalian toxicity studies reported with cyanides. For example, in long- term dietary and drinking-water studies with cyanide in rodents NOAELs were ~10 - 25 mg CN^-/kg bw/day. This is markedly above the median acute lethal (LD50) bolus dose of ~3 - 4 mg CN^-/kg bw.

Executive summaries and list of endpoints for ethanedinitrile

Unless otherwise noted, all studies were conducted according to Good Laboratory Practice (GLP) and were fully compliant with the requirements of the international test guidelines followed.

Acute toxicity, skin and eye irritation, contact sensitisation and genotoxicity data for ethanedinitrile are summarised in Table 15.

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Table 15: Summary of acute toxicity, irritation, sensitisation and genotoxicity data for mammalian toxicology data for ethanedinitrile

Endpoint (Test Guideline)

Klimisch

score Result HSNO

Classification Reference

Acute inhalation toxicity

(OECD TG 403)

1 (GLP) LC50 = ~136 ppm (rats) 6.1B

Ethanedinitrile: Acute Inhalation Toxicity in Rats;

Lab Study Num.:

44021; April 12, 2017.

Acute dermal toxicity (Non-Guideline)

2 (non- GLP)

LC50 ≥10,000 ppm

(rabbits) No

McNerney, J.M. and Schrenk, H.H. (1960).

The acute toxicity of cyanogen. Am Ind Hyg Assoc J 21:121-124.

Skin irritation/corrosion (Non-Guideline)

2 (non- GLP)

Non irritating to rabbits following an 8 hr exposure to 10,000 ppm

No

Eye irritation/corrosion (Non-guideline)

2 (non- GLP)

7/7 human subjects reported irritant effects after an 8 minute exposure to 16 ppm

ND – Sensory irritation is not classifiable

Genotoxicity (OECD TG 471)

1 Negative No

Woods, I. (2016);

Envigo Study Number:

BT66SP, Envigo CRS Limited, Wooley Road, Alconbury, Huntingdon, Cambridgeshire, PE28 4HS, UK.

1 Positive (see discussion) No

Woods, I. (2016);

WS10TH, Envigo CRS Limited, Wooley Road, Alconbury, Huntingdon, Cambridgeshire, PE28 4HS, UK.

1 Positive (see discussion) No

Woods, I. (2016);

TJ774JS, Envigo CRS Limited, Wooley Road, Alconbury, Huntingdon, Cambridgeshire, PE28 4HS, UK.

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Although the results from the genotoxicity studies were considered “positive”, there were multiple indicators noted within the observed responses that, when taking into account the mechanism of ethanedinitrile toxicity (metabolic inhibitor), provide evidence for a secondary mechanism. Thus, the observed effects may be related to a non-direct effect on the DNA through its cytotoxicity. A similar phenomenon was noted in the chromosomal aberration studies conducted with other cyanide compounds.

 “Cyanide has only an indirect genotoxic effect in vitro and in vivo in that dying cells release endonucleases into the cytosol, ultimately resulting in DNA fragmentation” (ATDSR).

 “Valid data are available for all genetic endpoints and there is no indication of mutagenic or genotoxic activity of cyanide” (ECETOC).

 “Although somewhat limited, the weight of evidence of available data indicates that cyanide is not genotoxic” (WHO)

 “Cyanide has not been subjected to a complete standard battery of genotoxicity assays, although, overall, the available data indicate that cyanide is not genotoxic” (US EPA).

As a result of this International consensus in regard to the genotoxicity of cyanides, staff have concluded that ethanedinitrile is also not likely to be genotoxic or classifiable.

Results of the repeated dose toxicity studies with ethanedinitrile are summarised in Table 17.

Table 16: Summary of repeated dose studies with ethanedinitrile

Study type NOAEL (mg/kg

bw/day)

LOAEL (mg/kg

bw/day Key effect Reference

180-day inhalation toxicity: rats 11.2 ppm 25.3 ppm Decreased body weights

Lewis, T.R., et al.

(1984). J Environ Pathol Toxicol Oncol

180-day inhalation toxicity: primates 25.3 ppm (highest dose tested)

Lewis, T.R., et al.

(1984). J Environ Pathol Toxicol Oncol

These two inhalation studies lacked robustness in many areas. These include the number of toxicity endpoints assessed, number of tissues examined, use of only a single sex (males), and the lack of three treatment levels to assess a dose response. It is also unknown as to whether this study was conducted under GLP. Nonetheless, it does represent a sub-chronic exposure study conducted on ethanedinitrile with minimal adverse effects observed following a 6-month exposure. No evidence of thyroid toxicity was observed at the highest exposure level in either species.

Toxicokinetics and dermal absorption studies with ethanedinitrile are summarised in Table 17.

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Table 17: Summary of toxicokinetics and dermal absorption studies with ethanedinitrile

Study type Results

Toxicokinetics No data were submitted or available

Acute Dermal toxicity

Rabbits (shaved) exposed to ethanedinitrile at a concentration of 10,000 ppm for 8 hours did not show evidence of toxicity indicating it is not significantly absorbed through the skin.

