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EPA STAFF REPORT
www.epa.govt.nz
Application for approval to import HFO-1234yf for release
APP202547
November 2016
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
Overview
Substance HFO-1234yf
Application code APP202547
Application type To import or manufacture for release any hazardous substance
under Section 28 of the Hazardous Substances and New Organisms
Act 1996 (“the Act”)
Applicant Honeywell International Inc.
Purpose of the application To import HFO-1234yf, a gas for use in refrigeration and air
conditioning
Date application received 5 July 2016
Submission period 18 July 2016 – 29 August 2016
Submissions Eleven submissions were received
Information requests and
time waivers
The timeframe for submissions was waived under section 59 of the
Act to allow a submission after submissions had closed.
Further information was requested under section 58 of the Act, and
consequently the timeframe for consideration of this application was
waived under section 59 of the Act.
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
Table of Contents
Overview .................................................................................................................................................... 2
1. Executive summary ........................................................................................................................ 4
2. Background ..................................................................................................................................... 6
3. Process, consultation and notification ........................................................................................ 8
4. Hazardous properties .................................................................................................................. 10
5. Submissions ................................................................................................................................. 10
6. Risk, cost, and benefit assessment............................................................................................ 16
7. The effects of the substance being unavailable ....................................................................... 21
8. Controls ......................................................................................................................................... 21
9. Overall evaluation and recommendation ................................................................................... 23
Appendix A: Controls recommended for HFO-1234yf ........................................................................ 24
Appendix B: Hazard classifications ...................................................................................................... 30
Appendix C: Physico-chemical properties .......................................................................................... 32
Appendix D: Mammalian toxicology ..................................................................................................... 33
Appendix E: Ecotoxicology ................................................................................................................... 73
Appendix F: Confidential information .................................................................................................. 81
Appendix G: Standard terms and abbreviations ................................................................................. 82
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
1. Executive summary
1.1. Honeywell International Inc. applied to import the substance 2,3,3,3-tetrafluoropropene, also known as
HFO-1234yf or R1234yf. This substance is a flammable gas and is intended for use as a heat transfer
agent in refrigeration systems and in air conditioning. This includes use in blends with other
refrigerants.
1.2. HFO-1234yf has a low global warming potential (GWP) compared to many existing refrigerants, and it
is not ozone depleting.
1.3. We recommend that the hazard classification that is applicable to HFO-1234yf based on product data,
the composition of the substance, and the properties of its components, is 2.1.1A.
Hazard Endpoint EPA staff classification
Flammable Gas 2.1.1A
1.4. The application was publicly notified and eleven submissions were received.
Submissions
1.5. There was strong support among submitters for the approval of HFO-1234yf.
1.6. Six of the submitters requested to speak at a hearing.
1.7. A significant issue raised by submitters is whether the current training system requirements will ensure
that users of HFO-1234yf and other flammable refrigerants are adequately trained in the safe handling
of these substances. Submitters expressed concern that without appropriate training, people could
attempt to retrofit existing air-conditioning systems that are not designed for flammable gases with
HFO-1234yf. Several submitters considered that Approved Filler Certificates should be required, and
that these certificates should be specific to flammable gases.
1.8. Several submitters noted the ASHRAE1 Standard 34 classification used in the refrigerant industry for
HFO-1234yf of A2L – ‘mildly flammable refrigerant’. Submitters noted that more flammable refrigerants
were likely to be used in future due to the low GWP refrigerants largely being flammable. They
expressed concern that the highly flammable but cheaper substances isobutane, propane and LPG
could be used in favour of the less flammable HFO-1234yf if they were considered by users of
refrigerants to have the same degree of flammability. One submitter noted that inappropriate use of
butane or other hydrocarbons has already been observed in Australia in automotive refrigeration.
1.9. A wide range of other concerns were also expressed, which are discussed in detail in this report.
1.10. WorkSafe provided information to the EPA regarding the submissions. They noted that existing
requirements under the Health and Safety at Work Act 2015 and associated regulations impose a duty
1 The American Society of Heating, Refrigerating and Air-Conditioning Engineers. Standard 34 relates to the Designation and
Safety Classification of Refrigerants
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
on persons conducting a business or undertaking (PCBUs). PCBUs have a duty towards every person
carrying out work of any kind, using plant (equipment) of any kind, or dealing with a substance of any
kind that is capable of causing a risk in a workplace. They considered that this duty ensures that
anyone working with flammable gases is required to be trained in the safe use of refrigerant gases that
are flammable. There are also requirements for plant to be designed and manufactured so as not to
cause risks to the health and safety of persons.
1.11. WorkSafe noted that the Electricity (Safety) Regulations 2010 do not allow a flammable gas to be
refilled into a system that is not designed for the substance.
1.12. We acknowledge the release of two recent Australian/New Zealand Standards regarding refrigerants,
AS/NZS 817:2016 and AS/NZS 5149.1-4:2016 that incorporate differences in the requirements
between A2L refrigerants such as HFO-1234yf and more highly flammable refrigerants. We have
taken this and information provided by WorkSafe New Zealand into account in our risk assessment.
Risk assessment
1.13. We did not undertake a quantitative assessment of the risks to human health and the environment
because HFO-1234yf does not have human health or ecotoxicological hazard classifications and is not
expected to cause significant effects as a result of any toxicological or ecotoxicological hazards.
1.14. However, there are some potential risks associated with the physical properties of the substance,
including its flammability, the potential for cryogenic burns due to rapid evaporation of the liquefied
gas, and the potential for asphyxiation in enclosed spaces where there is poor ventilation.
1.15. We propose to apply the default controls for a 2.1.1A flammable gas. We propose additional label
information requirements to communicate the potential for cryogenic and asphyxiation effects on
people handling HFO-1234yf.
1.16. We consider that the potential risks to human health and aquatic and terrestrial environments are
negligible with the proposed controls in place.
1.17. We consider that the potential risks to Māori culture or traditional relationships with the environment
are negligible.
1.18. We note that the approval of HFO-1234yf could assist New Zealand in complying with its obligations
under the Montreal Protocol, New Zealand’s international climate change obligations, and related
agreements, as a result of its low global warming potential and zero ozone depleting potential.
1.19. We note that HFO-1234yf is expected by the applicant to have improved energy efficiency compared
with existing refrigerants it is intended to replace.
1.20. Overall, we consider that there are significant benefits associated with the approval of HFO-1234yf,
including financial benefits to the refrigerant industry, a reduction in harm to the environment
compared with existing refrigerants, and benefits with respect to New Zealand’s international
obligations.
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
1.21. We consider that the risks of this substance are negligible, and that the significant benefits of the
substance outweigh any risks or costs. Accordingly we recommend that the application be approved
with controls.
2. Background
2.1. 2,3,3,3-tetrachloropropene, which is referred to as HFO-1234yf throughout this report, is a flammable
gas to be used as a heat transfer fluid for refrigeration and air conditioning systems, including those in
passenger cars. It will also be a component of gas mixtures for use in refrigeration and air conditioning
systems.
2.2. The applicant intends that the substance will be imported into New Zealand in 4.5 kg and 11.3 kg net
fill steel cylinders, and the cylinders will be transported within New Zealand by road and sea.
2.3. HFO-1234yf is intended to be disposed of by recycling or controlled destruction.
Global warming potential and ozone depletion potential
2.4. Global warming potential (GWP) is a relative measure of how much heat a greenhouse gas causes to
be trapped in the atmosphere. It is usually expressed by comparison of the warming potential with the
same mass of carbon dioxide, where the GWP of carbon dioxide is exactly 1. GWP values differ based
on the timeframe for comparison. GWP values given in this report are 100-year time horizon values.
Where possible, these values are taken from the International Panel on Climate Change (IPCC)
Fourth Assessment Report: Climate Change 20072, and these values are the values most frequently
used in international literature to compare GWP.
2.5. Ozone depletion potential (ODP) is a relative measure of how much degradation a substance can
cause to the ozone layer. It is usually expressed by comparison with the ODP of
trichlorofluoromethane (R-11), which is fixed at exactly 1. ODP values given in this report, with the
exception of the value for HFO-1234yf, are taken from New Zealand’s Ozone Layer Protection
Regulations 19963, Schedule 5, Annexes A-E.
2.6. HFO-1234yf has a GWP of 4 according to information provided by the applicant. It does not contain
bromine or chlorine atoms that are involved in the catalytic destruction of ozone in the stratosphere,
and therefore is effectively not ozone depleting (ODP = 0), based on information provided by the
applicant.
2 The table of direct GWP values and related information is on pages 212-213 of the report, available at:
http://www.ipcc.ch/pdf/assessment-report/ar4/wg1/ar4-wg1-chapter2.pdf
3 http://www.legislation.govt.nz/regulation/public/1996/0222/18.0/whole.html
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Application for approval to import HFO-1234yf for release (APP202547)
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Other refrigerants mentioned in this report
2.7. Several other refrigerants and classes of refrigerants are mentioned in this report. These are
described briefly in this section, and names used in the rest of the report are given in bold.
2.8. Liquid carbon dioxide, or R-744, is able to be used as a refrigerant. It is non-toxic, non-ozone
depleting, non-flammable, and has a GWP of 1. While it is a highly efficient refrigerant, it needs to be
used at high pressures that require specially designed components to prevent equipment failure from
rapid gas expansion.
HCFCs
2.9. Hydrochlorofluorocarbons, or HCFCs are a family of refrigerants containing hydrogen, chlorine,
fluorine and carbon atoms. These substances are ozone depleting and their use has been phased out
under the Montreal Protocol. These substances also have significant global warming potential, with
GWP values ranging from 77 – 2310.
HFCs
2.10. Hydrofluorocarbons, or HFCs are a family of refrigerants containing hydrogen, fluorine, and carbon
atoms. Substances in this class of refrigerants have insignificant ozone depleting potential, but have
high global warming potential. These substances are subject to the Climate Change Response Act
2002.
2.11. Difluoromethane is an HFC known as R-32 or HFC-32. R-32 is not ozone depleting and has a GWP of
675. R-32 is flammable, and is classified as 2.1.1A in New Zealand.
2.12. Chlorodifluoromethane is an HFC known as R-22. R-22 has an ozone-depleting potential of 0.05 and
a GWP of 1810.
2.13. Pentafluoroethane is an HFC known as R-125. It is not ozone depleting and has a GWP of 3500.
2.14. 1,1,1,2-tetrafluoroethane is an HFC known as R-134a, HFC-134a or norflurane. R-134a is not ozone
depleting and has a GWP of 1430. It is non-flammable. HFO-1234yf, and blends containing HFO-
1234yf, are intended by the applicant to be a replacement for R-134a and blends containing R-134a.
2.15. 1,1,1-trifluoroethane is an HFC known as R-143a. It is not ozone depleting and has a GWP of 4470.
HFOs
2.16. Hydrofluoroolefins, or HFOs are a new family of refrigerants. Substances in this class of refrigerants
have insignificant ozone depleting potential, and have lower global warming potential than HFCs. This
application for HFO-1234yf is the first application under the HSNO Act 1996 for a hydrofluoroolefin
substance. These substances are not subject to the Climate Change Response Act 2002.
2.17. HFO-1234ze, or trans-1,3,3,3-tetrafluoroprop-1-ene is another HFO. It has a GWP < 1 and has a (Z)
and an (E) isomer, the latter of which is used in some blends with HFO-1234yf.
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
Blends
2.18. A wide variety of blended refrigerants is available. The following blends are referred to in this
document.
2.19. R404A is a blend containing R-143a (52%), R-125 (44%), and R-134a (4%). It has a GWP of 3922.
2.20. R448A, also known as Solstice N40 is a blend containing the HFOs HFO-1234yf (20%) and HFO-
1234ze (E-isomer) (7%) as well as R-32 (26%), R-125 (26%), and R-134a (21%). It has a GWP of
1273.
International obligations
2.21. The United Nations Framework Convention on Climate Change (UNFCCC) is an international treaty
involving commitments to reduce greenhouse gas emissions. New Zealand has taken an emissions
reduction commitment for the period 2013-2020 under the UNFCCC. New Zealand implemented the
Emissions Trading Scheme through the Climate Change Response Act 2002 in recognition of its
commitments. HFCs are included in the UNFCCC and in the New Zealand Emissions Trading
Scheme.
2.22. The Montreal Protocol on Substances that Deplete the Ozone Layer is an international treaty
regarding the phasing out of production of substances that are responsible for ozone depletion. New
Zealand has implemented its obligations under the Montreal Protocol through the Ozone Layer
Protection Act 1996 (OLPA) and its associated regulations.
2.23. The Montreal Protocol and OLPA cover, among other substances, HCFCs.
2.24. In October 2016 the Kigali Amendment to the Montreal Protocol was adopted. The Kigali Amendment
is an agreement to also phase out the use of HFCs.
3. Process, consultation and notification
3.1. The application was formally received on 5 July 2016.
3.2. The Ministry for the Environment, WorkSafe New Zealand (“WorkSafe”), and the Agricultural
Compounds and Veterinary Medicines (ACVM) group of the Ministry for Primary Industries were
advised of the application and notified of the submission period. No comments were received.
3.3. The application was publicly notified and was open for submissions from 18 July to 29 August 2016.
3.4. The application was publicly notified because it was considered it would be of significant public
interest and because the EPA sought information from the refrigerant industry and other affected
parties regarding the management of the risks related to the flammability of HFO-1234yf.
3.5. Eleven submissions were received from:
Sythree Pty Ltd
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
Climate Controls Companies Association and the Institute of Refrigeration Heating and Air
Conditioning Engineers (“CCCA” and “IRHACE” – joint submission)
Refrigerant License Trust Board (“RLTB”)
Refrigerant Recovery New Zealand Limited (“RRNZ”)
Chemiplas
Te Rūnanga o Ngāti Whātua
CoolCar Air-Conditioning Centres (“CoolCar”)
Tru-Test Ltd
Motor Industry Association (Inc) (“MIA”)
VASA Automotive Air Conditioning, Electrical and Cooling Technicians of Australasia (“VASA”)
Motor Trade Association Inc (“MTA”)
3.6. CCCA/IRHACE did not state support or opposition to the application. The remaining ten submitters
supported the application.
3.7. The timeframe for the close of submissions was waived under section 59 of the Act to allow the
submission of the Motor Trade Association to be accepted after submissions had closed.
3.8. Six submitters requested to speak at a hearing – CCCA/IRHACE, RLTB, RRNZ, CoolCar, Tru-Test
Ltd, and VASA.
3.9. During the evaluation of the application, the EPA determined that further information was required in
order to complete the evaluation and risk assessment. Further information was requested from
WorkSafe and the New Zealand Fire Service under section 58 of the Act and the timeframe for holding
a hearing for this application was waived under section 59 of the Act. Information was received from
WorkSafe on 20 October 2016.
3.10. In preparing this report, the following documents and information were taken into account:
the application form
confidential material submitted by the applicant with the application form, including:
toxicological and ecotoxicological studies on HFO-1234yf
physical properties and physical hazard information for HFO-1234yf
the submissions
information received from WorkSafe
other available information
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
4. Hazardous properties
4.1. We determined the hazard profile of HFO-1234yf (Table 1) as described in Appendix B.
4.2. Physico-chemical, mammalian toxicology and ecotoxicology studies were provided for HFO-1234yf.
Information from these studies and mixture rules were used to classify the substance. Based on these
studies we determined that no human health or ecotoxicological classifications are appropriate for
HFO-1234yf.
4.3. HFO-1234yf is classified as a 2.1.1A flammable gas: high hazard because its range of flammability in
mixture with air (6.0 – 13.3%) satisfies one of the two criteria that result in classification as 2.1.1A –
specifically the criterion that the gas is ignitable in a mixture of 13% or less by volume with air.
Table 1 Hazard classifications of HFO-1234yf
Hazard Endpoint Applicant classification EPA Staff classification
Flammable Gas 2.1.1A 2.1.1A
5. Submissions
5.1. There was strong overall support for the application amongst the submissions, with no submitters
opposing the application. The submissions were particularly consistent in their support for the move to
refrigerants that are not ozone-depleting and that have much lower global warming potential than
currently used refrigerants such as HFCs.
5.2. We have used the information gained from submissions, where relevant, to inform our risk
assessment. Key issues raised in submissions are highlighted below.
Approved Filler Certificates and training requirements
Submissions
5.3. Several submitters noted the need for a robust training system for users of flammable refrigerants.
These submitters recommended that there be a requirement for appropriate trade qualifications for
handling flammable refrigerants, and a requirement for an Approved Filler Certificate. Chemiplas
noted that training was important so that HFO-1234yf is only used in systems designed for flammable
refrigerants.
5.4. These submitters considered that there is a need to widen the current minimum requirement to obtain
an Approved Filler Certificate (required for transferring a gas into a compressed gas cylinder) so that it
is also required for transferring gas into and out of a refrigeration system or unit. This was considered
important with flammable refrigerants due to the potential for overcharging these systems to cause a
catastrophic failure and result in human injury. Submitters also expressed concern should attempts be
made to retrofit existing air-conditioning systems to use HFO-1234yf.
5.5. Some submitters also considered that Approved Filler Certificates that are specific to refrigerant gases
should be required, rather than the certificate being obtained from courses that focus on other gases.
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
5.6. Submitters also recommended that there be more stringent requirements around moderation and
review of Approved Filler Certificates.
