Polyhaloalkene

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

950 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: German MAK value based on documented review of toxicology data. See discussion in 'additional information - Worker' field for more detail.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

186 400 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Modified dose descriptor starting point:

NOAEC

Value:

466 000 mg/m³

Explanation for the modification of the dose descriptor starting point:

Not applicable

AF for dose response relationship:

1

Justification:

Based on REACH guidance R.8.4.3.1, an assessment factor of 1 is justified. The DNEL was calculated used a NOAEL concentration in a highly sensitive species. The substance demonstrated no acute toxicity even in a highly sensitive species (rabbits) exposed to 466000 mg/m3 for 1 hour and in a rodent species exposed to 1865680 mg/m3 for 4 hour.

AF for interspecies differences (allometric scaling):

1

Justification:

Not applicable, DNEL derived from inhalation exposure

AF for other interspecies differences:

1

Justification:

R.8.4.3.1 and Table R. 8-4, an assessment factor of 1 is appropriate. This is supported by the inhalation-to-inhalation relationship between laboratory data and likely human exposure route. Further, the value reflects the pharmacokinetic and pharmacodynamic behavior of the substance. The assessment factor is further supported by: (1) measurement of the blood: air partition coefficient for rabbits compared to man demonstrated that rabbits will adsorb twice the amount of chemical as humans exposed under the same condition and (2) the metabolic rate measurements have shown that humans do not metabolize the substance at a faster rate than rabbits.

AF for intraspecies differences:

5

Justification:

Based on REACH guidance R.8.4.3 and R.8.4.3.1, an assessment factor of 5 is appropriate to protect sensitive subpopulations. The substance demonstrated no acute toxicity even in a highly sensitive species (rabbits) exposed to 466000 mg/m3 for 1 hour and in a rodent species exposed to 1.865,680 mg/m3 for 4 hour. The use of an assessment factor of 5 instead of the default of 10 is justified based on the limited intraspecies kinetic and dynamic differences that would be associated with a very short-term exposure, the fact that the 1-hr no observed adverse effect concentration was 466,000 mg/m3 (100,000 ppm), the highest concentration tested, pregnant rabbits were evaluated, rabbits are more heterogenous species compared to rodents. The similarity in response in all these groups supports an intraspecies assessment factor of 5 for humans.

AF for the quality of the whole database:

1

Justification:

Based on REACH guidance R.8.4.3.1, an assessment factor of 1 is justified. The substance demonstrated no acute toxicity even in a highly sensitive species (rabbits) exposed to 466,000 mg/m3 for 1 hour and in a rodent species exposed to 1865680 mg/m3 for 4 hour.

AF for remaining uncertainties:

1

Justification:

No additional AF are needed for remaining uncertainties.

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

As no local effects were observed in any of the available studies, no DNELs need to be derived for these effects. The inhalation DNEL for workers was derived in accordance with REACH guidance R.8.4.3.1. In view of the physicochemical properties of the test substance, dermal exposure was considered not relevant for workers and a DNEL was not derived. HFO-1234yf is not classified as acutely toxic and no acute DNEL is appropriate. An extensive toxicology testing program has been completed on the test substance. Based on an inhalation 4-hour LC₅₀> 400000 ppm, and the absence of cardiac sensitization at the highest concentration tested (120000 ppm), HFO-1234yf is not considered an acute inhalation hazard. For the worker DNEL systemic exposure, the German MAK value of 950 mg/m3 (200 ppm) set by the MAK commission in 2015 was used. The MAK value was peer reviewed and also available for public comment. As noted in REACH Guidance Chapter R.8: Characterisation of dose [concentration]-response for human health Appendix 8-13 (Nov 2012, v 2.1) “A registrant cannot use a national OEL in place of a DNEL without an evaluation of the scientific background for setting the national OEL. However, in cases where toxicological information and evaluations of health effects used for setting the national OEL are documented and available, this may, as for IOELs, be used and taken into account in deriving the DNEL. In this evaluation, the approach used for setting the national OEL should be compared to the approach for deriving DNELs as described in the in the main body of this chapter, and any differences in approach should be taken into account.” Below is the rationale for the MAK value taken from the 2,3,3,3 -tetrafluoropropene documentation.

