Norflurane

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

13 936 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

7.5

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

According to the REACH "Guidance on information requirements and chemical safety assessment", a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

As the substance is a gas, oral and dermal routes of exposure are considered to be irrelevant, therefore no DNELs were derived for these routes.

As the substance is not classified for acute toxicity, according to the REACH "Guidance on information requirements and chemical safety assessment" (R.8.4.3.1), no acute/short-term exposure DNELs need to be derived.

For long-term exposure, a combined chronic / carcinogenicty study is available. The increased incidence of Leydig cell tumours observed in senescent male rats at the highest exposure concentration (50 000 ppm) is considered to be of no biological or toxicological relevance to humans. In the absence of any other adverse findings in both male and female rats, the No Adverse Effect Concentration (NOAEC) in this study can be considered to be 50 000ppm (208 000 mg/m3).

As no local effects were observed in long-term exposure studies, no DNEL for local effects was derived.

The DNEL for long-term exposure - systemic effects for workers is derived as follows:

Step 1. Relevant dose descriptor (NOAEC = 208000 mg/m3) the highest concentration tested in the 2-year inhalation study at which no relevant adverse effects have been observed.

Step 2. Modification of Relevant Dose Descriptor by the following modification factors:

6/8 was considered appropriate to address the differences in the daily exposure duration (6hr/day in the 2-year study vs 8 hr/day of occupational exposure).

6.7/10 m3 was considered appropriate to address the different respiratory volumes between humans at rest and workers under light work activity.

Step 3. Application of assessment factors (AF)

2.5 was used to address the interspecies extrapolation (toxicodynamic differences)

3 was considered appropriate to address the intraspecies extrapolation (worker sub-population). As no relevant effects were observed at the highest tested concentration (50 000 ppm) in the 2-year study an intraspecies AF of 3 is considered sufficient.

A factor of 1 is considered appropriate for exposure duration as the starting point is the NOAEC in a 2-year chronic/carcinogenicity study.

A factor of 1 addresses dose response.

A factor of 1 is considered appropriate for the quality of the database.

Corrected NOAEC = 208 000 x 6/8 x 6.7/10 = 104 520 mg/m3

Overall, the DNEL for long-term occupational exposure by inhalation is calculated by dividing the corrected NOAEC by the assessment factors (AF):

DNEL (long-term effects in workers)= 104 520 / (2.5 x 3) =13 936 mg/m3 = 3342ppm

Update October 2011

Point of Departure for the derivation of the DNEL for HFC 134a

Following a review of the data the registrant has concluded that there are no grounds for changing the point of departure for derviation of the DNEL (see 7.7 Carcinogenicity and attachments to this section). Therefore it is concluded that the point of departure for the derivation of the DNEL should be the NOAEC in the long-term inhalation carcinogenicity study in rats which is 50000 ppm (208000 mg/m3).

Selection of Assement Factors (AFs) for HFC 134a.

There are a number of important features in the toxicology and use of HFC 134a that should be taken into account in the overall assessment of choice of AFs.

1)     All of the laboratory studies that are used to establish the NOAEC for HFC134a have been conducted by inhalation. The only significant route of exposure of humans to HFC134a is the inhalation route. As the risk characterisation involves extrapolation from inhalation studies in rats to the inhalation route in humans, there is no requirement to use an AF to take account of allometric scaling from rats to humans.                                                                                                  

2)     The toxicological effects of HFC134a have been studied extensively. It has been shown conclusively that it has a low level of toxicity, with only minimal effects being seen in all studies conducted, including reproductive toxicity and carcinogenicity studies.

3)     It is known that the kinetics of HFC134a following inhalation exposure are similar in both rats and humans and are characterised by limited absorption and the rapid excretion of the majority of the inhaled dose via the lungs (Green et al, 1995; Emmen et al, 2000).

4)     It is known that any HFC134a that is absorbed is subject to only limited metabolism in both rats and humans (Ellis et al, 1993; Ellis, 1996).

5) HFC134a is used as a propellant in medical aerosols (metered dose inhalers – MDIs) that are used by all sectors of the population, including all ethnicities, both males and females, the young and the aged, in patients with a compromised respiratory system.HFC134a-based MDIs were introduced in the EU in 1994 and most MDIs that were used by 2006 contained HFC134a.It is estimated that the number of patients in the EU using HFC134a-based MDIs is at least 5 million.There are no indications of increased susceptibility of individual groups to the effect of HFC134a during its use in this application (see Appendix 1 attached).

Assement factor for Inter-Species Extrapolation

No AF is required to take account of allometric scaling between species.

The fact that HFC134a is of low toxicity and that it is well established that its pharmacokinetic and pharmacodynamic behaviour is the same in both rats and humans lends support to the selection of an AF of 1 (one), rather than the default AF of 2.5, for any “remaining uncertainties” in extrapolation from rats to humans.