5.7. These submitters considered that a restriction should be placed on the sale of refrigerants to ensure
that sale of refrigerants is only to persons with an Approved Filler Certificate and appropriate training
to use the substances. Similarly, the submitters recommended that the current voluntary wholesaler
restriction of refrigerant sale to persons with an Approved Filler Certificate be made into an
enforceable requirement among all wholesalers and anyone who imports or sells refrigerants.
5.8. RLTB considered that it should be mandatory for people working with mildly flammable and highly
flammable refrigerants under the ASHRAE Standard 34 on the Designation and Safety Classification
of Refrigerants to have an Approved Filler Certificate.
5.9. RLTB noted that a unit standard for Flammable Refrigerant Safety Awareness has been developed
and considered that this or a similar training course should be made a requirement.
EPA response
5.10. We note the concerns of several submitters regarding training requirements and the potential for
untrained users to handle the substance or refill equipment inappropriately.
5.11. WorkSafe noted that an Approved Filler Certificate is required by the regulations when discharging
from a refrigeration system into a compressed gas cylinder. WorkSafe did not agree with submitters
that an Approved Filler Certificate is required for transferring gas to a refrigeration system. They noted
that Regulation 9 of the Health and Safety at Work (General Risk and Workplace Management)
Regulations 2016 requires PCBUs to ensure all persons are provided the information training,
instruction or supervision they need to protect them from health and safety risks arising from the
PCBUs work. They noted that PCBUs have a duty towards every person who carries out work of any
kind, uses plant of any kind, or deals with a substance of any kind that is capable of causing a risk in a
workplace. WorkSafe considered that this duty ensures that anybody working with flammable
refrigerant gases is required to be trained in the safe use of flammable refrigerant gases.
5.12. WorkSafe noted the potential for retrofitting of existing air-conditioning systems to use HFO-1234yf,
and the potential for over-filling to cause a catastrophic failure. WorkSafe noted that regulation 20 of
the Electricity (Safety) Regulations 2010 does not allow a flammable gas to be filled into a system that
is not designed for the substance.
5.13. WorkSafe also noted that regulations 39-41 of the Health and Safety At Work Act 2015 place duties on
upstream PCBUs to design, manufacture and supply plant that is without risks to the health and safety
of persons.
5.14. We therefore consider that existing regulation addresses these concerns.
Benefits of HFO-1234yf
5.15. Sythree Pty Ltd considered that there are significant environmental benefits.
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
5.16. Sythree Pty Ltd considered that use of HFO-1234yf and blends containing it in refrigeration will
provide cost savings for end users as a result of increased energy efficiency.
5.17. We note the benefits described by submitters, including cost savings for end users from increased
energy efficiency, and environmental benefits from using a refrigerant with low GWP and no ODP. We
have taken these benefits into account in our risk assessment of HFO-1234yf.
Changes to the Compressed Gases Regulations4
Submissions
5.18. Several submitters recommended changes be made to the Compressed Gases Regulations. This
includes the above recommendations related to Approved Filler Certificates.
5.19. CCCA and IRHACE requested a change in the Compressed Gases Regulations to allow greater
enforcement by the EPA or WorkSafe of the requirements for access to and safe use of refrigerants.
5.20. CCCA and IRHACE consider that a system should be introduced similar to the EU F Gas classification
of types of work requiring specific types of training. RLTB supported CCCA and IRHACE’s proposal.
EPA response
5.21. The EPA notes that WorkSafe responded to this issue. In its response it referred to Regulation 9 of the
Health and Safety at Work (General Risk and Workplace Management) Regulations 2016 that
provided requirements as described above in 5.11. They noted that they have many means by which
they can secure the health and safety of workers and workplaces, including education, engagement,
and enforcement. They noted that when using the enforcement lever, their Enforcement Decision-
Making Model assists inspectors when they are considering what enforcement, if any, is suitable for
the situation. WorkSafe noted that breach of Regulation 9 above is an enforceable offence.
Classification of refrigerants under the HSNO Act and AS/NZS Standards
Submissions
5.22. Multiple submitters noted that any regulatory changes for refrigerants will need to align with the joint
classification system set out in the revised version of AS/NZS 1677.2:1998 Refrigerating Systems and
its replacements AS/NZS 817:2016 Refrigerants – Designation and Safety Classification and AS/NZS
5149.1-4:2016 Refrigerating Systems and Heat Pumps – Safety and Environmental Requirements.
5.23. Several submitters noted that in the refrigerant industry HFO-1234yf is an A2L mildly flammable
refrigerant and that this is a new classification for certain flammable refrigerants under ASHRAE
Standard 34. This classification distinguishes HFO-1234yf and other A2L or B2L mildly flammable
refrigerants from more highly flammable refrigerants (classes A2, A3, B2 and B3). These submitters
considered that because of this classification there will need to be amendments to the charge limit
4 Hazardous Substances (Compressed Gases) Regulations 2004
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
information for the storage and transportation of flammable refrigerants. Further discussion is included
below under “Flammability”.
5.24. Several submitters noted that while HFO-1234yf is classified as highly flammable under the New
Zealand HSNO system (which is based on the range of flammability in air), HFO-1234yf is a mildly
flammable gas according to the classification system of the ASHRAE Standard 34.
EPA response
5.25. HFO-1234yf is classified as a 2.1.1A flammable gas – high hazard under the Hazardous Substances
(Classification) Regulations 2001. This classification triggers a number of default controls to be applied
to HFO-1234yf to manage the risk from flammability. These controls apply standard requirements to
flammable gases regardless of the degree of flammability of the 2.1.1A gas, and we consider it
appropriate to retain these requirements.
5.26. The EPA notes that the classification system adopted by Standards Australia / Standards New
Zealand is not within the scope of this application process.
Flammability of the substance
Submissions
5.27. RRNZ noted that the applicant stated in their application that “most of the better performing blends
containing HFO-1234yf are non-flammable”. RRNZ expressed concern with this statement as they
noted that many blends containing this refrigerant are flammable. RRNZ also noted that the blends
containing HFO-1234yf that have GWP under 500 and are most likely to be used as long term
refrigerants are all flammable.
5.28. RRNZ also considered the application to be misleading in stating that the risks in using HFO-1234yf
“do not vary markedly from the HFC and HCFC refrigerants it will replace,” because other than R-32,
the HFC and HCFC refrigerants in common use in New Zealand are non-flammable. RRNZ noted that
in the past, the refrigeration industry has not been trained to handle flammable hazards due to the use
of non-flammable refrigerants.
5.29. CoolCar Air-Conditioning Centres and VASA noted that due to the high price of HFO-1234yf and the
rising price of R134a, consumers would seek cheaper alternatives. They expressed concern that given
HFO-1234yf and cheaper isobutane/propane or LPG would each have a 2.1.1A highly flammable gas
classification consumers may be misled into believing that these gases present the same level of
flammability risk when HFO-1234yf presents a much lower flammability risk than isobutane, pentane
or LPG. They reported that Australia has seen this issue with hydrocarbon gases being inappropriately
used as automotive refrigerants.
5.30. In response to the above concern, several submitters recommended that changes in the marketplace
from approval of HFO-1234yf should not have the unintended consequence of encouraging greater
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
use of highly flammable hydrocarbon gases as refrigerants in systems that are not designed for their
use, and noted that this was the case in the Tamahere cool store fire.
5.31. The Motor Industry Association noted that some of their members do not support the use of HFO-
1234yf due to concerns regarding flammability. This is because of in-house testing showing that a
serious head-on collision in which the refrigerant line is severed can result in ignition of HFO-1234yf in
a hot engine compartment, whereas currently used R-134a does not ignite.
5.32. In contrast to some of the other submitters, the Motor Trade Association noted that it was their
understanding that the potential for fire as the result of motor vehicle accidents was unrealistic, and
considered that they were satisfied that use of HFO-1234yf as a motor vehicle refrigerant did not pose
a danger to the industry or the public.
EPA response
5.33. WorkSafe proposed that in addition to the default controls for a 2.1.1A substance, variations to certain
controls be applied to ensure that the controls on HFO-1234yf are in line with those applied to LPG,
propane, butane and isobutene in refrigeration systems.
5.34. We have taken relevant information on this matter into account in our risk assessment and our
proposed controls for HFO-1234yf. We consider that the risks related to the flammability of HFO-
1234yf are managed by the proposed controls.
Disposal and recovery, and levies
Submissions
5.35. RRNZ noted that they had confirmed with the facility that destroys their recovered refrigerants that the
controlled incineration method of disposal used for other refrigerant gases is suitable for destruction of
HFOs such as HFO-1234yf.
5.36. They also noted that the cost of destruction of refrigerant gases is currently funded only by the
collection of a voluntary levy on the importation of bulk HFC refrigerants and through the NZ Units
(under the Emissions Trading Scheme) received from the export of HFC refrigerants exported for
destruction. Funding is not received from the equipment and vehicles arriving with HFCs in them, and
yet RRNZ noted that they still need to fund destruction of those refrigerants. For HFOs, RRNZ
considered that there needed to be an effective method to fund the destruction of HFOs, or less
funding would be available for HFC destruction. They noted that NZ Units collected for export or
disposal of HFOs would not be likely to cover the costs of their destruction.
5.37. While RRNZ noted that HFOs are not currently subject to requirements under the Climate Change
Response Act and that HFO-1234yf has a comparatively low Global Warming Potential (100 year
GWP = 4), they considered it important that industry ensures that all synthetic refrigerants are not
released to the atmosphere when no longer required.
5.38. As a result they considered that HFOs should be required to be collected and destroyed.
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5.39. CoolCar Air-Conditioning Centres and VASA noted that CFCs and HFCs were considered safe when
initially approved and later found to cause unacceptable ozone depletion (CFCs) and contribute to
global warming. For this reason they recommend that recovery of HFO-1234yf be mandatory, with
recycling and re-use where possible, lest there be unforeseen consequences from the release of the
substance.
5.40. There is currently a voluntary training and destruction levy for refrigerants. RLTB recommended that
all sellers of refrigerant should be required to collect this levy.
5.41. The Motor Trade Association recommended investigation of an import levy to support the destruction
of end-of-life refrigerants.
EPA response
5.42. We note the concerns raised by industry. However, the issue of industry levies is out of scope of the
EPA application process and has no bearing on our risk assesment.
5.43. We note that there is the potential for there to be costs incurred by organisations undertaking disposal
and recovery activities on refrigerant gases in order for those organisations to have suitable
equipment for handling HFO-1234yf. We have taken these costs into account in our assessment.
5.44. We consider that the proposed controls for HFO-1234yf adequately manage risks to people and the
environment from the disposal of this substance.
Emissions Trading Scheme
Submissions
5.45. CoolCar Air-Conditioning Centres expressed a number of concerns relating to the Emissions Trading
Scheme and enforcement of requirements under the Ozone Layer Protection Act 1996 and the
Climate Change Response Act 2002.
5.46. Submitters noted that costs have increased recently due to the rise in the price of emissions units.
This has increased the cost of importing HFCs. Submitters noted that this may create a perverse
incentive to use improper substitutes for HFCs.
EPA response
5.47. We note the concerns raised by industry, and that HFO-1234yf (along with all HFOs) is not currently
included within the ETS. However, enforcement of the Scheme, and differing costs of gases included
or not, are outside the scope of this risk assessment.
Existing market for the product
Submissions
5.48. Sythree Pty Ltd noted that there is a market for this refrigerant and blends containing the refrigerant.
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5.49. Several submitters noted that vehicle refrigeration systems containing HFO-1234yf are already
entering New Zealand. It was also noted that several vehicle manufacturers have adopted HFO-
1234yf as their refrigerant of choice, to replace R134a. The submitters stated that they have
encountered vehicles in New Zealand using HFO-1234yf for which replacement refrigerant has not
been available. This means those vehicles are unable to undergo service to the air-conditioning
system at this time. They also noted that HFO-1234yf systems [in automobiles] cannot be retrofitted to
use any other refrigerant.
5.50. The Motor Industry Association noted that the European Union has mandated5 that refrigerant
systems in all new approved motor vehicle models from 1 January 2013 must not be filled with a
refrigerant with a Global Warming Potential higher than 150, and at present HFO-1234yf is the only
permitted refrigerant that satisfies these requirements. They therefore expect the number of vehicles
containing HFO-1234yf imported to New Zealand to increase.
EPA response
5.51. We note these submissions acknowledging that HFO-1234yf will already be entering New Zealand in
vehicle air-conditioning systems. We have taken into account the expected market for the substance
in our benefits assessment.
Regulatory Process
5.52. We note Tru-Test Ltd’s comments regarding regulatory process and their recommendation for a new
group standard for HFO refrigerants.
5.53. We note that there are existing group standards for compressed gas mixtures that blends containing
HFO-1234yf will be able to use should HFO-1234yf be approved.
6. Risk, cost, and benefit assessment
6.1. HFO-1234yf is intended to be manufactured in the United States of America and imported fully
labelled and packaged in 4.5 kg and 11.3 steel pressure cylinders with refrigerant valves. The
applicant intends that the cylinders only be made available for industrial and commercial users.
6.2. HFO-1234yf will be used to make blends with other refrigerant gases. These blends will be
transported in 800 kg steel pressure cylinders. These mixtures are not covered by this application and
are instead expected to be assigned to one of the Compressed Gas Mixtures Group Standards.
6.3. HFO-1234yf will also be used (unblended) in motor vehicle air conditioning systems.
5 In Directive 2006/40/EC, entering into effect in the EU in 2011: http://eur-
lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2006:161:0012:0018:EN:PDF
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Effects from fire
6.4. HFO-1234yf is a flammable gas and therefore presents potential risks from fire, including harm to
human health, property damage, wider communities and surrounding environments.
6.5. We recommend that the default controls for 2.1.1A flammable gases be applied to HFO-1234yf.
WorkSafe New Zealand also recommended that variations to some of the default controls be applied
to align requirements with those for certain existing flammable gases. We consider that these controls
and requirements under other legislation will manage the risks associated with the flammability of
HFO-1234yf such that the resulting level of risk is negligible.
Human health effects
6.6. HFO-1234yf is intended for use in closed refrigeration and air-conditioning systems, and as such,
human exposure is expected to be very limited. Some exposure may occur in the event of leakage,
other types of equipment failures, or human error. Some installed systems will be vulnerable to
physical impact, in particular air conditioning systems in motor vehicles.
6.7. A qualitative assessment of the risks to human health was undertaken. We have also considered
information from other sources, including the NICNAS (National Industrial Chemicals Notification and
Assessment Scheme, Australia) risk assessment of the health significance of potential exposure to the
substance from a private motor vehicle.
6.8. We note that HFO-1234yf has no human health classifications and do not anticipate that there are
likely to be any significant adverse effects related to its human toxicological properties from intended
uses.
6.9. However, gases stored as liquids under pressure have the potential to cause some adverse effects
related to their physical properties. We note that there is the potential for skin or eye contact with the
liquid, and that such contact could cause cryogenic burns as a result of rapid evaporation of the
liquefied gas. We consider that this risk can be managed by ensuring that people handling the
substance are aware of this risk and have recommended a labelling control. With this control in place,
we consider that the risk is negligible.
6.10. HFO-1234yf is also more dense than air, and therefore has the potential to accumulate in enclosed
spaces if there is insufficient air movement or ventilation. This presents potential risks of fire and
asphyxiation. We consider that the risk of fire is managed by the controls applied to flammable gases.
We have recommended a labelling control to inform users of the potential for asphyxia in areas where
there is insufficient air movement or ventilation, and with this control in place we consider that the risk
is negligible.
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Environmental effects
Ecotoxicology
6.11. We did not undertake quantitative exposure modelling for environmental endpoints for HFO-1234yf,
because the use pattern of the substance and the gaseous form of the substance limits the potential
for a significant environmental exposure.
6.12. We have therefore qualitatively assessed the potential risks to aquatic and terrestrial ecosystems. We
note that liquefied gas released during an accidental spill will evaporate. We consider that it is highly
unlikely that there would be a significant environmental exposure other than atmospheric exposure.
Additionally HFO-1234yf is non-toxic to the aquatic environment and we consider it highly unlikely that
there would be a sufficiently large inhalation exposure to terrestrial vertebrates to cause adverse
effects. We therefore do not anticipate that there are likely to be any significant adverse effects related
to its ecotoxicological properties.
Environmental fate
6.13. HFO-1234yf is unlikely to enter the waterways or contaminate soils for a prolonged period of time due
to the volatility and physical state of the substance.
6.14. The atmospheric lifetime of HFO-1234yf is relatively short compared with HFC and HCFC refrigerants,
and we note that the substance has a much smaller contribution to global warming effects than the
refrigerants it is intended to replace. We have taken this into account in our benefits assessment.
6.15. We also note that HFO-1234yf is considered not ozone depleting.
Relationship of Māori to the Environment
Kupu arataki (context)
6.16. The potential effects of HFO-1234yf on the relationship of Māori to the environment have been
assessed in accordance with sections 5(b), 6(d) and 8 of the Act. Under these sections all persons
exercising functions, powers and duties under this Act shall: recognise and provide for the
maintenance and enhancement of people and communities to provide for their cultural well-being,
and; take into account the relationship of Māori and their culture and traditions with their ancestral
lands, water, taonga and the principles of the Treaty of Waitangi (Te Tiriti o Waitangi).