MAK value. No data are available for humans. After 13 weeks of inhalative exposure, there was no irritant effect on rats up to a concentration of 50000 mL 2,3,3,3-tetrafluoropropene/m³. Mononuclear cell infiltrates in kidneys, lungs and the nose were to be observed in this concentration. After a 28-day inhalative exposure to concentrations up to 10000 mL/m³ no adverse effects were observed in the heart of muscles of minipigs. Concentration-dependent focal myocardnecroses and cardiac muscle inflammations were found in pregnant rabbits from the lowest tested concentration of 2500 mL/m³. A 28-day inhalation study on rabbits enables a NOAEC of 500 mL/m³ to be determined for the effects on the heart and for the elevation of creatine kinase activity. Because the rabbit is the most sensitive species and it is not proven that the findings in relation to the heart are a species-specific effect, the NOAEC of 500 mL/m³will be used to determine the MAK value. Because the study is only a 28-day inhalation study but the concentration in the NOAEC range probably has a greater influence than the duration, the concentration from the seven-day exposure per week is not to be converted to the five-day exposure at the workplace and only a slight drop in the NOAEC is expected with chronic exposure. Because there were no cardio effects in rats up to 50000 mL/m³and in minipigs up to 10000 mL/m³, significantly greater sensitivity among rabbits is to be assumed in relation to cardio effects, even though the precise mechanism is unknown. This is why the "preferred value approach" is to be used in setting the MAK value to 200 mL/m³. The commission does not consider a further decrease to be necessary in the light of the high sensitivity of rabbits.

 

Acute inhalation DNEL

In addition to the acute inhalation DNELs for consumers, an acute inhalation DNEL for workers has been derived.

 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEC: 466000 mg/m^3 (100000 ppm)	No toxicity observed at highest concentration evaluated in rabbits following a 1-hour inhalation exposure. In addition, no toxic effects observed in rats exposed to greater than 1865680 mg/m^3(400000 ppm) for 4 hours.
Step 2) Modification of starting point	2	Based on REACH guidance R.8.4.2, an adjustment for a 15 minute exposure can be used. This acute inhalation DNEL is for the specific purpose of assessing short-term inhalation in a vehicle compartment. The data is from inhalation studies and the human route of exposure is also inhalation. In these instances, a conservative estimate of how long a consumer would be exposed in an automobile compartment is 15 minutes following an accident based on a conservative emergency response estimate. Using a time*concentration modification, the 100000 ppm for 1 hour would be converted to 200000 ppm for 15 minutes.
Step 3) Assessment factors
Interspecies	1	Based on REACH guidance R.8.4.3.1 and Table R. 8-4, an assessment factor of 1 is appropriate. This is supported by the inhalation-to-inhalation relationship between laboratory data and likely human exposure route. Further, the value reflects the pharmacokinetic and pharmacodynamic behavior of the substance. The assessment factor is further supported by: (1) measurement of the blood: air partition coefficient for rabbits compared to man demonstrated that rabbits will adsorb twice the amount of chemical as humans exposed under the same condition and (2) the metabolic rate measurements have shown that humans metabolize the substance at a lower rate than rabbits.
Intraspecies	5	Based on REACH guidance R.8.4.3 and R.8.4.3.1, an assessment factor of 5 is appropriate to protect sensitive subpopulations.
Exposure duration	1	Based on REACH guidance R.8.4.3.1, an assessment factor of 1 is justified. This is an acute DNEL, and the laboratory data exceeded any plausible acute exposure scenario in humans. Further, HFO-1234yf is poorly adsorbed, undergoes minimal metabolism, and is rapidly cleared form the body.
Dose response	1	Based on REACH guidance R.8.4.3.1, an assessment factor of 1 is justified. The DNEL was calculated used a NOAEL concentration in a highly sensitive species. The substance demonstrated no acute toxicity even in a highly sensitive species (rabbits) exposed to 466000 mg/m3 for 1 hour and in a rodent species exposed to 1865680 mg/m^3for 4 hour.
Quality of database	1	Based on REACH guidance R.8.4.3.1, an assessment factor of 1 is justified. The substance demonstrated no acute toxicity even in a highly sensitive species (rabbits) exposed to 466000 mg/m3 for 1 hour and in a rodent species exposed to 1865680 mg/m^3for 4 hour.
DNELacute(15 min)	Value
For consumers	466000 x 2 / (1 x 5 x 1 x 1 x 1) =186400 mg/m^3(40000 ppm)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

113.1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: German MAK value based on documented review of toxicology data. See discussion for more detail

Overall assessment factor (AF):

2

Dose descriptor starting point:

other: Worker inhalation DNEL (long term) based on German MAK value

Value:

950 mg/m³

Modified dose descriptor starting point:

other: Worker inhalation DNEL (long term) based for consumers on German MAK value

Value:

226.19 mg/m³

Explanation for the modification of the dose descriptor starting point:

The long term exposure DNEL for workers is based on a German MAK value, which is equivalent to an OEL (occupational exposure limit) and can be used for deriving a DNEL according to R.8.1.1. For workers the DNEL is based on an exposure duration of 8 hours for 5 days a week, while for consumers the DNEL is based on an exposure duration of 24 hours for 7 days a week. For this reason correction for exposure duration is performed. Correction for a higher respiratory volume under light activity is not performed since the activity of the workers (bus driver) is not considered to be different form the general population (passenger). In addition not correcting the MAK value for respiratory volume for the general population is considered to be conservative: 950 * (8/24)* (5/7) = 226.19 mg/m³.