General conclusion about mammalian toxicology of ethanedinitrile

Data of sufficient quality from studies using ethanedinitrile were available to assess the acute inhalation toxicity, dermal irritation potential, genotoxicity, and sub-chronic toxicity potential of ethanedinitrile.

Other toxicity endpoints were assessed using data from studies conducted on numerous other surrogate cyanide compounds. These studies were summarized in various reviews completed by the World Health Organization (WHO), the United States (US) Department of Health and Human Services – Public Health Service – Agency for Toxic Substances and Disease Registry (ATSDR), the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), the US- National Research Council (NRC), the US-National Institutes of Environmental Health Sciences – National Toxicology Program (NTP), and the Australian Pesticides and Veterinary Medicines Authority (APVMA). These surrogate compounds consisted of hydrogen cyanide (HCN), cyanide salts such as sodium cyanide (NaCN) and potassium cyanide (KCN), and from compounds that metabolically release cyanide such as

acetonitrile and acetone-cyanohydrin (ACH). The use of a structure-activity-relationship for making a hazard assessment for ethanedinitrile is based on the fact that ethanedinitrile gas is, upon inhalation, absorbed in the lungs and is hydrolysed in the blood into HCN and cyanic acid (HCNO).

The dose rate in which cyanide enters the body is a critical factor in cyanide poisoning as the exposure rate has to overwhelm the detoxification rate for acute toxicity to be manifested. Thus, the total amount of cyanide that can be internalized and tolerated can be quite large when the dose rate is below the detoxification rate. However, there is a very steep dose response resulting in death when exceeded. For example, in long-term (13 weeks) animal studies, no deaths and minimal adverse effects were observed following exposure to NaCN at a daily dose of ~24 mg CN^-/kg bw/day slowly administered over an entire day via drinking water (NTP: NIH pub. 94-3386). However, acute LD50 for NaCN following a single oral bolus dose is only ~5 mg/kg bw (ATSDR, 2006). Some cyanide

compounds also require metabolism to release the cyanide ion and as such detoxification mechanisms are not saturated as rapidly. Ethanedinitrile needs to first be metabolized through hydrolysis to release CN^- (half-life of cyanogen at pH 7.0 and 23°C is 50 min.), whereas HCN gas readily disassociates into H⁺and CN^-. The 15 min LC50 for HCN is 415 ppm while the 15 min LC50 for ethanedinitrile is between 1000 ppm (0/6 deaths) and 2,000 ppm (6/6 deaths) (ATSDR, 2006). This difference in acute toxicity could also be associated with differences in respiratory absorption kinetics as HCN is much more soluble in water than ethanedinitrile.

APP202804 – EDN

SCIENCE MEMO

APP202804 – EDN

Executive Summary

Table of Contents

1. Background

1.1 Regulatory status

Table 1: Regulatory status in New Zealand and overseas

2. Hazardous properties

Table 2: Proposed classification for active and substance

Physical/chemical hazard classifications (classes 1-5)

Toxicity hazard classifications (class 6)

Ecotoxicity hazard classifications (class 9)

3. Risk assessment context

4. Human health risk assessment

5. Environmental risk assessment summary

6. Proposed controls

Appendix A: Proposed controls

Physical hazards controls

Toxicity controls

Exposure thresholds

Table 3: Current international workplace exposure standards for ethanedinitrile

Table 4: Long-term exposure thresholds for ethanedinitrile or CN

in air, food, and water

Table 5: Short-term exposure thresholds for ethanedinitrile in air: Acute Exposure Guideline Levels (AEGL) for Selected Airborne Chemicals

Other toxicity controls

Ecotoxicity controls

Maximum application rate

Table 6: Active ingredient(s) maximum application rates

Other ecotoxicity controls

Table 7: List of components requiring identification

Appendix B: Identity of the active ingredient, use pattern and mode of action

Identity of the active ingredient and metabolites

Table 8: Identification of the active substance ethanedinitrile

Use pattern and mode of action

Use pattern

Mode of action

Table 9: List of intended uses for EDN

Appendix C: Hazard classification of ethanedinitrile

Table 10: Applicant and EPA Staff classification of ethanedinitrile

Appendix D: Physico-chemical properties of ethanedinitrile

Table 11: Physical and chemical properties of ethanedinitrile

Appendix E: List of environmental fate endpoints

Residues relevant to the environment

Degradation and fate of ethanedinitrile in aquatic environments

Table 12: Degradation and fate in aquatic environments

Table 13: Bioaccumulation potential

Degradation and fate of ethanedinitrile and its metabolites in soil

Table 14: Degradation and fate in soil

General conclusion about environmental fate

Appendix F: Mammalian toxicology

Executive summaries and list of endpoints for ethanedinitrile

Table 15: Summary of acute toxicity, irritation, sensitisation and genotoxicity data for mammalian toxicology data for ethanedinitrile

Table 16: Summary of repeated dose studies with ethanedinitrile

Table 17: Summary of toxicokinetics and dermal absorption studies with ethanedinitrile

General conclusion about mammalian toxicology of ethanedinitrile