6.17. We note that HFO-1234yf is a flammable gas, and that there is the potential for cultural risk from this
hazardous property. Cultural risk includes any negative impacts to treasured flora and fauna species,
the environment, and the general health and well-being of individuals and the community.
6.18. In general, the introduction and use of hazardous substances has the potential to inhibit the ability of
Māori to fulfil their role as kaitiaki.
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Mahinga kai (food resources)
6.19. HFO-1234yf is not expected to pose any significant risk to mahinga kai as mahinga kai species are not
expected to be adversely impacted in the event of a fire arising from the hazard properties of this
substance. We note that the expected environmental concentrations are below levels that would
cause harm to mahinga kai species.
Te Marae o Maru me Te Marae o Tāne (freshwater and terrestrial ecosystems)
6.20. HFO-1234yf is not expected to pose any significant risk or impacts in relation to Te Marae o Maru
(freshwater ecosystems) or Te Marae o Tāne (terrestrial ecosystems), including culturally significant
species associated with mahinga kai, rongoā (medicine), pūere (textiles), taputapu (tools and
equipment), mahi toi (arts and craft) and whakarākei (ornamentation).
6.21. No significant risk is anticipated in relation to:
Ngā wai koiora me ngā rauropi wai (aquatic habitats and aquatic organisms)
Te Aitanga Pepeke (insects and arthropods)
Ngā one me Te Aitanga a Punga (soils and soil dwelling organisms)
Ngā manu (birds)
Ngā ngāngara (reptiles)
Ngā otaota (plants)
Ngā rīroi (rodents)
Ngā mōkaikai me ngā kararehe (pets and quadrupeds).
Taha hauora (human health)
6.22. As HFO-1234yf is a flammable gas, HFO-1234yf poses a risk to taha hauora, in particular the
dimensions of taha wairua (spiritual health and well-being obtained through the maintainance of a
balance with nature and the protection of mauri) and taha tinana (physical health and wellbeing).
6.23. Fire caused by HFO-1234yf would have the potential to inhibit taha whānaunga – the responsibility to
belong, care for and share in the collective, includings relationships and social cohesion. Adverse
impacts on the ability of people to protect co-workers and others could impact on collective welfare,
well-being, and safety amongst those using HFO-1234yf and in wider communities.
6.24. We note that HFO-1234yf will generally be used on private premises or other areas where access to
systems or facilities using HFO-1234yf is controlled, or in closed refrigeration systems. We note that
persons responsible for these places will be obliged to advise others of the hazards associated with
use of HFO-1234yf. We note that there will be controls on the use of HFO-1234yf to mitigate these
risks to taha hauora from the flammability of HFO-1234yf.
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6.25. We therefore consider that the risks to taha hauora will be mitigated by users, operators, installers and
service people following the controls on this substance.
Ētahi atu mea (other matters)
6.26. The use of HFO-1234yf as a heat transfer fluid is expected to bring economic benefits for people who
own or work with refrigeration and air conditioning facilities – some of whom will be Māori.
Kupu whakatepe (conclusion)
6.27. Based on the information provided, including the use pattern and the controls proposed to be assigned
to HFO-1234yf, the potential risks to Māori culture or traditional relationships with the environment are
expected to be negligible.
6.28. If HFO-1234yf is used in the intended manner it is considered that it is not likely to breach the
principles of the Treaty of Waitangi, including the principle of active protection.
New Zealand’s international obligations
6.29. HFO-1234yf is not itself currently subject to any international obligations that affect this approval.
However, there are a number of international obligations that apply to other refrigerants, specifically
obligations related to the Kyoto Protocol and the Montreal Protocol. These protocols are described in
section 2 of this document and involve worldwide commitments to eliminate or reduce the use of
ozone-depleting substances and substances with global warming properties.
6.30. HFO-1234yf is an alternative refrigerant that has no ozone-depleting potential and a comparatively low
global warming potential. HFO-1234yf and blends containing HFO-1234yf will likely be used in place
of substances subject to the protocols. Approval of this application for HFO-1234yf would assist New
Zealand in meeting its obligations under these protocols by providing an alternative to HCFCs and
HFCs for the refrigerant industry. Approval of HFO-1234yf is expected to improve New Zealand’s
ability to meet its Montreal Protocol obligations and its emissions reduction commitment under the
UNFCCC.
Assessment of costs
6.31. We note that approval of HFO-1234yf could potentially lead to costs for organisations undertaking
recovery and disposal activities on refrigerants, should handling and recovery of HFO-1234yf be more
expensive due to the requirement for new or upgraded equipment. We consider that these potential
costs are likely to be not significant in terms of their overall impact.
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Assessment of benefits
Applicant
6.32. The applicant notes that HFO-1234yf is non-ozone depleting, and has a much lower global warming
potential than the substances it is intended to replace. They note that the blends containing HFO-
1234yf will also have a lower GWP than the gases or blends of gases they are intended to replace.
6.33. They also note that blends containing HFO-1234yf are showing performance improvements in energy
efficiency in refrigerant applications, referring to the blend R448A compared with the existing blend
R404A and with R22.
6.34. They also noted that HFO-1234yf degrades readily in the environment, with an 11 day lifetime in the
atmosphere.
Submissions
6.35. We note the benefits described by submitters, including cost savings for end users from increased
energy efficiency, and environmental benefits from using a refrigerant with low GWP and no ODP.
EPA assessment
6.36. We consider that HFO-1234yf provides a non-ozone depleting, low global warming potential
refrigerant gas alternative to existing refrigerants that are subject to international regulation.
Accordingly we consider that availability of HFO-1234yf would provide significant benefits to the
refrigeration industry, to the environment and to New Zealand’s ability to meet its international
obligations.
7. The effects of the substance being unavailable
7.1. We consider that if HFO-1234yf was not approved, the significant benefits described above to the
refrigeration industry, the environment, and to New Zealand’s international obligations, would not be
realised. We also note that the potential costs to the organisations undertaking recovery of refrigerants
would not be incurred.
8. Controls
8.1. A set of default controls are specified by regulations under the Act, based on the hazard classifications
determined for HFO-1234yf. The default controls form the basis of the controls proposed to be applied
to HFO-1234yf as set out in Appendix A. Based on the risk assessment, we recommend that the
following additions, variations and deletions are applicable to HFO-1234yf.
The setting of exposure limits
8.2. We note that HFO-1234yf does not trigger the controls that prescribe for Tolerable Exposure Limits
(TELs), Acceptable Daily Exposure (ADE), and Potential Daily Exposure (PDE) values to be set.
Nevertheless, we considered whether these values should be set for HFO-1234yf. We concluded that
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Application for approval to import HFO-1234yf for release (APP202547)
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due to the low toxicity of the substance with no identified target organ effect following acute or chronic
exposures, these values should not be set for HFO-1234yf.
8.3. Environmental Exposure Limits (EELs) can be set to limit hazardous substances from entering the
environment in quantities sufficient to present a risk to it. No EEL values are proposed for HFO-1234yf
as the substance does not trigger any ecotoxic hazard classifcations.
Variation and deletion of controls
8.4. Approved handler requirements for flammable substances apply to this substance as a result of its
flammable gas classification. We consider it appropriate to apply approved handler requirements
through the lifecycle of this substance, but to apply a variation to the default control so that approved
handler requirements do not need to be met during transportation of HFO-1234yf. This is because the
Dangerous Goods Regulations provide sufficient measures to mitigate the potential risks of HFO-
1234yf during transport of the substance.
8.5. WorkSafe New Zealand proposed variations to some of the controls that are the same variations as
are currently applied to LPG, butane, propane, and isobutane. They consider that these variations will
ensure consistency in regulation of flammable gases, and we recommend these variations be applied.
Additional controls
8.6. HFO-1234yf presents a potential risk to people handling the substance if there is a significant release
of the substance, due to cryogenic effects from rapid evaporation of the liquefied gas. The default
controls for HFO-1234yf do not include identification requirements that would require this potential risk
be identified to users of the substance. We therefore recommend that an additional control be applied
to HFO-1234yf to require that information about the potential risk from cryogenic effects be included
on the label for the substance, along with information about the appropriate personal protective
equipment (PPE) to be worn to protect from cryogenic effects.
8.7. HFO-1234yf is heavier than air and therefore a leak of the substance presents the potential for pooling
of the substance in areas where there is poor ventilation and air flow. This leads to the potential for
asphyxiation where there is reduced oxygen available for breathing. We therefore recommend that an
additional control be applied to HFO-1234yf to require that information about this risk appear on the
label for the substance, to communicate this information to users of the substance.
Risks of the substance given the recommended controls
8.8. We consider that with the proposed controls in place, the level of risk to human health and the
environment will be negligible.
Review of controls for cost-effectiveness
8.9. We consider that the proposed controls are the most cost-effective means of managing the identified
potential risks and costs associated with this substance.
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Application for approval to import HFO-1234yf for release (APP202547)
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9. Overall evaluation and recommendation
9.1. We consider that there are significant, non-negligible benefits associated with the approval of HFO-
1234yf.
9.2. The risk assessment indicates that there is a negligible level of risk to human health and the
environment, to Māori culture, and to society, community and the local economy, when using HFO-
1234yf with the proposed controls in place.
9.3. We consider that the controlled use of HFO-1234yf is consistent with the principles of the Treaty of
Waitangi. We also consider that the proposed controls (see Appendix A) will appropriately manage the
cultural impacts of this substance.
9.4. With the proposed controls in place, the benefits provided by HFO-1234yf will outweigh the risks and
any costs associated with the adoption of HFO-1234yf. Therefore, we recommend that the application
be approved with the controls documented in Appendix A, in accordance with clause 26 of the
Methodology.
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Application for approval to import HFO-1234yf for release (APP202547)
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Appendix A: Controls recommended for HFO-1234yf
Please refer to the Hazardous Substances Regulations6 for the requirements prescribed for each control and
the modifications listed as set out in Section 6 of this document.
Hazardous Substances (Classes 1 to 5 Controls) Regulations 2001
Code Regulation Description Variation
F1 7 General test certification
requirements for hazardous
substance locations
F2 8 Restrictions on the carriage of
flammable substances on passenger
service vehicles
F3 55 General limits on flammable
substances
F4 56 Approved handler/security
requirements for certain flammable
substances
The following regulation is inserted
immediately after regulation 56:
56A Exception to approved handler
requirement for transportation of this
substance when packaged
(1) Regulation 56 is deemed to be
complied with if:
(a) when this substance is being
transported on land—
(i) by rail, the person who drives the
rail vehicle that is transporting the
substance is appropriately licensed
under the Railways Act 2005; and
(ii) other than by rail, the person who
drives, loads, and unloads the
vehicle that is transporting the
substance has a current dangerous
goods endorsement on his or her
driver licence; and
(iii) in all cases, Land Transport
Rule: Dangerous Goods 2005 (Rule
45001/1) is complied with; or
(b) when this substance is being
transported by sea, one of the
following is complied with:
6 The regulations can be found on the New Zealand Legislation website; http://www.legislation.co.nz
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Application for approval to import HFO-1234yf for release (APP202547)
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(i) Maritime Rules: Part 24A –
Carriage of Cargoes – Dangerous
Goods (MR024A):
(ii) International Maritime Dangerous
Goods Code; or
(c) when this substance is being
transported by air, Part 92 of the Civil
Aviation Rules is complied with.
(2) Subclause (1)(a)—
(a) does not apply to a tank wagon or
a transportable container to which the
Hazardous Substances (Tank Wagons
and Transportable Containers)
Regulations 2004 applies; but
(b) despite paragraph (a), does apply
to an intermediate bulk container that
complies with chapter 6.5 of the UN
Model Regulations.
(3) Subclause (1)(c)—
(a) applies to pilots, aircrew, and
airline ground personnel loading and
managing this substance within an
aerodrome; but
(b) does not apply to—
(i) the handling of this substance in
any place that is not within an
aerodrome; or
(ii) the loading and managing of this
substance for the purpose of aerial
spraying or dropping.
(4) In this regulation, UN Model
Regulations means the 19th revised
edition of the Recommendation on the
Transport of Dangerous Goods Model
Regulations, published in 2015 by the
United Nations
F5 58, 59 Requirements regarding hazardous
atmosphere zones for class 2.1.1,
2.1.2 and 3.1 substances
F6 60 – 70 Requirements to prevent unintended
ignition of class 2.1.1, 2.1.2 and 3.1
substances
F11 76 Segregation of incompatible
substances
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F12 77 Requirement to establish a
hazardous substance locations if
flammable substances are present
F14 81 Test certification requirements for
facilities where class 2.1.1, 2.1.2 or
3.1 substances are present
F16 83 Controls on transit depots where
flammable substances are present
Hazardous Substances (Identification) Regulations 2001
Code Regulation Description Variation
I1 6, 7, 32 – 35,
36(1) – (7)
Identification requirements, duties of
persons in charge, accessibility,
comprehensibility, clarity and
durability
I5 11 Priority identifiers for flammable
substances
I9 18 Secondary identifiers for all
hazardous substances
I13 22 Secondary identifiers for flammable
substances
I19 29 – 31 Additional information requirements,
including situations where substances
are in multiple packaging
I21 37 – 39,
47 – 50
General documentation requirements
I25 43 Specific documentation requirements
for flammable substances
I29 51, 52 Signage requirements Regulation 51(1) of the Hazardous
Substances (Identification) Regulations
2001 applies to the substances as if the
words
“the quantities of any hazardous
substances of a hazard classification
specified in Schedule 3 exceed the
amount specified in that schedule for
hazardous substances of that
classification”
were omitted and the following
substituted:
“greater than 50 kg of the substances is
held within a building, or where any
quantity of the substances is held in an
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Code Regulation Description Variation
integral part of a refrigeration system and
the refrigeration system is contained in a
machinery room as defined in section
1.4.34 of AS/NZS 1677.2:1998
Refrigerating Systems Part 2: Safety
requirements for fixed applications, or
any other place where greater than 250
kg of the substance is present”
Hazardous Substances (Compressed Gases) Regulations 2004
Code Regulation/description Variation
CG The Hazardous Substance (Compressed Gases)
Regulations 2004 prescribe a number of controls
relating to compressed gases including aerosols and
gas cylinders
Hazardous Substances (Disposal) Regulations 2001
Code Regulation Description Variation
D2 6 Disposal requirements for flammable
substances
D6 10 Disposal requirements for packages
D7 11, 12 Information requirements for
manufacturers, importers and
suppliers, and persons in charge
D8 13, 14 Documentation requirements for
manufacturers, importers and
suppliers, and persons in charge
Hazardous Substances (Emergency Management) Regulations 2001
Code Regulation Description Variation
EM1 6, 7, 9 – 11 Level 1 information requirements for
suppliers and persons in charge
EM8 12 – 16, 18 –
20
Level 2 information requirements for
suppliers and persons in charge
EM9 17 Additional information requirements
for flammable and oxidising
substances and organic peroxides
EM10 21 – 24 Fire extinguisher requirements
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Code Regulation Description Variation
EM11 25 – 34 Level 3 emergency management
requirements: duties of person in
charge, emergency response plans
EM13 42 Level 3 emergency management
requirements: signage
Regulation 42(1) of the Hazardous
Substances (Emergency Management)
Regulations 2001 applies to the substances
as if the words:
“a quantity of a hazardous substance that is
equal to or greater than the quantity specified
for hazardous substances of that
classification in Schedule 5”
were omitted and the following substituted:
“greater than 50 kg of the substances is held
within a building, or where any quantity of the
substances is held in an integral part of a
refrigeration system and the refrigeration
system is contained in a machinery room as
defined in section 1.4.34 of AS/NZS
1677.2:1998 Refrigerating Systems Part 2:
Safety requirements for fixed applications, or
any other place where greater than 250 kg of
the substance is present”
Hazardous Substances and New Organisms (Personnel Qualifications) Regulations 2001
Code Regulation Description Variation
AH 17 4 – 6 Approved Handler requirements
(including test certificate and
qualification requirements)
Hazardous Substances (Tank Wagons and Transportable Containers) Regulations 2004
Code Regulation Description Variation
Tank
Wagon
4 – 43, as
applicable
Controls relating to tank wagons
and transportable containers
7 Refer to Control F4
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Additional controls
Code Section of
the Act Control
Use control 77A A restriction has been placed on refrigeration systems containing this substance.
(1) A person in charge of a refrigeration system that contains the substance
as an integral part of that refrigeration system must ensure that the quantity and
the means of containing the substances are in accordance with:
(a) AS/NZS 5419.1-4:2016; or
(b) a code of practice approved by the Authority under section 78(1) of the
Act that sets out the requirements for containing the substances in a refrigeration
system.
(2) Clause (1) does not apply to domestic refrigerators, domestic heat
pumps or room air conditioners.
Label 77A The label for the substance must include information about the following:
- The potential for skin or eye damage as a result of cryogenic effects following a
significant release of HFO-1234yf
- Appropriate personal protective equipment to protect from cryogenic effects
where significant release of HFO-1234yf may occur
- The following statement, or words to the same effect:
Vapours of this substance are heavier than air and can pool in enclosed areas
with low ventilation. This could cause suffocation by reducing oxygen available
for breathing. Ensure that there is adequate ventilation and air flow when using
this substance.