AF for dose response relationship:

1

Justification:

Based on review of the extensive dataset including over 15 studies conducted in 3 reputable contract laboratories and 2 distinguished research centers, a dose response factor of 1 was applied per REACH guidance R.8.4.3.1

AF for differences in duration of exposure:

1

Justification:

HFO-1234yf will be poorly adsorbed, undergo minimal metabolism, and be rapidly cleared from the body. It will not bioaccumulate. In addition, no systemic toxicity was observed in following repeated exposure and no genotoxicity was observed following in vivo exposure. For these reasons adjustment factor of 1 is considered adequate to account for exposure duration per REACH guidance R.8.4.3.1

AF for interspecies differences (allometric scaling):

1

Justification:

Per REACH guidance R.8.4.3.1, a factor of 1 is supported because allometric scaling is not applicable for the German MAK value

AF for other interspecies differences:

1

Justification:

Not applicable, the DNEL is derived from the German MAK value.

AF for intraspecies differences:

2

Justification:

Per REACH guidance R.8.4.3.1 an assessment factor of 2 was applied based to be protective for sensitive sub-populations. Since the MAK value (used as dose descriptor starting point) is derived for the worker population, which is considered to be more homogenous than the general population, an additional assessment factors should be included to protect more sensitive sub-population, e.g. children, elderly, diseased and others. The standard intraspecies assessment factors for workers and consumers differ with a factor 2.

AF for the quality of the whole database:

1

Justification:

Based on review of the extensive dataset including over 15 studies conducted in 3 reputable contract laboratories and 2 distinguished research centers, a dose response factor of 1 was applied per REACH guidance R.8.4.3.1

AF for remaining uncertainties:

1

Justification:

For all the reasons stated above, there are no remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

186 400 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Modified dose descriptor starting point:

NOAEC

Value:

466 000 mg/m³

Explanation for the modification of the dose descriptor starting point:

Not applicable

AF for dose response relationship:

1

Justification:

Based on REACH guidance R.8.4.3.1, an assessment factor of 1 is justified. The DNEL was calculated used a NOAEL concentration in a highly sensitive species. The substance demonstrated no acute toxicity even in a highly sensitive species (rabbits) exposed to 466000 mg/m3 for 1 hour and in a rodent species exposed to 1865680 mg/m3 for 4 hour.

AF for interspecies differences (allometric scaling):

1

Justification:

Not applicable, DNEL derived from inhalation exposure

AF for other interspecies differences:

1

Justification:

R.8.4.3.1 and Table R. 8-4, an assessment factor of 1 is appropriate. This is supported by the inhalation-to-inhalation relationship between laboratory data and likely human exposure route. Further, the value reflects the pharmacokinetic and pharmacodynamic behavior of the substance. The assessment factor is further supported by: (1) measurement of the blood: air partition coefficient for rabbits compared to man demonstrated that rabbits will adsorb twice the amount of chemical as humans exposed under the same condition and (2) the metabolic rate measurements have shown that humans do not metabolize the substance at a faster rate than rabbits.

AF for intraspecies differences:

5

Justification:

Based on REACH guidance R.8.4.3 and R.8.4.3.1, an assessment factor of 5 is appropriate to protect sensitive subpopulations. The substance demonstrated no acute toxicity even in a highly sensitive species (rabbits) exposed to 466000 mg/m3 for 1 hour and in a rodent species exposed to 1.865,680 mg/m3 for 4 hour. The use of an assessment factor of 5 instead of the default of 10 is justified based on the limited intraspecies kinetic and dynamic differences that would be associated with a very short-term exposure, the fact that the 1-hr no observed adverse effect concentration was 466,000 mg/m3 (100,000 ppm), the highest concentration tested, pregnant rabbits were evaluated, rabbits are more heterogenous species compared to rodents. The similarity in response in all these groups supports an intraspecies assessment factor of 5 for humans.