Thus, it could be argued that an AF of 1 (one) be selected for inter-species extrapolation for HFC134a. However, as an AF of 2.5 was selected in the original Registration Dossier to take account of any remaining uncertainties in extrapolation between species in a conservative manner, the Registrant chooses to retain this AF.

Assement factor for Intra-Species Extrapolation

The Agency has questioned the selection of an AF of 3 to take account of intra-species differences in populations of workers, rather than the default value of 5 recommended in the Guidance Document.

The fact that HFC134a is known to be subject to only limited absorption in humans, that the majority of the inhaled dose is rapidly excreted via the lungs and that any residual absorbed HFC134a is known to be subject to only limited metabolism in humans lends support to the use of a lower AF than the default factors for workers. This choice is exemplified by the fact that HFC134a is extensively used as a propellant in MDIs in all sectors of the populations without any reports of the existence of susceptible populations (see Appendix 1 attached).

As a consequence of these arguments, the Registrant chooses to retain it selection of an AF of 3 to take account of any remaining intra-species differences in the sensitivity of workers to the effects of HFC 134a.

References

Ellis, MK, Gowans, LA, Green, T and Tanner, RJN. “Metabolic fate and disposition of l, 1, 1, 2-HFC-134a (HCFC134a) in the rat following a single exposure by inhalation”. Xenobiotica 93, 719-729, 1993.

Ellis, MK. “Hydrofluorocarbon 134a: uptake and metabolic fate in the rat”, Report No: CTL/R/1240, ICI Central Toxicology Laboratory, 1996.

Emmen, HH et al. Human safety and pharmacokinetics of the CFC alternative propellants HFC134a (1,1,1,2-tetrafluoroethane) and HFC 227ea (1,1,1,2,3,3,3-heptafluoropropane) following whole body exposure. Regul. Toxicol. Pharmacol. 32, 33-35, (2000).

Green, T, Ellis, MK and Tseung, K. “Hydrofluorocarbon 134a: physiologically based pharmacokinetic modelling to predict uptake and metabolism in rats and humans”. Report No: CTL/R/1275, ICI Central Toxicology Laboratory, 1995. Derivation of DNEL for long-term effects in workers

AF Description	AF Worker
Route to route extrapolation	1
Scaling factor animal to man	1
Other interspecies differences	2.5
Intraspecies variability	3
Duration extrapolation	1
Dose-response	1
Quality database	1
Total Assessment Factor	7.5
Worker - Long-term inhalation
Point of Departure	208000 mg/m3
Test exposure time adjustment	6/8
Ventilation adjustment	0.67
Adjusted Starting Point	104520 mg/m3
DNEL	13936 mg/3
DNEL	3342 ppm

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 476 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

15

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

According to the REACH "Guidance on information requirements and chemical safety assessment", a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

As the substance is a gas, oral and dermal routes of exposure are considered to be irrelevant, therefore no DNELs were derived for these routes.

As the substance is not classified for acute toxicity, according to the REACH "Guidance on information requirements and chemical safety assessment" (R.8.4.3.1), no acute/short-term exposure DNELs need to be derived.

For long-term exposure, a combined chronic / carcinogenicty study is available. The increased incidence of Leydig cell tumours observed in senescent male rats at the highest exposure concentration (50 000 ppm) is considered to be of no biological or toxicological relevance to humans.In the absence of any other adverse findings in both male and female rats, the No Adverse Effect Concentration (NOAEC) in this study can be considered to be 50 000ppm (208 000 mg/m3).

As no local effects were observed in long-term exposure studies, no DNEL for local effects was derived.

The DNEL for long-term exposure - systemic effects for the general population is derived as follows:

Step 1. Relevant dose descriptor (NOAEC = 208 000 mg/m3) the highest concentration tested in the 2-year inhalation study at which no relevant adverse effects have been observed.

Step 2. Modification of Relevant Dose Descriptor by the following modification factors:

6/24 was considered appropriate to address the differences in the daily exposure duration (6hr/day in the 2-year study vs 24 hr/day for the general population).

5/7 was considered appropriate to address the different exposure conditions (5 days/week in the 2-year study vs 7 days week for exposure of the general population).

Step 3. Application of assessment factors (AF)

2.5 was used to address the interspecies extrapolation (toxicodynamic differences)

6 was considered appropriate to address the intraspecies extrapolation (general population). Since there is very little metabolism of HFC 134a (<1%) large differences in sensitivity are not expected and the factor is made up of worker variation = 3 x adjustment for a sensitive population = 2.

A factor of 1 is considered appropriate for exposure duration as the starting point is the NOAEC in a 2-year chronic/carcinogenicity study.

A factor of 1 addresses dose response.

A factor of 1 is considered appropriate for the quality of the database.