Unintended
ignition
Schedule 10 SCHEDULE 10 OF THE HAZARDOUS SUBSTANCES (DANGEROUS GOODS
AND SCHEDULED TOXIC SUBSTANCES) TRANSFER NOTICE 2004
This schedule prescribes the controls for unintended ignition of class 2 and 3.1
hazardous substances. The requirements of this schedule are detailed in the
consolidated version of the Hazardous Substances (Dangerous Goods and
Schedule Toxic Substances) Transfer Notice 2004, available from
http://www.epa.govt.nz/Publications/Transfer-Notice-35-2004.pdf
The following clause replaces Clause 1 of Schedule 10 of the Hazardous
Substances (Dangerous Goods and Scheduled Toxic Substances) Transfer
Notice 2004:
This Schedule applies to this substance.
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Appendix B: Hazard classifications
We classified HFO-1234yf based on studies and other information provided by the applicant.
Unless otherwise noted, all studies relied upon to support a conclusion on classification were conducted
according to Good Laboratory Practice (GLP) and were fully compliant with all requirements of the standard
international test methods where these are available.
Classification of HFO-1234yf
Table 3 Application and EPA classifications of HFO-1234yf
Hazard Class/Subclass
Substance
classification
Method of
classification
Remarks
Ap
plican
t
EP
A
Su
bsta
nce
data
Read
acro
ss
Mix
ture
ru
les
Class 1 Explosiveness No No
Class 2, 3 & 4 Flammability 2.1.1A 2.1.1A The study report provided
identified the ignition range from
10% (small blue flame) - 14%
(medium blue flame) (Younis,
2006 – see appendix C).
We note that flammability range at
20°C and standard atmospheric
pressure reported in the SDS is
slightly higher, 6.0 – 13.3%. This
was also reported by NICNAS.
(NICNAS, 20158).
The gas meets the criteria (a) for
classification as a high hazard
flammable gas in Table 4.1 User
Guide to Threshold and
Classification, 2008, p4-2.
Class 5 Oxidisers/Organic Peroxides No No The molecule contains no
functional groups which would
give oxidising potential.
Subclass 8.1 Metallic corrosiveness ND ND
Subclass 6.1 Acute toxicity (oral) ND ND
Subclass 6.1 Acute toxicity (dermal) ND ND
8 NICNAS, 2015. Public Report: 1-Propene, 2,3,3,3-tetrafluoro- File No: STD/1556.
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Hazard Class/Subclass
Substance
classification
Method of
classification
Remarks
Ap
plican
t
EP
A
Su
bsta
nce
data
Read
acro
ss
Mix
ture
ru
les
Subclass 6.1 Acute toxicity (inhalation) No No
Subclass 6.1 Aspiration hazard ND ND
Subclass 6.3/8.2 Skin
irritancy/corrosion
ND ND
Subclass 6.4/8.3 Eye irritancy/corrosion ND ND
Subclass 6.5A Respiratory sensitisation ND ND
Subclass 6.5B Contact sensitisation ND ND
Subclass 6.6 Mutagenicity No No
Subclass 6.7 Carcinogenicity No No
Subclass 6.8 Reproductive/
developmental toxicity
No No
Subclass 6.8 Reproductive/
developmental toxicity (via lactation)
ND No
Subclass 6.9 Target organ systemic
toxicity (inhalation)
No No No classification for single or
repeat exposure by inhalation.
Subclass 9.1 Aquatic ecotoxicity No No
Subclass 9.2 Soil ecotoxicity ND ND
Subclass 9.3 Terrestrial vertebrate
ecotoxicity
ND ND We note the classification as ND
as no oral or dermal studies in
terrestrial vertebrates were
performed, and inhalation studies
are not relevant for class 9.3.
Subclass 9.4 Terrestrial invertebrate
ecotoxicity
No ND
NA: Not Applicable --> For instance when testing is technically not possible: 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: No Data --> There is a lack of data for the substance.
No: Data are available for the substance and classification is not triggered.
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Appendix C: Physico-chemical properties
Physical and chemical properties of HFO-1234yf
Table C1 Physical and chemical properties of the mixture
Table 1 Physical and chemical properties of the substance, HFO-1234yf.
Property Results Test method Klimisch Score
(1-4) Reference
Colour Colourless 4 (no guideline but
mentioned in GLP
report)
Younis (2006). Flammable
and Explosive Properties of
HFO-1234yf (2,3,3,3-
tetrafluoroprop-1-ene).
Chilworth Technology Ltd.
Chilworth Science Park,
Southampton, UK. Report
Number
GLP15024A1R1V1/06
Physical state Gas
Odour ND
Flammability of
gases
Highly
flammable
EC-method-A11 1 Younis (2006). Flammable
and Explosive Properties of
HFO-1234yf (2,3,3,3-
tetrafluoroprop-1-ene).
Chilworth Technology Ltd.
Chilworth Science Park,
Southampton, UK. Report
Number
GLP15024A1R1V1/06
Auto-ignition 405ºC EC-method A15
Explosive
properties
The material
will not
possess
oxidising or
explosive
properties
EC-testing
method A14
Oxidising properties
Solubility 198.2 mg/L EC-method-A6,
with some
adaption to test
a gas
2 (statements not
signed)
Spruit, Mak, Schouten
(2006). Determination of
some physico-chemical
properties of HFO-1234yf.
TNO. Report No: TNO
Defence, Security and
Safety, Lange Kleiweg 137,
Rijswijk, The Netherlands.
DV2 2006-
031.10607/01.03-01
Log Kow 2.15 KOWWIN v1.66
(estimate)
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Appendix D: Mammalian toxicology
Robust study summaries for HFO-1234yf
Acute toxicity [6.1]
Acute Oral Toxicity [6.1 (oral)]
No oral studies were provided by the applicant. The substance is a gas at room temperature and under
pressure so we considered significant oral exposure is unlikely.
Acute Dermal Toxicity [6.1 (dermal)]
No dermal studies were provided by the applicant. The substance is a gas at room temperature and under
pressure so we considered significant dermal exposure is unlikely.
Acute Inhalation Toxicity [6.1 (inhalation)]
Type of study Acute (4 hour) inhalation range finding study in mice
Flag Supporting information
Test Substance HFO-1234yf
Endpoint Mortality, signs of toxicity
Value LC50 > 99,830 ppm
Reference
Hoffman, G.; 2004. HFO 1234yf: An acute (4-hour) inhalation range finding
study in the mouse via whole body exposure. Huntingdon Life Sciences,
100 Mettlers Road, East Millstone, NJ 08875-2360, USA. HLS Study No
03-5479C
Klimisch Score N/A
Amendments/Deviations N/A
GLP No information
Test Guideline/s No information
Species Mice
Strain No information
No/Sex/Group 2
Dose Levels Target (actual): 20,000ppm (23,480 ppm), (100,000 ppm) (99,830 ppm)
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Exposure Type Whole body inhalation for 4 hours
Study summary
Two groups of mice were exposed, consisting of 2 male and 2 female
animals per dose group. There were no deaths and all exposed mice
survived the 7 – day post-exposure period
Additional Comments None
Conclusion LC50 >99,830 ppm
Type of study Acute (4-hour) inhalation study in rats
Flag Key study
Test Substance HFO-1234yf
Endpoint Mortality, signs of toxicity
Value LC50 >405,800 ppm
Reference
Muijser, H.; 2006. Acute (4-hour) inhalation toxicity study with HFO-1234yf
in rats. TNO Quality of Life, Toxicology and Applied Pharmacology,
Utrechtseweg 48, P.O.Box 360, 3700 AJ Zeist, The Netherlands. TNO
Report V6201/06 Final
Klimisch Score 1
Amendments/Deviations None
GLP Yes
Test Guidelines OECD 403 (1997)
Species Rat
Strain Sprague Dawley
No/Sex/Group 5
Dose Levels 201,600 (±800) ppm and 405,800 (±1200) ppm. [There were no control
animals9.]
9 OECD 403 (2009) does not require the use of control animals.
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Exposure Type Inhalation (nose-only) for 4 hours
Study summary
During the exposure to 201,600 ppm a slightly decreased breathing rate
was seen in two male and two female animals at the last two hourly
observation and an additional male animal at the 4 hour observation point.
During exposure to 405,800 ppm a slightly decreased breathing rate and
slightly laboured breathing were seen in two male and three female
animals at the second hourly observation time point and in all animals at
the third and fourth observation time point. In both groups, abnormalities
shortly after exposure and, in particular, signs of narcosis were not seen.
In both groups the body weight gain was considered to be within normal
range.
At necropsy, grey discoloured lungs were seen in one male and one
female animal of the group exposed at 201,600 ppm and in three male and
one female animal of the group exposed to 405,800 ppm. A red
discoloured spot on one lung lobe was seen in one male animal and a
petechia on one lobe in one female animal in the 201,600 ppm group.
Study authors report these findings are often seen in Wistar rats and
assume that this applies to Sprague Dawley rats also, but no evidence in
support of this claim was provided.
Additional Comments
We consider the grey lung discolouration in some animals in both groups
to be exposure-related in the absence of controls for comparison.
We note a non-statistically significant reduction in body weight gain in the
female rats dosed with 405,800 ppm in comparison to those dosed at
201,600 ppm.
These observations do not invalidate the conclusion that no LC50 value has
been established.
Conclusion LC50 > 405,800 ppm
Skin Irritation [6.3/8.2]
No skin irritation/corrosion studies were provided by the applicant. The substance is a gas at room
temperature and under pressure, so we consider significant dermal exposure is unlikely.
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Eye Irritation [6.4/8.3]
No eye irritation/corrosion studies were provided by the applicant. The substance is a gas at room
temperature and under pressure, so we consider significant exposure of the eyes to the liquid is unlikely.
Sensitisation [6.5]
No respiratory or contact sensitisation studies were provided by the applicant. The substance is a gas at
room temperature and under pressure so we consider significant dermal exposure is unlikely. No animal
models are available for respiratory sensitisation. A respiratory sensitisation classification would be derived
from human exposure reports. No such reports were provided by the applicant.
General conclusion about acute toxicity classification
The substance is a gas at room temperature and under pressure so no tests for a range of endpoints were
required as those routes of exposure are not relevant. This applies to acute oral and dermal toxicity, skin and
eye irritancy/corrosivity, and contact sensitisation. Due to the storage of the substance as a liquefied gas, it
is possible that skin and/or eye damage could occur due to its cryogenic properties if exposure to the liquid
occurred. Since this is the result of the physical properties of the substance it does not trigger any
classification, but an identification control for these effects is proposed. Acute inhalation studies demonstrate
the substance is of very low acute toxicity by this route. No studies relevant to respiratory sensitisation were
presented. The substance is not classified for any acute toxicity endpoint.
Genotoxicity [6.6]
In Vitro Studies
Study type/Test Guideline Result Reference
Salmonella typhimurium strains TS
1535, TA 1537, TA 98, TA 100 and
Escherichia coli str WP2 uvrA
with/without S9 (OECD 471)
[NB Using incubator chambers suitable
for a gas.]
Positive
under the
conditions of
this test for
TA100 and
WP2 uvrA
indicative of
base-pair
substitutions
(in the
presence of
S9 metabolic
activation)
van den Wijngaard, M. J. M. et al.; 2009.
Bacterial reverse mutation test with HFO-
1234yf. TNO Quality of Life, Physiological
Sciences Location Zeist, Utrechtseweg 48,
P.O.Box 360, 3700 AJ Zeist, The Netherlands.
TNO Report V6205/09 Final
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In vitro chromosomal aberration assay
in cultured human lymphocytes (OECD
473)
Negative for
clastogenicity
with and
without
metabolic
activation
de Vogel, N.; 2005. Chromosomal aberration
test with HFO-1234yf in cultured human
lymphocytes. TNO Quality of Life,
Physiological Sciences Location Zeist,
Utrechtseweg 48, 3704 HE Zeist, The
Netherlands. TNO Report V6202/07 Final
Conclusion Positive for bacterial mutagenicity but not clastogenic in
mammalian cells in vitro
In Vivo Studies
Type of study In vivo micronucleus test in mice
Flag Key study
Test Substance HFO-1234yf
Endpoint Clastogenicity and effects on spindle apparatus
Value Negative
Reference
de Vogel, N. and Muijser, H.; 2005. Micronucleus test in bone marrow cells of
mice treated with HFO-1234yf, administered by inhalation. TNO Quality of Life,
Physiological Sciences Location Zeist, Utrechtseweg 48, P.O. Box 360, 3700
AJ Zeist, The Netherlands. TNO Report V6204/03 Final
Klimisch Score 1
Amendments/Deviations None
GLP Yes
Test Guidelines OECD 474
Species Mice
Strain Charles River CD-1 albino
No/Sex/Group
Male mice were used. Twelve for the higher dose group (to allow two reserve
mice), 5 males for the mid- and low dose groups. A positive control group of 5
mice was exposed to mitomycin C (0.75 mg/kg bw by intraperitoneal injection).
A negative control group of 10 was exposed to clean air.
Dose Levels 0, 12,500, 50,000 and 200,000 ppm [The actual concentrations were 12,552,
50,021 and 199,046 ppm respectively.]
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Study Summary
Five of each group were killed at 24 hours, but for the high dose and negative
control groups an additional 5 animals were also sacrificed at 48 hours.
The bone marrow from both femurs of each mouse was collected into calf foetal
serum and two slide smears prepared and stained with May – Grunwald
Giemsa solution. One smear was analysed and the other kept in reserve.
No increase in micronucleated polychromatic erythrocytes was seen in the
exposed animals.
The study was considered valid by study authors because the positive controls
gave the anticipated response and the negative controls were within the
historical range.
The conclusion by study authors was that the substance is not clastogenic.
Additional Comments
The inhalation route was selected because this is the likely exposure route for
humans. We note the study did not demonstrate exposure of bone marrow in
the study, but due to the nature of the molecule, distribution to all body
compartments is anticipated. The high dose group was exposed at the same
time as the rats for the 4 hour inhalation study in rats TNO study plan P6201/06
(see report above).
Conclusion The substance is not clastogenic in vivo.
Type of study Unscheduled DNA synthesis in hepatocytes after inhalation exposure
Flag Key study
Test Substance HFO-1234yf
Endpoint Nuclear repair (mean grains/nucleus)
Value Negative
Reference
Muijser, H. and Wijnands, M. V. W.; 2006. Sub-acute (4-week) inhalation
toxicity study (including Unscheduled DNA Synthesis and Micronucleus test)
with 2-week recovery period, with HFO-1234yf in rats. TNO Quality of Life,
Toxicology and Applied Pharmacology, Utrechtseweg 48, P.O Box 360 3700 AJ
Zeist, The Netherlands. TNO Report V6872/02.
(Annex 7 (p81ff) of this report)
Klimisch Score 1
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Amendments/Deviations None
GLP Yes
Test Guidelines OECD 486 (1997)
Species Rat
Strain Sprague-Dawley
No/Sex/Group 5 males (with 2 reserve animals). One reserve animal was used in the 50,000
ppm group
Dose Levels
The dose groups used in the UDS investigation were:
Clean air controls, 15,000 and 50,000 ppm (actual mean concentrations given
in the review of the 4-week acute inhalation study below). The test animals had
been exposed for 20 or 21 days and were sacrificed within 24h of the last
exposure period. A positive control using 2-acetylaminofluorene (2-AAF) was
used to validate the study
Study Summary
Both the test material exposed groups and the control air group analyses
yielded net nuclear grains (NNG) ≤ 0. The criteria for a positive finding is NNG ≥
5. Therefore the substance did not produce unscheduled DNA synthesis in rat
hepatocytes.
The positive control group produced the anticipated result NNG ≥ 5 with at least
20% of the cells in repair, demonstrating the validity of the test system.
Additional Comments None
Conclusion Negative
Type of study Micronucleus test in rats after inhalation exposure
Flag Key study
Test Substance HFO-1234yf
Endpoint Micronuclei
Value Negative
Reference
Muijser, H. and Wijnands, M. V. W.; 2006. Sub-acute (4-week) inhalation
toxicity study (including Unscheduled DNA Synthesis and Micronucleus test)
with 2-week recovery period, with HFO-1234yf in rats. TNO Quality of Life,
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Toxicology and Applied Pharmacology. Utrechtseweg 48, P.O.Box 360, 3700
AJ Zeist, The Netherlands. TNO Report V6872/02.
(Annex 8 (p129ff) of the report)
Klimisch Score 1
Amendments/Deviations None
GLP Yes
Test Guideline/s OECD 474 (1997)
Species Rat
Strain Sprague-Dawley
No/Sex/Group 5
Dose Levels
0 (Air control), 5,000, 15,000, and 50,000 ppm. (Actual mean concentrations
given in the review of the 4-week acute inhalation study below). The test
animals had been exposed for 20 or 21 days.
A positive control group exposed to mitomycin C was used to validate the study.
Study Summary
The exposure groups did not demonstrate a statistically significant increase in
micronucleated polychromatic erythrocytes (MPE).
The proportion of polychromatic erythrocytes (PE)/erythrocytes (E) in the
exposed animals was not different from the negative controls, demonstrating
that no cytotoxicity in the bone marrow could be demonstrated up to the
maximum dose concentration of 50,000 ppm.