AF for the quality of the whole database:

1

Justification:

Based on REACH guidance R.8.4.3.1, an assessment factor of 1 is justified. The substance demonstrated no acute toxicity even in a highly sensitive species (rabbits) exposed to 466,000 mg/m3 for 1 hour and in a rodent species exposed to 1865680 mg/m3 for 4 hour.

AF for remaining uncertainties:

1

Justification:

No additional AF are needed for remaining uncertainties.

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

According to the REACH guidance on information requirements and chemical safety assessment a leading DNEL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible. If applicable, separate DNELs for local and systemic effects need to be derived.

As noted during the Member State Committee meeting in January 2011, several members requested a DNEL for consumer exposure resulting from an automobile accident. Repeated exposure of HFO-1234yf to consumers is not expected under normal conditions of use. In view of the toxicological and physicochemical properties of HFO-1234yf, the dermal and oral exposures were considered as not relevant for consumers, and DNEL derivation was limited to the exposure by inhalation. Based on REACH guidance R.8.1.2.5 and Appendix R. 8-8, derivation of an acute DNEL is not required or warranted. However, an acute inhalation DNEL will be derived to satisfy the request from Member State Committee members. The details of the acute inhalation DNEL derivation are shown below.

 

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEC: 466000 mg/m^3 (100000 ppm)	No toxicity observed at highest concentration evaluated in rabbits following a 1-hour inhalation exposure. In addition, no toxic effects observed in rats exposed to greater than 1865680 mg/m^3(400000 ppm) for 4 hours.
Step 2) Modification of starting point	2	Based on REACH guidance R.8.4.2, an adjustment for a 15 minute exposure can be used. This acute inhalation DNEL is for the specific purpose of assessing short-term inhalation in a vehicle compartment. The data is from inhalation studies and the human route of exposure is also inhalation. In these instances, a conservative estimate of how long a consumer would be exposed in an automobile compartment is 15 minutes following an accident based on a conservative emergency response estimate. Using a time*concentration modification, the 100000 ppm for 1 hour would be converted to 200000 ppm for 15 minutes.
Step 3) Assessment factors
Interspecies	1	Based on REACH guidance R.8.4.3.1 and Table R. 8-4, an assessment factor of 1 is appropriate. This is supported by the inhalation-to-inhalation relationship between laboratory data and likely human exposure route. Further, the value reflects the pharmacokinetic and pharmacodynamic behavior of the substance. The assessment factor is further supported by: (1) measurement of the blood: air partition coefficient for rabbits compared to man demonstrated that rabbits will adsorb twice the amount of chemical as humans exposed under the same condition and (2) the metabolic rate measurements have shown that humans metabolize the substance at a lower rate than rabbits.
Intraspecies	5	Based on REACH guidance R.8.4.3 and R.8.4.3.1, an assessment factor of 5 is appropriate to protect sensitive subpopulations. The substance demonstrated no acute toxicity even in a highly sensitive species (rabbits) exposed to 466000 mg/m3 for 1 hour and in a rodent species exposed to 1865680 mg/m^3for 4 hour. The use of an assessment factor of 5 instead of the default of 10 is justified based on the limited intraspecies kinetic and dynamic differences that would be associated with a very short-term exposure, the fact that the 1-hr no observed adverse effect concentration was 466000 mg/m3 (100000 ppm), the highest concentration tested, pregnant rabbits were evaluated, rabbits are more heterogeneous species compared to rodents. The similarity in response in all these groups supports an intraspecies assessment factor of 5 for humans.
Exposure duration	1	Based on REACH guidance R.8.4.3.1, an assessment factor of 1 is justified. This is an acute DNEL, and the laboratory data exceeded any plausible acute exposure scenario in humans. Further, HFO-1234yf is poorly adsorbed, undergoes minimal metabolism, and is rapidly cleared form the body.
Dose response	1	Based on REACH guidance R.8.4.3.1, an assessment factor of 1 is justified. The DNEL was calculated used a NOAEL concentration in a highly sensitive species. The substance demonstrated no acute toxicity even in a highly sensitive species (rabbits) exposed to 466000 mg/m3 for 1 hour and in a rodent species exposed to 1865680 mg/m^3for 4 hour.
Quality of database	1	Based on REACH guidance R.8.4.3.1, an assessment factor of 1 is justified. The substance demonstrated no acute toxicity even in a highly sensitive species (rabbits) exposed to 466000 mg/m3 for 1 hour and in a rodent species exposed to 1865680 mg/m^3for 4 hour.
DNELacute(15 min)	Value
For consumers	466000 x 2 / (1 x 5 x 1 x 1 x 1) =186400 mg/m^3(40000 ppm)