The report noted that the maximum concentration (50,000 ppm) corresponds to
a dose of approximately 17,000 mg/rat/day when the minute ventilation rate of
200 ml/min and a 6 hour exposure period is considered (assuming 100%
absorption of the substance via the inhalation route). This is far above the limit
dose required for studies of this type, 1000 mg/kg bw.
The number of MPEs in the positive control group was statistically significantly
different from the negative control, demonstrating the validity of the study.
The mean number of PE per E in the positive controls was statistically
significantly lower than in controls, demonstrating the cytotoxicity of the positive
control agent.
Additional Comments None
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Conclusion Negative
General conclusion about genotoxicity classification
The substance demonstrated mutagenic activity (base pair substitution) in in vitro bacterial test systems. It
was not clastogenic to mammalian cells in vitro. Unscheduled DNA synthesis and a micronucleus assay in
vivo following inhalation exposure for 20 or 21 days in rats were negative. We therefore consider that the
substance is not genotoxic. We recommend that no classification for genotoxicity is applied to HFO-1234yf.
Carcinogenicity [6.7]
No carcinogenicity studies (life-time bioassays in rodents) have been provided by the applicant.
A toxicogenomic study to assess the potential of the substance to cause tumours in the liver of mice and the
kidney of rats was provided by the applicant and is summarised below. Two supplementary reports were also
provided and the key points from these are included.
Toxicogenomic studies
Type of study Toxicogenomic study to predict potential human carcinogenicity in comparison
selected test chemicals following a 90 day exposure in rats
Flag Key study
Test Substance HFO-1234yf
Endpoint
Lowest Observable Adverse Effect Concentration (LOAEC): >50,000 ppm (No
adverse effects including histopathology findings reported after 90 days)
No Observable Adverse Effect Concentration (NOAEC): 50,000 ppm
Reference
Thomas R. S.; 2007. Toxicogenomic Assessment of the Carcinogenic Potential of
2,3,3,3-tetrafluoropropene. The Hamner Institutes for Health Sciences, 6 Davis
Drive, P. O. Box 12137, Research Triangle Park, NC 27709, USA. Laboratory
Protocol ID 06014.
Klimisch Score 1
Amendments/Deviation
s None
GLP Yes
Test Guidelines No guidelines apply for a study of this type
Species Mice and rats
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Strain Female B6C3F1/Crl mice and male F344/CrlBR rats.
No/Sex/Group 6/dose level
Dose Levels
For the test substance HFO-1234yf the target dose levels were 10,000 and 50,000
ppm. The actual daily mean concentrations were 10,054 and 49,728 ppm
respectively. The dosing for the gases was 6 hours/day, 5 days/week for 13 weeks.
Study Summary
The test set of chemicals were:
trichlorofluoromethane (TCFM, CAS 75-69-4)
N-(1-naphthyl)ethylenediamine dihydrochloride (NEDD, CAS 1465-25-4)
Iodoform (IODO, CAS 75-47-8)
1-amino-2,4-dibromoanthraquinone (ADBQ, CAS 81-49-2) [Carc]
Tris (2,3-dibromopropyl)phosphate (TDPP, CAS 126-72-7 [Carc]
tetrafluoroethylene, (TFEL, CAS 116-14-3) [Carc]
tetrafluoroethane (TFEA, CAS 811-97-2)
Three of the substances in the test set are identified as the positive (carcinogenic)
compounds for female mouse liver and male rat kidney cancers in US National
Toxicology Programme (NTP) bioassays as indicated [Carc]. The other four
substances were negative for these tumours.
Solutions were prepared for gavage administration for the solids, while the gas
exposures regime matched that for the target chemical, HFO-1234yf.
Dose regimes for the groups
Chemical No of
animals Route
Dose
(males)
Dose
(females)
TCFM 12 Gavage 977 mg/kg
bw/day
3925 mg/kg
bw/day
IODO 12 Gavage 142 mg/kg
bw/day
93 mg/kg
bw/day
Corn oil
(control) 12 Gavage N/A N/A
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ADBQ 10 Feed# 10,000
mg/kg 20,000 mg/kg
TDPP 10 Feed# 100 mg/kg 1000 mg/kg
NEDD 10 Feed# 1,000 mg/kg N/A
Feed
(control) 10 Feed# N/A N/A
TFEL 10 Inhalation 625 ppm 1250 ppm
TFEA 10 Inhalation 50,000 ppm 50,000 ppm
HFO 1234yf
(L) 10 Inhalation 10,000 ppm 10,000 ppm
HFO 1234yf
(H) 10 Inhalation 50,000 ppm 50,000 ppm
Air control 10 Inhalation N/A N/A
# We assumed that for the dietary studies this is the feed concentration not the
dose.
The dosing was 6 hour/day, 5 days/week for inhalation, 5 days/week for gavage and
7 days/week for feed, all for 13 weeks.
Gene expression changes following a sub-chronic exposure were used to assess
the carcinogenic potential of 2,3,3,3-tetrafluoropropene (HFO-1234yf) in the female
mouse liver and male rat kidney. No treatment-related histopathological lesions
were observed following a 90 day (6 hour/day, 5 days/week) exposure to HFO-
1234yf at 10,000 and 50,000 ppm.
We consider this indicates that the NOAEC for HFO-1234yf in mice and rats after
treatment for 13 weeks is 50,000 ppm.
Statistical classification analysis predicted HFO-1234yf to be non-carcinogenic in
both female mouse liver and male rat kidney.
In both the male rat kidney and female mouse liver, the test chemical HFO-1234yf
was predicted to be non-carcinogenic. In the female mouse liver, the statistical
classification analysis was able to accurately discriminate between the carcinogenic
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and non-carcinogenic control chemicals providing confidence in the carcinogenic
predictions for the three test chemicals.
However, study authors reported that the statistical classification analysis was more
problematic in the male rat kidney, thereby demanding more caution in interpreting
the results. Due to the consistent misclassification of TFEL as non-carcinogenic (in
this study), the chemical was removed from the analysis in the male rat kidney and
the number of known carcinogenic chemicals used to build the classification model
was limited to two.
This represents a relatively small set of chemicals from which to derive predictive
gene sets and make broad predictions about the carcinogenic potential in the rat
kidney. TFEL was chosen as a positive control due to its similarity to the untested
chemicals in containing fluorine. The remaining positive control chemicals (TDPP
and ADBQ) are not fluorinated and are not as chemically similar to the untested
chemicals, making any predictions more tenuous. However, despite the problems
associated with TFEL in the classification analysis, there were few gene expression
changes that were conserved between TFEL and HFO-1234yf suggesting that they
behave quite differently on a gene expression basis.
Despite the non-carcinogenic prediction, gene expression changes in the male rat
kidney following treatment with HFO-1234yf suggested potential endocrine-related
effects and were consistent with a reduction in circulating androgens. In addition,
HFO-1234yf showed a significant upregulation of the SA rat hypertension-
associated gene (Sah) in the male rat kidney. Increased expression of the human
homolog of this gene has been linked to increases in body mass index, triglyceride
levels, cholesterol, and blood pressure status.
There are two supplemental reports to this investigation.
Additional comments from the supplemental report Number 1.
(Thomas R. S.; 2009. Report Supplement on the Toxicogenomic Assessment of the
Carcinogenic Potential of 2,3,3,3,-tetrafluoropropene (HFO-1234yf). The Hamner
Institutes for Health Sciences, 6 Davis Drive, P. O. Box 12137, Research Triangle
Park, NC 27709, USA. Laboratory Protocol ID 06014)
In relation the TFEL findings there was discussion of the possible genetic difference
in between rat colonies used for the work the NTP carcinogenicity finding being with
F344/N rats, and an observation that the NTP F344/N rat colony has been retired
due to declining fertility, sporadic seizure activity and chylothorax. Researchers
argue that the negative genomic predictions are not present in isolation and note the
lack of genotoxicity in mammalian systems in vitro and in vivo, the lack of
histopathological changes in a 13-week study and assessment of the metabolism of
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HFO-1234yf. The study concludes: “Taken together, the results from the genomic
study when interpreted together with the other studies suggest that HFO-1234yf is
non-carcinogenic in the tissues studied”.
In relation to the endocrine effects we note that as with all genomic studies,
interpretation of the biological significance of the observed gene expression
changes is difficult. The study comments: “In many cases it is not known what a two-
fold, three-fold or even statistically-significant change in mRNA levels means in
respect to protein changes or, more importantly, on a functional level. In any case,
reproductive changes consistent with alterations in circulating androgens were not
evident in subsequent follow-up [developmental and reproductive toxicity] studies.”
Additional comments from the supplemental report Number 2.
(Thomas R. S.; 2009. Toxicogenomic Assessment of the Carcinogenic Potential of
2,3,3,3,-tetrafluoropropene (HFO-1234yf) in the Female Mouse Lung. The Hamner
Institutes for Health Sciences, 6 Davis Drive, P. O. Box 12137, Research Triangle
Park, NC 27709, USA. Laboratory Protocol ID 06014 Supplement Number 2.)
The B6C3F1 female mice were exposed for 13 weeks to a selection of 26
chemicals, of which approximately half produced an increased incidence of lung
tumours in a two year rodent cancer bioassay. The conclusion was that: “Based on
the results of this study, HFO-1234yf was predicted to be similar to other substances
found to be carcinogenic in the female mouse lung”. The report noted that there is
evidence both to support and oppose the positive prediction.
Expert opinion
An expert opinion10 was presented by the applicant to assess the extent to which
the prediction that HFO-1234yf is similar to other substances which cause lung
tumours in female mice is of relevance for human risk assessment.
Additional Comments
The EPA has not been provided with a report of the 90 day study used to generated
the NOAEC/LOAEC values referred to in this report. This is not considered a
significant deficiency in the data set as the purpose of the study is to present the
toxicogenomic findings.
10 Dekant W, 2009. “Expert report on the potential of HFO-1234-yf and HFO-1234ze to induce lung tumours in mice after
inhalation exposure and the relevance of this information for hazard assessment.” Institut fur Toxikologie, Universitat Wurzburg,
Versbacher Str. 9, 97078, Wurzburg, Germany.
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Conclusion
The toxicogenomic model indicates that the substance is unlikely to be carcinogenic
in mouse liver or rat kidney, but identifies a possible endocrine-related effect and
possible potential for carcinogenicity in the lung.
EPA staff conclusion on carcinogenicity classification
No life-time bioassays for carcinogenicity have been performed in mice or rats. The applicant has provided
an assessment of the likelihood that the substance presents a carcinogenicity hazard in relation to specific
target organs using toxicogenomics, specifically for mouse liver and lung and rat kidneys. The strains of
mouse and rat used are selected for their sensitivity based on the US National Toxicology Program database
(http://ntp-server.niehs.nih.gov/). While the analysis suggested the possibility that the substance has a
potential cause of lung tumours in mice, we conclude that its metabolic profile and a comparison of the
metabolic activity of mouse, rat and human lung means this conclusion is unlikely to be of relevance to
human exposure levels.
The overall conclusion is that there are sufficient data to conclude no classification of the substance for
carcinogenicity should be assigned. The results of the toxicogenomic study together with the negative
findings for genotoxicity and absence of histopathologic effects in subacute and subchronic toxicity studies
provide support for the conclusion that the substance is not likely to be carcinogenic. We therefore
recommend no classification for carcinogenicity.
Reproductive/Developmental Toxicity [6.8]
Developmental Toxicity
Type of study Pre-natal developmental toxicity in the rat
Flag Key study
Test Substance HFO-1234yf
Endpoints
Maternal Toxicity
LOAEC: >50,315 ppm
NOAEC: 50,315 ppm
Foetal Toxicity
LOAEC: >50,315 ppm
NOAEC: 50,315 ppm
Reference
Tegelenbosch-Schouten M. M.; 2007. Prenatal developmental inhalation toxicity
study with HFO-1234yf in rats. TNO Quality of Life, Toxicology and Applied
Pharmacology, Utrechtseweg 48, P.O. Box 360, 3700 AJ Zeist, The
Netherlands. TNO Report V6986 Final.
Klimisch Score 1
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Amendments/Deviations None
GLP Yes
Test Guidelines
OECD 414
EU Commission Directive 2004/73/EC, B31, Annex 2F.
Species Rat
Strain Wistar outbred (Crl: WI (WU)BR)
No/ Group 25 (females)
Dose Levels 0, 5000. 15,000, and 50,000pm. The actual mean concentrations were: 5,000 (±
20), 15,106 (± 290) and 50,315 (± 935) ppm.
Exposure Type Animals were only dosed during the period Gestation Day (GD) 6 – 19, using a
nose-only exposure equipment, for 6 h/day.
Study Summary
There were no mortalities and no findings in condition or behaviour related to
the test substance.
There was no effect on body weight attributed to the test substance, but the
body weights of all groups (including control animals) reduced during the GD 6 -
9 which was attributed by the study authors to reduced access to feed and
changes in animal husbandry.
Food consumption data showed reduced feed consumption in all groups for the
period GD 6-9.
Of the 25 females in each group 24, 21, 24 and 25 were pregnant and had live
foetuses at Caesarean section in the control, 5,000, 15,000, and 50,000 ppm
group respectively. Female 59 of the low-dose group had an early delivery.
No statistically significant differences were observed in female fecundity index
and gestation index between the groups. The number of corpora lutea was
statistically significantly increased in the mid dose group. No differences were
observed in the number of implantation sites, pre and post-implantation loss,
live and dead foetuses, resorptions or the sex ratio between groups. Variations
in body weight of dams were not test-substance-related.
Findings in the foetuses
A filiform tail was seen in one fetus of a low dose dam and one fetus of a high
dose dam. The incidence of this finding was 0.0, 0.4, 0.0 and 0.4% in the
control, low, mid and high dose groups respectively.
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The incidence of small foetus (<75% of the mean body weight in the control
group) was statistically significantly higher in mid and high dose groups both in
relation to litters and foetuses. The incidence of large foetuses (>125 % of the
mean body weight in the control group) was statistically increased in the low
dose group.
An increase in the placental weight for male and females and combined
foetuses was clearly statistically significant (P <000.1) in comparison to
controls. However, no dose-response was established and in the absence of
other findings (including foetal weight), this was not considered adverse
(although study protocol meant that investigation into the placentas was limited
to gross pathology).
The incidence of visceral anomalies were comparable between test and control
groups.
No dose response relationship applied in relation to visceral variations so the
findings were considered unrelated to exposure.
An increase in skeletal variants (two or more wavy ribs/ separated sternebrae)
and retarded ossification was seen in low, mid, and high dose groups, but this
was not dose related and such findings are considered reversible variations not
malformations.
The NICNAS report (date) stated: “The cases of wavy ribs seen in some
developing foetuses were considered to be of some concern by US EPA (US
EPA 2011). The US EPA also pointed out that the reversibility of the effect was
unclear and that the interim results from a two generation reproductive study
(TNO 2011) did not find an association between exposure to the notified
chemical and skeletal effects (US EPA 2011).”
We concluded that exposure to up to 50,315 ppm of the substance during
organogenesis is not associated with any test-substance adverse effect on
maternal animals or any pre-natal developmental effects on pups.
Additional Comments None
Conclusion Negative for pre-natal developmental toxicity in rats
Type of study Pre-natal toxicity in the rabbit
Flag Supporting study
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Test Substance
HFO-1234yf (Two separate commercial sources of the substance were used for
the mid-dose testing. The substance provided by the study sponsor [Honeywell
International Inc.] and the substance available from Du Pont.)
Endpoints
Parental Toxicity
LOAEC: 5,500 ppm based on mortality, moribundity,
abortions, premature delivery, lower mean body weight
gain, mean body weight loss and/or lower food
consumption observed at 5,500 and 7,500 ppm
NOAEC: 4,000 ppm
Foetal Toxicity
LOAEC: 5,500 ppm for visceral malformations (cardiac
and large vessel malformations)
NOAEC: 4,000 ppm for visceral malformations
Reference
Fleeman, T. L.; 2008. An Inhalation Prenatal Developmental Toxicity Study of
HFO-1234yf (2,3,3,3-tetrafluoropropene) in rabbits. WIL Research Laboratories,
LLC, 1407 George Road, Ashland, OH 44805-8946. USA. Study number: WIL-
447022.
Klimisch Score 1
Amendments/Deviations None
GLP Yes
Test Guidelines OECD No 414, US EPA OPPTS 870.3700
Species Rabbit
Strain New Zealand White
No/ Group 12
Dose Levels
0, 2,500, 4,000, 4,000 [Du Pont source], and 7,500 ppm in Phase I.
In Phase II, the mid dose level was increased from 4,000 to 5,500 ppm.
The measured concentrations were: 2,504, 3,982, 4,013 (Du Pont) and 7512
ppm respectively for the 2500, 4000, 4000 (Du Pont), and 7,500 ppm groups
respectively in Phase I and 2,479, 5,408, 5,479 (Du Pont) and 7,441 ppm for
the 2500, 5,500, 5,500 (Du Pont), and 7,500 ppm groups respectively Phase II.
Exposure Type Whole body exposure for Day 6 – Day 28 of gestation (6h/day).
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Study Summary
The dosing was done in two phases.
Four and seven of the animals were found dead or euthanised in extremis in the
5,500 and 7,500 ppm group respectively. The signs of toxicity seen prior to
death or euthanasia were laboured and/or decreased respiration and/or
hypoactivity for 2 and 3 females in the 5,500 and 7,500 ppm groups
respectively. One and 3 of the females in these respective groups aborted on
day 26, 28 or 29 and one female in the 7500 ppm group delivered on Gestation
Day 29.
The mortality, morbidity, abortions and premature deliver in these groups were
attributed to exposure to the test substance. No test substance-related
macroscopic findings were found in these animals. All other animals survived to
the scheduled necropsy.
No test substance-related findings were noted at the daily examination or the
mid-point of, or 1 hour following, the exposure at any concentration.
Lower mean body weight gain was noted in the 7,500 ppm group during
Gestation Days 12 -20, with occasional corresponding reductions in mean feed
consumption. Since the most affected animals died or were euthanised prior to
the schedule necropsy the mean net body weight and net body weight change
in this group were not significantly different from the control group.
Pups: Heart and great vessel malformations (bulbus aorta, stenotic pulmonary
trunk, interventricular septal defects [absent septa], absent tricuspid valve
and/or interrupted aortic arch) were noted in 2 and 3 foetuses in the 5,500 and
7,500 ppm groups respectively. The mean litter proportions for these findings
exceed the maximum mean value in the laboratories historical control data for
these findings. Because of the increase in comparison to historical control data
and the similarity of the findings, the malformations in the cardiovascular
system of foetuses in these groups was considered test substance-related. The
malformations were noted in the presence of maternal toxicity. No test
substance-related effects on intrauterine groups and survival were noted at any
exposure level.
The conclusions of the researchers were that based on mortality, moribundity,
abortions, premature delivery, lower mean body weight gain, mean body weight
loss and/or lower food consumption observed at 5,500 and 7,500 ppm, an
exposure concentration of 4,000 ppm was considered to be the NOAEC for
maternal toxicity.
Substance-related visceral malformations in the heart, and/or great vessels
were observed in the 5,500 and 7.500 ppm groups in the presence of maternal
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toxicity, and an exposure concentration of 4,000 ppm was considered a NOAEC
for embryo/foetal development in the rabbit.
Additional Comments None
Conclusion The study did not identify any visceral malformations in rabbits at non-
maternally toxic dose concentrations by inhalation.
Reproductive toxicity
Type of study Two generation reproductive toxicity test in rats by inhalation
Flag Key study
Test Substance HFO-1234yf
Endpoints
Parental Toxicity
LOAEC: > 49,958 ppm (No systemic toxicity seen in
parental animals)
NOAEC: 49,958 ppm
Reproductive Toxicity
LOAEC: >49,958 ppm (No adverse reproductive or
developmental effects seen)
NOAEC: 49,958 ppm
Reference
Waalkens-Berendsen, D. H.; 2011. Inhalatory Two-generation Reproduction
Toxicity Study with HFO-1234yf in Wistar Rats. TNO Quality of Life,
Utrechtseweg 48, P.O.Box 360, 3700 AJ Zeist, The Netherlands. TNO Report
V7931/Final.
Klimisch Score 1
Amendments/Deviations
A relatively long list of protocol deviations are documented in this study,
although these are claimed by study authors not to have impacted on its
validity.
GLP Yes
Test Guidelines OECD 416 (2001) and US EPA OPPTS 870.3800 (1998)
Species Rat
Strain Wistar (Crl: WI (WU))
No/Sex/Group 28
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Dose Levels 0, 5,000, 15,000, 50,000 ppm. The average actual measured concentrations for
exposure were: 0, 4,995, 15,013, and 49,958 ppm
Exposure Type
Inhalation 6 hours/day 5 days/week during pre-mating, mating, gestation and
weaning using nose-only exposure, except during lactation during which whole
body exposure was used.
Study Summary
Males were exposed for at least 10 weeks prior to mating 6 hours/day, 5
days/week, and 6 hours/day during mating.
Female animals were exposed for at least 10 weeks prior to mating 6
hours/day, 5 days/week then during mating and up to gestation day 19 (nose-
only). From day 5 of lactation onwards females were exposed daily to 6
hours/day, to the test system by whole body exposure until the end of the
lactation period (Day 21).
Dams were allowed to raise one litter.
At the end of lactation the pups were weaned and selected for the next
generation or sacrificed. F0 females were sacrificed at or shortly after weaning.
F0 males were sacrificed after at least 11 weeks of exposure (for sperm
analyses and necropsy). F1 were then exposed at the same concentration as
their parents from weaning until maturity and through mating, gestation and
lactation to weaning of the F2 generation.
Clinical signs and mortalities did not reveal any treatment-related effects.
No dose-related changes in the oestrus cycles were observed in the HFO-
1234yf exposed animals.
Reproduction and fertility parameters were not affected by exposure to HFO-
1234yf by inhalation.
In both generations, the number of live and dead pups at delivery, the viability
of the pups, the sex ratio, pup body weights and body weight changes were not
affected by exposure to HFO-1234yf.
In the F1-male animals, no statistically significant difference was observed
between the day of achievement of preputial separation between the HFO-
1234yf-exposed groups and the control group. In F1-females, there was an
apparent delay in the onset of puberty evident as a delay in days to
achievement of vaginal opening, but we consider that this is likely to be be
related to food consumption parameters and not exposure to the test
substance.
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Sperm analysis did not reveal a treatment-related effects.
Macroscopic observation of the F0- and F1-pups selected for necropsy did not
indicate any treatment-related effect. No differences were observed between
pup brain and spleen weights. Microscopic observation of the thymus of the
control and high-concentration groups of the F1-generation, F2-pups, did not
reveal any treatment-related effects. For that reason the decrease detected in
absolute and relative thymus weight of the F2-pups, F1-generation, of the high-
concentration group was not considered to be a relevant effect. In addition, the
decrease in absolute and relative thymus weight (F1-pups, F0-generation) and
in relative thymus weight (F2-pups, F1-generation) of the low concentration
group were not considered to be treatment-related.
No relation to the concentration of the test substance was observed on the
effects on organ weights. The decrease in absolute organ weights and the
decrease and increase in relative organ weights were considered by
researchers to be related to the decreased terminal body weights of the HFO-
1234yf -exposed groups.
No treatment-related effects on the ribs of the F1 pups were observed.
The macroscopic and microscopic changes observed in the intercurrent death
and at scheduled sacrifice are common findings in rats of this strain and age or
occurred as individual fortuitous findings according to researchers. Furthermore,
they were equally distributed amongst the different treatment groups or
occurred in only one or a few animals. Therefore, they were not considered by
researchers to be related to treatment.
Two dams of the high-concentration group gave birth to three pups with
malformations. One pup showed acauda and anal atresia and another pup of
the same dam showed polypodia of the right hind limb. A pup of another dam
showed acauda. As no malformations were observed in the prenatal
developmental toxicity study with HFO-1234yf (TNO report V6986) [see above],
this finding was not considered by researchers to be a treatment-related effect.
Vaginal opening of the F1-female animals was statistically significantly delayed
in the mid- and high-concentration groups when compared to the control group.
When vaginal opening was statistically analysed using ANCOVA with pup
weight on PN 21 as the covariate, the delay was significant in the high-
concentration group.
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In conclusion, based on the data from this two-generation reproductive toxicity
study in rats, the high-concentration (50,000 ppm) is considered to be NOAEC
for systemic toxicity and reproductive toxicity.
Additional Comments
We note that in the original report of this study an NOAEC of 15,000ppm was
proposed due to the delayed vaginal opening in the female rats of the F1
generation at 50,000ppm. In the revised report this is seen as a reversible,
secondary effect of reduced body weight in the pups. We note that the higher
NOAEC was accepted in the NICNAS review.
Conclusion
No direct reproductive or developmental effects of the substance were identified
up to the highest concentration tested (49,958 ppm) included exposure via
lactation.
EPA staff conclusion on reproductive/developmental toxicity classification
Our overall conclusion is that the substance does not cause developmental or reproductive toxicity, directly
or via exposure during lactation.
The pre-natal (developmental) studies in rabbits demonstrate that the rabbit heart and skeletal muscle may
be more sensitive to the substance than in other species that have been studied, and lead to investigation of
the effects of inhalation in minipigs. This finding in rabbits is possibly reflected in the visceral findings in the
heart and large vessels in pups, but these only occurred at maternally toxic doses. We assume this is the
reason for the ND rather than No classification proposed by the applicant. We consider the rabbit appears
particularly sensitive in this respect and did not apply a classification based on this finding.
We note also the findings in the toxicogenomics report (discussed above) suggesting the substance may
have endocrine disruption potential. We concur with the conclusion that the significance of this in the
absence of any carcinogenicity or reproductive/developmental toxicity is unclear. We therefore recommend
no classification for reproductive/developmental toxicity is applied to HFO-1234yf.
Target Organ Systemic Toxicity [6.9]
Type of study 28 day inhalation study in rabbits
Flag Key study
Test Substance HFO-1234yf
Endpoint
LOAEC: 1000 ppm (males), 1500 ppm (females) based on anatomic
pathology findings in heart and skeletal muscle
NOAEC: 500 ppm (males), 1000 ppm (females)
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Reference
Hoffman, G. M.; 2013. A 28-day Inhalation (Whole-Body Exposure) study
in Rabbits with a 28 Day Recovery Period. Huntingdon Life Sciences, 100
Mettlers Road, East Millstone, New Jersey 08875-2360, USA. Study
Number 11-6387
Klimisch Score 1
Amendments/Deviations None
GLP Yes
Test Guidelines OECD 412
Species Rabbits
Strain New Zealand White
No/Sex/Group 25
Dose Levels
0, 500, 1500, 5500/4500 ppm daily for 6 hours for 6 or 13 days (Phase 1)
or 0, 500, 1000, 4500 ppm for 28 days (Phase 2). [Note the different dose
values for mid and top dose animals.] The top dose animals were exposed
to 5500 ppm for Days 1 - 6) and 4500 ppm for Days 7 – 15 in Phase 1. The
top dose group for the Phase 2 (28 day exposure) was also 4500 ppm,
while the mid dose was 1000 ppm.
The actual measure concentrations (in brackets) were 0 (0), 500 (497),
1500 (1508) 5500 (5533), 4500 (4338) ppm for phase 1, and 0 (0), 500
(478), 1000 (1010), and 4500 (4378) ppm respectively for Phase 2. The
size characterisation identified that exposure to the substance was
essentially a gas.
The modification of the dose regime was the result of findings in the interim
sacrifice animals (see below).
Note that this study used 6 hours/day, 7 days/week exposures, whereas
repeat dose studies typically use 6 hours/day, 5 days/week exposures.
This was done to reflect the previous rabbit developmental study. The
exposure type was whole body.
Study Summary
Five animals/sex/group were euthanised and necropsied at the end of up
to 7 or 13 days ((interim sacrificed 1 and 2, respectively), and 10
animals/sex/group were euthanised and necropsied at the end of 28 days
of treatment (terminal sacrifice). Recovery animals, 5/sex/group, were
euthanised and necropsied at the end of 28 days of recovery.
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Based on the results from the interim sacrifices at Day 7 and Day 14,
(elevation of creatinine kinase with corresponding effects on the hearts),
during Phase 1, the exposure levels for the 28 day Group 3 were lowered
from 1500 to 1000 ppm for Phase II.
Based on unscheduled deaths in Group 4 of Phase 1, the Group 4 animals
were not exposed on Day 7 and were sacrificed as scheduled on Day 8
after 6 exposures. When resuming exposure for the animals scheduled for
sacrifice on Day 14, the dose was reduced from 5500 to 4500 ppm (from
Day 8 onwards). These animals had only 13 days of exposure before
sacrifice on Day 14.
There were unscheduled deaths/sacrifices at 4500 ppm (1 female) and
5500 ppm (1 male and 1 female) in Phase 1). Exposure to the substance
was associated with microscopic findings in the heart and skeletal muscle
at ≥1000 ppm with males more frequently affected than females.
Subacute/chronic [sic] myocardial inflammation was observed in one 1000
ppm male and 1 male/3 females at 1500 ppm, and 6 males/4 females at
45000 ppm, 2 males at 5500/4500 ppm and 5 males/2 females at 5500
ppm on Days 8, 15 and/or 29. Lesions were minimal to slight, did not
progress over time and recovery animals were clear after 28 days without
exposure.
There was minimal to moderate skeletal muscle necrosis in both sexes at ≥
1500 ppm on Day 15, and on Day 29 in males at ≥ 1000 ppm and females
at 4500 ppm.
Significant serum enzyme changes were found related to the effect on the
muscle tissue. Elevated myoglobin, total creatinine kinase (total CK),
isoenzyme CK-MM11, heart fatty acid-binding protein (H-FABP12),
isoenzyme CK-MB13, aspartate aminotransferase (AST), and/or alanine
aminotransferase (ALT) in males at ≥1000 ppm and females at ≥500 ppm.
11 CK-MM is a CK isoenzyme found in the heart and skeletal muscle
12 H-FABP is identified as a specific marker of myocardial infarction.
13 CK-MB is a CK isoenzyme found in the heart.
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The greatest elevations were noted for total CK and CK-MM which were
consistent with an effect on skeletal muscle and were only observed in
treated animals.
At no time in the study were H-FABP or CK-MB elevated in an animal
without concurrent pronounced elevations in total CK, CK-MM and or
myoglobin, suggesting (to researchers) that elevations in H-FABP and CK-
MB were secondary to skeletal muscle injury rather than cardiotoxicity.
Test substance-related increases in liver weight occurred in the 1500 and
5500 ppm males on Day 8 only, which had no associated
micropathological findings, so were considered a non-adverse adaptive
response.
The anatomic and clinical pathology changes fully resolved following the 28
day recovery period.
NOAEC was reported as 500 ppm in males and 1000 ppm in females,
based on anatomic pathology findings at higher dose levels. [We note that
the pathological findings were considered by the researchers to drive the
NOAEC assignments rather than the clinical pathology findings.]
Additional Comments
The researchers (and the NICNAS report) suggest that the rabbit is more
sensitive to these findings, which is why studies in minipigs were
undertaken. This suggested greater scrutiny should be attributed to the
findings in minipigs.
Conclusion
Repeated exposure to the substance for 28 days by inhalation in the rabbit
produced pathological changes in heart and skeletal muscle which were
rapidly reversible. As a result of this finding studies were done in minipigs
which are considered a more suitable animal model for assessment of
cardiovascular effects.
Type of study Sub-acute (2-week) inhalation toxicity study in rats
Flag Supporting study
Test Substance HFO-1234yf
Endpoint
LOAEC: >51,960 ppm no adverse effects established
NOAEC: 51,960 ppm
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Reference
Mommers, C.; 2005. Sub-acute (2-week) inhalation toxicity study with HFO-
1234yf in rats. TNO Quality of Life, Toxicology and Applied Pharmacology.
Utrechtseweg 48, P.O. Box 360, 3700 AJ Zeist, The Netherlands. TNO Report
V6394/Final
Klimisch Score 1
Amendments/Deviations None
GLP Yes
Test Guidelines OECD 412
Species Rat
Strain Sprague Dawley (Crl:CD[SD])
No/Sex/Group 5
Dose Levels 0, 5,000, 20,000, and 50,000 ppm, 6 h/day, 5 days/week. The measured mean
concentrations were 4,990 (±36), 19,599 (±99) and 51,690 (±620) ppm.
Study Summary
Daily observation of the animals did not reveal any clinical abnormalities.
No treatment-related change in red blood cell variables, coagulation variables,
total white blood cell counts and differential white blood cell counts were
observed.
Clinical chemistry showed a statistically significant increase in calcium levels in
the plasma of the mid- and high-dose males, but these finding were not
considered by the researchers to represent adverse effects of the test material
because the differences were slight, not concentration-related, within the range
of historical control values and not accompanied by changes in any of the other
endpoints examined in the study.
No treatment-related changes in absolute or relative organ weights were
recorded.
Macroscopic examination at necropsy did not reveal treatment-related gross
changes.
Microscopic examination did not reveal treatment-related histopathological
changes in any of the organs/tissues examined (which included the complete
respiratory tract and nasal passages).
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The conclusion was that exposure did cause any adverse effects at any dose
levels, so the NOAEC proposed by researchers was 51,960 ppm.
Additional Comments None
Conclusion No adverse effects identified in the study up to 51,960 ppm over 2 weeks.
Type of study 28 day inhalation study in rats with Unscheduled DNA Synthesis (UDS)
and micronucleus test
Flag Key study
Test Substance HFO-1234yf
Endpoint
LOAEC: >50,031 ppm (no adverse effects identified)
NOAEC: 50,031 ppm
Reference
Muijser, H. and Wijnands, M. V. W.; 2006. Sub-acute (4-week) inhalation
toxicity study (including Unscheduled DNA Synthesis and Micronucleus
test) with 2-week recovery period, with HFO-1234yf in rats. TNO Quality of
Life, Toxicology and Applied Pharmacology. Utrechtseweg 48, P.O. Box
360, 3700 AJ Zeist, The Netherlands. TNO Report V6872/02
Klimisch Score 1
Amendments/Deviations None
GLP Yes
Test Guidelines OECD 412
Species Rat
Strain Sprague-Dawley
No/Sex/Group 5
Dose Levels
0, 5,000, 15,000 and 50,000 ppm. The measured mean concentrations
were 4,997 (±7), 15,167 (±459) and 50,031 (±83) ppm. The mean
concentrations were equivalent to 23.5, 71.4 and 235.6 g/m3 for the low,
med and high concentrations respectively. Exposure was 6 hours/day, 5
days/week for 4 weeks (20 -21 exposure days in total)
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Study Summary
Daily observation of the animals did not reveal any treatment-related
clinical abnormalities.
Differences in body weight between treated and control groups were not
seen except on Day 14 on which the body weight of the female mid dose
group was decreased compared to control. At the next weighing the body
weights had recovered. Treatment-related differences in body weight gain,
food consumption and food conversion efficiency were not seen. There
was a slight reduction and subsequent increase in food consumption and
food conversion efficiency in weeks 1 – 3 related to the mid dose female
animal’s body weight variations.
No treatment–related differences in haematology were seen.
There was an increase in urea concentration in low and high dose females
and an increase in creatinine in the high dose females. The increases
were small and the increase in urea was not concentration related. No
difference in the female animals was seen after the 14 day recovery
period. In contrast, male animals showed increased urea concentration at
the end of the 14 day recovery period [there was only a top dose group in
the recovery phase], but not at the end of the exposure period. In male
animals potassium plasma concentrations in all treatment groups were
increased in animals at the end of the exposure period, but a clear
concentration-response relationship was absent. No such change was
seen at the end of the recovery period (meaning the values had returned
to normal).
Changes in absolute or relative organ weight were not detected at the end
of the exposure period. At the end of the 14-day recovery period absolute
liver weights and liver weights relative to body weight were increased for
the male groups. Due to UDS test in male animals no liver weights for the
main male study groups were available for comparison. The differences
were unrelated to treatment as there were no histopathological or other
hepatic changes at the end of the exposure period, nor were there effects
in the female animals at the end of the exposure or recovery periods.
Macroscopic examination at necropsy did not reveal any treatment-related
findings.
Microscopic examination of selected organs including the respiratory tract
did not reveal any exposure-related findings.
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Unscheduled DNA synthesis (UDS) in liver cells of the male rats at the
terminal sacrifice in this study was not observed.
No damage to chromosomes and/or mitotic spindle apparatus
(micronuclei) in the bone marrow target cells of rats were induced in the
males investigated at the terminal sacrifice in this study.
Exposure of the rats to up to 50,000 ppm of the substance did not result in
adverse effects in any of the exposure groups. In the sub-acute inhalation
toxicity study, the NOAEC was therefore the top dose of 50,000ppm for
both males and female rats.
Additional Comments None
Conclusion No adverse effects were seen up to the maximum concentration tested,
50,031 ppm for 4 weeks.
Type of study 14 Day Inhalation Study in Minipigs
Flag Supporting study
Test Substance HFO-1234yf
Endpoint
LOAEC: >10,300 ppm
NOAEC: 10,300 ppm
Reference
Hoffman, G. M.; 2013. HFO-1234yf: A 14 Day Inhalation (Whole Body
Exposure) Investigative Study in Minipigs. Huntingdon Life Sciences 100
Mettlers Road, East Millstone, New Jersey 08875-2360, USA. Study
Number 13-6432.
Klimisch Score 1
Amendments/Deviations
Some protocol deviations are documented in the report, the most
significant of which was that the Group 2 males were only exposed for 3
hours on Day 1 due to a high relative humidity in the exposure chamber.
GLP Not certified as GLP compliant, but the investigation was performed at a
GLP facility.
Test Guidelines
OECD 412 Sub-acute inhalation toxicity (28 days).
(Procedures modified as appropriate for use of minipigs in place of rats for
this preliminary investigation.)
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Species Minipigs
Strain Gottingen
No/Sex/Group 3 males/group, 3 females/group for Groups 1 and 3, and 2 females/group
for Group 2.
Dose Levels
0, 5500, 10,000 ppm by whole body inhalation, 6h/day, 7 days/week. The
measured concentrations were 5490 and 10300 ppm (the average of the
male and female chambers.
Study Summary
The study focused on findings on cardiac or skeletal muscle specifically as
a follow up investigation in minipigs of the findings in the 28 day inhalation
study in rabbits, as minipigs are considered a better model to the human
cardiovascular system.
All animals survived to their scheduled termination.
There were no substance-related clinical signs.
There were no substance-related effects on body weight in comparison to
air control animals.
There were no substance-related effects on food consumption in
comparison to air control animals.
In relation to haematology, there were no substance-related effects. All
differences from controls, whether statistically significant or not, were not
considered substance-related. The effects were small in magnitude, not
dose-related, and/or individual values were comparable to pre-test findings
or consistent with normal biological variability.
In relation to clinical chemistry, there were no substance-related effects on
myoglobin, cardiac troponin, creatinine kinase (total CK, or isoenzymes
CK-MM and CK-MB), aspartate aminotransferase or alanine
aminotransferase.
There were no statistically significant changes in any organ weights.
All macroscopic findings occurred at a similar incidence in control and test
substance treated groups.
There were no substance-related microscopic findings involving the heart
(left ventricle, right ventricle and septum), or skeletal muscle (rectus
femoris, psoas, and soleus muscles as well as the diaphragm).
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The cardiac and skeletal muscle changes that were observed were
incidental. The findings were lymphocyte and macrophage aggregation.
At Day 15 there were no substance-related microscopic findings involving
the heart or skeletal muscle. Thus there was no evidence of cardiac or
skeletal muscle toxicity following exposure at up to 10,000ppm in this
study.
Additional Comments We note the limited nature of this study as a preliminary investigation to
establish dose concentration for the 28 day study (below).
Conclusion No adverse effects were seen at the maximum concentration used (10,000
ppm.
Type of study 28 Day Inhalation Study in Minipigs
Flag Key study
Test Substance HFO-1234yf
Endpoint
LOAEC: .>10,200 ppm
NOAEC: 10,200 ppm
Reference
Hoffman, G. M.; 2014. HFO-1234yf: A 28 Day Inhalation (Whole Body
Exposures) Toxicity Study in Minipigs. Huntingdon Life Sciences 100 Mettlers
Road, East Millstone, New Jersey 08875-2360, USA. Study Number 13-6434
Klimisch Score 1
Amendments/Deviations None
GLP Yes
Test Guidelines
OECD 412 Sub-acute inhalation toxicity (28 days).
(Modified as necessary to be appropriate for use of minipigs and to specifically
investigate cardiac and skeletal muscle toxicity.)
Species Minipigs
Strain Gottingen
No/Sex/Group 8
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Dose Levels
Exposure was by whole body inhalation. The target exposure concentrations
were: 0, 5,000, 10,000 ppm (which are equivalent to 0, 26 and 50 mg/L) for 6
hours/day, 7 days/week for up to 28 consecutive days. The measured mean
gas concentrations were: 0, 5145, 10,200 ppm.
Study Summary
There were no substance-related deaths or sacrifices.
There were no substance-related effects on clinical signs.
There were no substance-related effects on body weight.
There were no substance-related effects on food consumption.
There were no substance-related effects on haematological parameters.
There were no test substance-related effects on clinical chemistry parameters.
Minimal increase in total creatinine kinase (CK) and CK-MM isoenzyme noted in
3/8 females on Study Day 21 at 10,000 ppm were not considered substance-
related because they were transient and the values were within normal
biological variability.
An increase in absolute and relative liver weights (in comparison to body weight
and brain weights) were seen at exposure levels of 5000 ppm and higher in
females. Potential correlation to histopathological findings was not possible as
the protocol did provide for examination of the livers using histopathology.
At termination there were no microscopic findings involving the heart (left
ventricle, right ventricle and septum) and skeletal muscle (rectus femoris, psoas
and soleus muscles as well as the diaphragm). There was no microscopic
evidence of cardiotoxicity, or skeletal muscle toxicity following whole body
inhalation of the test substance at up to 10,000 ppm for 28 consecutive days.
The researchers report the NOEL was the average maximum exposure
concentration of 10,200 ppm, based on the lack of findings in cardiac and
skeletal muscle. We note this assumes the changes in absolute and relative
liver weight are not an adverse finding. This cannot be verified due to the
limitations in the protocol (which did not require any histopathological
examination of all tissues). This NOAEC value is reported by NICNAS as being
specific to cardiac and skeletal muscle effects, rather than a general NOAEC.
Additional Comments
The study authors note that there is a very limited database for repeat
inhalation toxicity studies in minipigs. This study was intended to clarify the
relevance of the effects of the substance on cardiac and skeletal muscle in the
rabbit studies discussed above. As a result limited investigations were
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undertaken in this study. The study demonstrates that minipigs respond very
differently to the substance than rabbits.
Conclusion
No adverse findings were identified so the NOAEC is the highest dose tested
10,200 ppm, although the investigations undertaken were more limited than in
standard sub-acute investigations. Note that the NOAEC value is reported by
NICNAS as being specific to cardiac and skeletal muscle effects, rather than a
general NOAEC.
Special studies: Cardiac sensitisation in dogs
Type of study Toxicology study to detect cardiac sensitisation potential in dogs
Flag Key study
Test Substance HFO-1234yf
Endpoint
LOAEC: >120,000 ppm (12%)
NOAEC: 120,000 ppm (12%)
Reference
Weinberg, J. T.; 2006. Acute Cardiac Sensitisation Study of HFO 1234ze and
HFO 1234yf in Dogs. WIL Research Laboratories, LLC, 1407 George Road,
Ashland, OH 44805-9281, USA. Study Report No. WIL-447008
Klimisch Score 1
Amendments/Deviations None
GLP Yes
Test Guidelines No guidelines apply for a study of this type
Species Dog
Strain Beagle
No/Sex/Group 6 (males)/dose level
Dose Levels
2, 6 and 12% (20,000, 60,000 or 120,000 ppm) of HFO1234yf via inhalation via
muzzle-only exposure for approximately 10 minutes. There were no controls as
each dog served as its own control. There was a minimum of 48 hours between
exposure of the animals to the different test substance concentrations.
Study Summary Dogs were administered a pre-exposure dose of epinephrine as a bolus
injection via a cephalic vein approximately 5 minutes prior to the exposure to
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the test article. The dose was started at 2 μg/kg bw, but increased to 3, 4, 6, or
8 μg/kg bw if necessary. The dose used in the post exposure challenge was
determined for each dog and was the highest dose level tested during the pre-
study evaluation that did not elicit a significant ECG finding (e.g. a premature
ventricular contraction).
Five minutes after exposure to the test substance the animals were
administered a challenge dose of epinephrine. Electrocardiographic data were
recorded continuously throughout the pre-exposure epinephrine dosing,
exposure to the test gas and for 5 minutes following administration of the
challenge epinephrine dose (a total of approximately 17 minutes).
The criteria for a sensitisation response included (but were not limited to) the
following criteria:
Eleven or more premature ventricular contractions (PVCs) in 10
seconds, with episodes of confluency
Ventricular tachycardia
Fibrillation
Results
All animals survived to study termination. No test article related clinical
observations were seen and body weights were unaffected by test article
administration.
There was no evidence of cardiac sensitisation following exposure to HFO-
1234yf at any of the concentrations tested, so the NOAEC for cardiac
sensitisation was 120,000 ppm.
Additional Comments None
Conclusion There was no evidence of cardiac sensitisation following exposure to HFO-
1234yf at any of the concentrations tested.
Discussion of classification for target organ systemic toxicity by the inhalation route
We note that the single dose toxicity data do not support classification as an single exposure target organ
systemic toxicant in comparison to the cut off thresholds of 5,000 ppm (EPA, User Guide, Table 17-1, p17-7).
In relation to repeat dose studies, none of the repeat dose inhalation tests from repeat exposures
6 hours/day for 14 days or more, identify adverse systemic target organ effects. All the studies in rats and
minipigs for the 14 – 28 day duration have an LOAEC >10,000 ppm. The 90 day repeat inhalation study in
rats also gives an LOAEC >50,000 ppm based on the NICNAS review (although that study was not available
to the EPA for review).
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The only species studied which appeared to suffer target organ effects was the rabbit, in which the cardiac
and skeletal muscle appear to be more sensitive than in other species. The LOAEC of 500 ppm in the male
rabbit in a 28 day study is the only LOAEC which could support any classification in comparison to the repeat
dose classification criterion cut off of 250 ppm for a 90 day study (EPA, User Guide, Table 17-2, p17-9).
Nevertheless, we consider that no classification is appropriate taking into account the negative data for the
rat and, in particular, the minipig, which is seen as a more appropriate model comparison for assessing
cardiovascular toxicity in the human.
We therefore recommend no classification for target organ systemic toxicity via the inhalation route for either
single or repeat exposure.
General conclusion about mammalian toxicology of active ingredient(s) and metabolite(s)
Table 2 Summary of studies with NOAEC and LOAEC values and key effects.
Study type NOAEC LOAEC Key effect
28 day inhalation study
in rabbits
500 ppm (males
1000 ppm (females)
1000 ppm (males
1500 ppm (females)
Anatomic pathology
findings in heart and
skeletal muscle
2 week inhalation study
in rats 51,690 ppm >51,690 ppm
No adverse effects
identified
28 day inhalation study
in rats 50,031 ppm >50,031 ppm
No adverse effects
identified
14 day inhalation study
in minipigs (by
inhalation)
10,300 ppm >10,300 ppm
No adverse effect, but
investigation focused
on cardiac and skeletal
muscle
28 day inhalation study
in minipigs (by
inhalation)
10,200 ppm >10,200 ppm
No adverse effect, but
investigation focused
on cardiac and skeletal
muscle
Cardiac sensitisation in
dogs (by inhalation) 120,000 ppm (12%) >120,000 ppm (12%)
No evidence of cardiac
sensitisation caused by
the substance with
epinephrine challenge
Pre-natal toxicity in the
rat (by inhalation)
50,315 ppm for both
maternal and foetal toxicity
>50,315 ppm for both
maternal and foetal toxicity
No adverse effects in
maternal or foetal
animals
Pre-natal toxicity in the
rabbit (by inhalation)
4000 ppm for maternal
animals
4000 ppm for visceral
malformations in pups
5,500 in maternal animals
5500 ppm for visceral
malformations in pups
Mortality, moribundity,
abortions, premature
delivery, lower mean
body weight gain,
mean body weight loss
and/or lower food
consumption observed
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at 5,5000 and 7,500
ppm (maternal
animals).
Adverse effects
visceral malformations
in pups only seen in
the presence of
maternal toxicity
Two generation
reproductive toxicity
study in rats (by
inhalation)
49,958 ppm in parental
animals
49,958 ppm for
reproductive/developmental
toxicity
>49,958 ppm in parental
animals
>49,958 ppm for
reproductive/developmental
toxicity
No systemic toxicity
seen in parental
animals
No adverse
reproductive or
developmental effects
seen
90 day inhalation study
in rat (not submitted to
EPA by applicant).
[NICNAS review data
summarised.]
NICNAS reported >50,116
ppm. This is confirmed in
the toxicogenomic report
for both rats and mice.
EPA would assign NOAEC
= 50,116 ppm.
>50,116 ppm
No systemic toxicity
seen in parental
animals
(No study report
available to the EPA
for review for the 90
day inhalation study).
Toxicokinetics
The toxicokinetic assessment from the NICNAS report made the following key concluding remarks on
toxicokinetics, metabolism and distribution of the substance:
“The major metabolic pathway of the notified chemical is likely to be cytochrome P450 2E1-mediated
epoxide formation at low rates, followed by glutathione conjugation.”
“The results of the study suggested a low extent of biotransformation of the notified chemical and the same
major metabolic pathway as that in rats and mice. Most of major metabolites (95%) were excreted within 12
hours after the end of exposure (t1/2 = approx. 9.5 h).”
Further comments on epoxidation are discussed below under Conclusion on Toxicokinetics and Metabolic
Pathway.
Special study relating to metabolism in pregnant rabbits
Type of study Special 1 hour inhalation study in rabbits including analysis of urinary
metabolites
Flag Supporting information
Test Substance HFO-1234yf
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Endpoint
LOAEC: N/A
NOAEC: N/A
Reference
Hoffman, G. M.; 2011. HFO-1234yf: A 2-phase Inhalation Screening Study
and Single Exposure Study in Rabbits via Whole-body Inhalation Exposure
(GLP). Huntingdon Life Sciences, 100 Mettlers Road, East Millstone, New
Jersey 08875-2360, USA. HLS Study No; 10-2226.
Including: Appendix I. Rabbit urine analysis. Dekant, W., et al.; 2011.
Biotransformation and toxicokinetics of 2,3,3,3-tetrafluoropropene (HFO-
1234yf) in male, pregnant and non-pregnant female rabbits. Institute of
Toxicology, University of Wurzburg, Versbacher Str. 9, 97078 Wurzburg,
Germany
Klimisch Score 1
Amendments/Deviations None
GLP Yes
Test Guidelines Not based on a test guideline but generally in accordance with US EPA
OPPTS 870.1300
Species Rabbit
Strain New Zealand White
No/Sex/Group
5 males/group, and 6 presumed pregnant females/group and 5 non
pregnant females (for control and top dose only). The exposure in the
presumed pregnant females being from Gestation Day 12 followed by a 14
day post exposure period.
Dose Levels
0, 50,000, and 100,000 ppm. The analytical concentrations were in Phase I
110,000 ppm and in Phase II 0, 45,000 (males), 47,000 (females), 100,000
(males) and 102,000 ppm (females)
Study Summary
This study was carried out due to earlier studies suggesting pregnant and
non-pregnant rabbits may be more sensitive to the substance than
expected in comparison to rats (see the pre-natal developmental study in
rabbits above).
The study was in two phases: Exposure in Phase 1 was to 100,000 ppm
only. In Phase 2 exposure was to 0, 50,000 or 100,000 ppm.
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The summary does not discuss the two phases, but we identified the
following:
Phase 1
This was a screening phase in which one non-pregnant and one presumed
pregnant group of female rabbits were given a whole body, 1-hour,
exposure of 100,000 ppm to HFO-1234yf.
Aside from confirming pregnancy status the animals were not examined.
Phase II
There were three dose levels and groups of presumed pregnant females,
non-pregnant females and males [PPF,NPF,M], as follows:
Air control/0 ppm: 6,5,5
50,000 ppm 6, 0, 5
100,000 ppm 6, 5, 5
The exposure was for 1 hour, whole body exposure. The animals were
euthanised 14 days after exposure and a complete post-mortem
undertaken (including determination of pregnancy status).
No key difference was seen between pregnant and non-pregnant rabbits,
but in relation to an unidentified metabolite there was a slight difference
between female and male rabbits.
All the animals survived until their scheduled sacrifice. There were no test
substance-related clinical signs in any of the test animals. There were not
test substance-related effects on body weights in any of the test groups of
animals.
Macroscopic pathology: In Phase I, all the presumed pregnant females
were pregnant. In Phase II all were presumed pregnant females were
pregnant except one control animal and one animal in the top dose.
In phase II there were no test substance-related macroscopic findings at
terminal sacrifice.
In phase II there were no test substance-related microscopic findings (in
the heart, kidney, liver or lungs) at terminal sacrifice.
In conclusion, no lethality and no clinical signs were observed in the
exposed animals. No substantial differences in urinary metabolite pattern
or quantity of metabolites excreted were observed between the different
groups, apart from the difference for the as yet unidentified metabolite
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found at 12-17% in female rabbits and >7% in male rabbits of the sex main
metabolites.
Additional Comments None
Conclusion
No significant metabolic differences were identified between pregnant
female rabbits, non-pregnant female rabbits or male rabbits which could
explain the previous findings of mortality in pregnant female rabbits in the
pre-natal toxicity test (above).
EPA Staff Conclusion on Toxicokinetic and Metabolic Pathway
We consider that the oxidation of the alkene group via an epoxide could potentially be a toxicologically
significant activation pathway based on comparison to other chemicals, particularly halogenated alkenes.
The total amount of metabolised HFO-1234yf was calculated to be less than 0.1% of the received dose in all
groups. We consider the small proportion of metabolic conversion is important when considering the
significance of the difference in proportion of the unidentified metabolite produced in males and females and
also in the broader context of a risk assessment for HFO-1234yf. We consider that while epoxidation is
referred to as the “major” pathway by the researchers, this is in relation to the other metabolic pathways. The
total extent of biotransformation of the test substance via this pathway is very low (calculated to be less than
0.1%), so the quantity undergoing epoxide formation is also very low and therefore unlikely to be of concern.
Human health risk assessment
Due to the proposed use pattern, human exposure to HFO-1234yf during the use stage of its lifecycle is
expected to be very limited. Nevertheless some human exposure is possible due to leakage. Some
installations will be vulnerable to impact, in particular, when used in motor vehicles. A quantitative human
health risk assessment has not been performed for all uses, but we have considered the NICNAS14 risk
assessment of the potential exposure from a private motor vehicle.
No human exposure and risk assessment was undertaken for industrial users due to the contained use
systems in which the substance will be used, either in pure form or as part of a refrigerant mixture and the
expectation that personal protective equipment will be used.
We considered the assessment NICNAS carried out associated with a worst case scenario and concluded
the risk to members of the public is low. In the NICNAS assessment a worst case scenario was examined in
which a pregnant individual was trapped in a motor vehicle and exposed to the entire refrigerant change
(within an unventilated car cabin) for 5 minutes.
NICNAS used a physiologically-based pharmacokinetic model the exposure was compared to the NOAEC
concentration for developmental toxicity in the rabbit pups. We note this rabbit value was used despite no
developmental effect being seen in the study at non-maternally toxic doses, so we consider it precautionary.
14 NICNAS, 2015. Public Report: 1-Propene, 2,3,3,3-tetrafluoro- File No: STD/1556.
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The total exposure in to the individual was estimated to be 1.2 mg/L.hr in comparison to the exposure for the
pregnant female rabbit (at the NOAEC concentration for the foetus) 225.6 mg/L.hr. So this represent a
margin of over 100. The conclusion is that the risks from the private use in motor vehicles is acceptable.
Based on this being a worst-case scenario, we also concluded the risks from other uses as in blend
(mixtures) are acceptable.
As discussed above, a special study was done to assess the potential of the substance to cause cardiac
sensitisation in dogs, which demonstrated that there was no evidence of this occurring up to a very high
concentration (120,000 ppm, 12% in air). We consider it noteworthy that this demonstrates that HFO-1234yf
has a much lower potential for cardiac sensitisation than other similar substances15. This is important due to
the possibility of deliberate inhalation of the substance.
Due to the relatively high gas density of HFO-1234yf (4 relative to air =1) there is a potential for asphyxiation
of person present in enclosed spaces where there is poor ventilation or lower bodies of air.
15 Mullin, L., Reinhardt, C. and Hemingway R. Cardiac arrhythmias and blood levels associated with inhalation of halon 1301.
American Industrial Hygiene Association Journal, 1979; pp 40, 653-358
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Appendix E: Ecotoxicology
Ecotoxicity - Robust study summaries for HFO-1234yf
Aquatic ecotoxicity – fish
Study type Acute toxicity study in Cyprinus carpio (Carp)
Flag Key Study
Test Substance HFO-1234yf
Endpoint LC50 96 hours
Value >197 mg/l
Reference
M. Bogers (2006). Acute toxicity study in carp with HFO-1234yf (static). Notox
B.V. Hambaken wetering 7, Den Bosch, The Netherlands. Report Number
V6472/04
Klimisch Score 1
Amendments/Deviations None that impacted the study
GLP Yes
Test Guideline/s OECD 203, ISO 7346-1:1996, EU C1
Dose Levels
Nominal: 30 and 60 minutes flow at approximately 100 ml/min
Measured: 197 mg/l (geometric mean) highest concentration
Analytical measurements GC-FID
Study Summary
Static toxicity with carp.
The tested substance was a gas which was bubbled for different time periods
through the medium.
Two tests were performed, one with solutions bubbled for 30 and 60 minutes at
approximately 100 l/min and one test with solutions bubbled for 60 minutes with
a flow of at approximately 100 ml/min.
In the first test average concentrations were below 100 mg/l. In the second test
the initial concentration was 114 mg/l and the geometric mean was 197 mg/l/.
Seven fish per concentration and the control were exposed.
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No fish died during the test and therefore the 96h-LC50 is determined to be
>197 mg/l. One fish in the second study showed slight signs of stress.
Conclusion LC50 > 197 mg/l (based on the geometric mean of the measured
concentrations)
Aquatic ecotoxicity - crustacea
Study type Acute toxicity study in Daphnia magna (waterflea)
Flag Key Study
Test Substance HFO-1234yf
Endpoint EC50 Immobility, 48 hours
Value >83 mg/l
Reference
M. Bogers (2006). Acute toxicity study in Daphnia magna with HFO-1234yf.
Notox B.V. Hambaken wetering 7, Den Bosch, The Netherlands. Report
Number V6472/03
Klimisch Score 1
Amendments/Deviations None that impacted the study
GLP yes
Test Guideline/s OECD 202; ISO 6341:1996; EU
Dose Levels
Nominal: 4, 7.5, 15, 30 and 60 minutes flow at approximately 20 ml/min
Measured: 83 mg/l (geometric mean) highest concentration.
Analytical measurements GC-FID
Study Summary
Static toxicity with Daphnia magna.
The tested substance was a gas which was bubbled for different time periods
through the medium.
After a range-finding test a final test was performed consisting of four replicates
per concentration containing 5 daphnids each.
The initial concentration was the concentration reached at 60 minutes flow at
approximately 20 ml/min. This was 102 mg/l at the start of the test and
decreased to 68 mg/l at the end of the test. The geometric mean was calculated
to be 83 mg/l.
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Not more than 5% of the daphnids were immobilised and therefore the 48h-
EC50 is determined to be >83 mg/l.
Conclusion EC50 > 83 mg/l (based on the geometric mean of the measured concentrations)
Aquatic ecotoxicity - algae
Study type Acute toxicity study in Selenastrum capricornutum
Flag Key Study
Test Substance HFO-1234yf
Endpoint ErC50 72- hours
Value >75 mg/l
Reference
M. Bogers (2006). Freshwater algal growth inhibition test with HFO-1234yf.
Notox B.V. Hambaken wetering 7, Den Bosch, The Netherlands. Report
Number V6472/02
Klimisch Score 1
Amendments/Deviations None that impacted the study
GLP Yes
Test Guideline/s OECD 201; ISO 8692:2004; EU C3
Dose Levels
Nominal: 4, 7.5, 15, 30 and 60 minutes flow at approximately 20 ml/min
Measured: 83 mg/l (geometric mean) of the highest nominal concentration
Analytical measurements GC-FID
Study Summary
A limit test with a saturated solution of HFO-1234yf was performed. The media
was purged for a 3-hour period. The initial concentration was 170 mg/l and this
decreased to 17-76 mg/l at the end of the exposure period. The overall average
exposure concentration was 75 mg/l.
Cell growth inhibition was <10%.
Although the maximum average concentration is 114 mg/l it is considered not to
be the ErC50 since the mean average concentration at this loading rate is lower.
The 114 mg/l was measured in one replicate at the highest loading rate,
however the average exposure concentration is considered more reliable.
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Conclusion 72-hour ErC50 > 75 mg/l (based on average exposure concentrations)
Summary of aquatic toxicity
An average exposure concentration at 100 mg/l was not reached for the Daphnia magna acute toxicity test and in the
algal growth inhibition test this concentration was almost achieved. Based on the results it is unlikely that the EC50 will be
below 100 mg/l. Therefore, no 9.1 classification is assigned.
Summary of other ecotoxicity classifications
No studies have been provided to determine the 9.2, 9.3 and 9.4 classification of the substance. Inhalation studies are
not used for the classification of terrestrial vertebrates.
Environmental fate - Robust study summaries
Biodegradability
Study type Readily biodegradability
Flag Key Study
Test Substance HFO-1234yf
Endpoint % of Theoretical Oxygen Demand (ThOD)
Value <5%
Reference
Daniel (2008). HFO-1234yf: Determination of 28 day ready biodegradability.
Brixham Environmental Laboratory, AstraZeneca UK Limited, Brixham, Devon,
UK. Report Number: BL8606/B
Klimisch Score 1
Amendments/Deviations None that impacted the study
GLP Yes
Test Guideline/s OECD 301F
Dose Levels 117 mg/l
Analytical measurements Oxitop respirometers
Study Summary The aerobic biodegradation was determined using the Manometric
Respirometric method (OECD 301F). Oxitop respirometers were attached to
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500 mL dark glass bottles with magnetic stirrers to ensure optimal contact of
the substance with the test organisms.
Sewage sludge was used as an inoculum. The inoculum was collected, washed
and re-suspended seven days prior to the start of the exposure.
It should be noted that the Biological Oxygen Demand (BOD) of the control was
low, indicating that the sludge was not very active.
The ThOD of the substance was 0.98 g O2/g substance. Less than 0.05 gram
O2 per gram of substance was consumed. Therefore, no significant
biodegradation was observed (<5% of ThOD).
Conclusion The substance is not readily biodegradable.
Study type Ready Biodegradability
Flag Key Study
Test Substance HFO-1234yf
Endpoint % of ThOD translated to % of substance biodegraded
Value 0% for both
Reference
Kayashima (2008). Biodegradation study on HFO-1234yf by microorganisms.
Kurume Laboratory and Research Institute Japan 2-7, 3-chome, Miyanojin,
Kurume-shi, Fukuoka, Japan. Study Number 15157
Klimisch Score 1
Amendments/Deviations None that impacted the study
GLP Yes
Test Guideline/s OECD 301D
Dose Levels 8.22 mg/l
Analytical measurements Oxygen meter and Gas Chromatography.
Study Summary
The aerobic biodegradation was determined using the closed bottle test (OECD
301D).
Closed bottles with a volume of 100 ml were cultivated “sealed and standing”
for 28 days. Sewage sludge was used as an inoculum. The inoculum was
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collected, washed and resuspended seven days prior to the start of the
exposure. 1 drop was added per litre of medium. Dissolved oxygen was
measured using a probe, the substance was measured using GC.
The percentage biodegradation based on BOD and substance concentration
was 0%
Conclusion The substance is not readily biodegradable.
Koc estimation
Study type Estimation of Koc
Flag Supporting study
Test Substance HFO-1234yf
Endpoint Log Koc
Value 1.7-2.1 L/kg
Reference Not provided (printout from programme supplied)
Klimisch Score 3 (no GLP or method specified)
Amendments/Deviations NA
GLP NA
Test Guideline/s Not specified programme KOCWIN v2.00
Dose Levels Calculation
Analytical measurements NA
Study Summary
The Koc was estimated using KOCWIN v 2.00, no guidance or method
description was provided by the applicant.
The calculated log Koc was 2.1342 or Koc 136.2 L/kg
When the log Kow is used for the estimation, the log Koc is 1.7354 and Koc
54.38 L/kg
Conclusion Log Koc 1.7-2.1 L/kg
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
Hydrolysis
Study type Expert statement on hydrolysis and biodegradation
Flag Supporting study
Test Substance HFO-1234yf
Endpoint Hydrolysis and biodegradation
Value Both processes are unlikely to have a significant impact on the fate of the
substance
Reference C. Hamwijk (2006). Expert statement on hydrolysis and biodegradation of HFO-
1234yf
Klimisch Score 3 (no study)
Amendments/Deviations NA
GLP NA
Test Guideline/s No guideline calculations are performed in BIOWIN v 4.02 and HYDROWIN
v1.67
Dose Levels NA
Analytical measurements NA
Study Summary
Calculations based on the molecular structure are claimed to indicate that
hydrolysis and biodegradation are likely to be negligible.
The structure of the substance was adjusted to allow the programme to
calculate the degradation rate (i.e. carbon double bond removal). This is
expected not to have a significant influence on the hydrolysis rate. DT50 for
hydrolysis was calculated to be 106-107 years. The substance was predicted to
be not ready biodegradable.
Conclusion Negligible
Summary of the Environmental Fate
The substance is not readily biodegradable and hydrolysis seems a non-significant degradation pathway. According to
the estimation of the Koc the substance is moderately mobile to mobile according to FAO criteria. Based on the estimated
log Kow bioaccumulation is unlikely. Based on the physical state of the substance (gas at room temperature) vertical
movement (leaching into groundwater) in the soil is unlikely.
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
Qualitative ecological risk assessment
The substance is used in closed systems and is not expected to be released in significant concentrations.
During an accident or leakage some of the substance might be released. The physical state of the substance
will be a gas, therefore limiting the exposure.
Exposure in the aquatic environment (pelagic and sediment) is considered unlikely because the substance is
highly volatile and is likely to quickly evaporate from the water if a spillage occurs. Furthermore the
substance is considered non-hazardous for the aquatic environment based on the data on Daphnia, fish and
algae. Although the substance is non-biodegradable, accumulation of the substance in the aquatic
environment is considered unlikely due to the use pattern and volatility of the substance. Inhalation might be
a relevant pathway for birds but due to the limited release of the gas expected exposure the risk is
considered negligible.
The atmospheric life is relatively short (DT100=11 days, Nielsen et al. 200716) and a reaction with ozone is not
expected to be the most dominant degradation pathway in the atmosphere. Because of the short
atmospheric life the substance is not expected to mix on a global scale. The global warming potential is 4.4
for the 100 year time horizon which is considered to represent a low climatic impact. The ozone-depletion
potential is considered to be nearly zero (Papadimitriou et al. 2007)17.
16 Nielsen et al (2007). Atmospheric chemistry CF3CF=CH2: Kinetics and mechanisms of gas-phase
reactions with Cl atoms, OH radicals and O3. Chemical Physics Letters, Vol 439, p 18-22.
17 Papadimitriou et al (2007). CF3CF=CH2 and (Z)-CF3CF=CHF: Temperature dependent OH ate coefficients
in global warming potentials. Physical Chemistry Chemical Physics, Vol 10, p 808-820.
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
Appendix F: Confidential information
This appendix contains the confidential information provided by the applicant and is not publicly
available.
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Application for approval to import HFO-1234yf for release (APP202547)
November 2016
Appendix G: Standard terms and abbreviations
Definitions
Unless defined below, terms used in the controls have the same meaning as defined in the Act or
regulations made under the Act.
Term Definition
DTx Time required to degrade x% of the substance
ECx Concentration which affects x% of the population
GC-FID Gas chromatography - flame ionisation detector
Kd Distribution coefficient
Koc Kd * 100 / % organic carbon
Kow Partitioning coefficient octanol - water
LCx Concentration which kills x% of the population
LOAEC Lowest observable adverse effect concentration
NOAEC No observed adverse effect concentration
ThOD Theoretical oxygen demand