Corrected NOAEC = 208 000 x 6/24 x 5/7 = 37 142 mg/m3

Overall, the DNEL for long-term occupational exposure by inhalation is calculated by dividing the corrected NOAEC by the assessment factors (AF):

DNEL (long-term effects in the general population)= 37 142 / (2.5 x 6) = 2476 mg/m3 = 594ppm

Update October 2011

Point of Departure for the derivation of the DNEL for HFC 134a

Following a review of the data the registrant has concluded that there are no grounds for changing the point of departure for derviation of the DNEL (see 7.7 Carcinogenicity and attachments to this section). Therefore it is concluded that the point of departure for the derivation of the DNEL should be the NOAEC in the long-term inhalation carcinogenicity study in rats which is 50000 ppm (208000 mg/m3).

Selection of Assement Factors (AFs) for HFC 134a.

There are a number of important features in the toxicology and use of HFC 134a that should be taken into account in the overall assessment of choice of AFs.

1)     All of the laboratory studies that are used to establish the NOAEC for HFC134a have been conducted by inhalation. The only significant route of exposure of humans to HFC134a is the inhalation route. As the risk characterisation involves extrapolation from inhalation studies in rats to the inhalation route in humans, there is no requirement to use an AF to take account of allometric scaling from rats to humans.                                                                                                  

2)     The toxicological effects of HFC134a have been studied extensively. It has been shown conclusively that it has a low level of toxicity, with only minimal effects being seen in all studies conducted, including reproductive toxicity and carcinogenicity studies.

3)     It is known that the kinetics of HFC134a following inhalation exposure are similar in both rats and humans and are characterised by limited absorption and the rapid excretion of the majority of the inhaled dose via the lungs (Green et al, 1995; Emmen et al, 2000).

4)     It is known that any HFC134a that is absorbed is subject to only limited metabolism in both rats and humans (Ellis et al, 1993; Ellis, 1996).

5) HFC134a is used as a propellant in medical aerosols (metered dose inhalers – MDIs) that are used by all sectors of the population, including all ethnicities, both males and females, the young and the aged, in patients with a compromised respiratory system.HFC134a-based MDIs were introduced in the EU in 1994 and most MDIs that were used by 2006 contained HFC134a.It is estimated that the number of patients in the EU using HFC134a-based MDIs is at least 5 million.There are no indications of increased susceptibility of individual groups to the effect of HFC134a during its use in this application (see Appendix 1 attached).

Assement factor for Inter-Species Extrapolation

No AF is required to take account of allometric scaling between species.

The fact that HFC134a is of low toxicity and that it is well established that its pharmacokinetic and pharmacodynamic behaviour is the same in both rats and humans lends support to the selection of an AF of 1 (one), rather than the default AF of 2.5, for any “remaining uncertainties” in extrapolation from rats to humans.

Thus, it could be argued that an AF of 1 (one) be selected for inter-species extrapolation for HFC134a. However, as an AF of 2.5 was selected in the original Registration Dossier to take account of any remaining uncertainties in extrapolation between species in a conservative manner, the Registrant chooses to retain this AF.

Assement factor for Intra-Species Extrapolation

The Agency has questioned the selection of an AF of 6 to take account of intra-species differences in the general public, rather than the default value of 10 recommended in the Guidance Document.

The fact that HFC134a is known to be subject to only limited absorption in humans, that the majority of the inhaled dose is rapidly excreted via the lungs and that any residual absorbed HFC134a is known to be subject to only limited metabolism in humans lends support to the use of a lower AF than the default factor for the general population. This choice is exemplified by the fact that HFC134a is extensively used as a propellant in MDIs in all sectors of the populations without any reports of the existence of susceptible populations (see Appendix 1 attached).

As a consequence of these arguments, the Registrant chooses to retain its selection of an AF of 6 to take account of any remaining intra-species differences in the sensitivity of the general population to the effects of HFC 134a.

References

Ellis, MK, Gowans, LA, Green, T and Tanner, RJN. “Metabolic fate and disposition of l, 1, 1, 2-HFC-134a (HCFC134a) in the rat following a single exposure by inhalation”. Xenobiotica 93, 719-729, 1993.

Ellis, MK. “Hydrofluorocarbon 134a: uptake and metabolic fate in the rat”, Report No: CTL/R/1240, ICI Central Toxicology Laboratory, 1996.

Emmen, HH et al. Human safety and pharmacokinetics of the CFC alternative propellants HFC134a (1,1,1,2-tetrafluoroethane) and HFC 227ea (1,1,1,2,3,3,3-heptafluoropropane) following whole body exposure. Regul. Toxicol. Pharmacol. 32, 33-35, (2000).

Green, T, Ellis, MK and Tseung, K. “Hydrofluorocarbon 134a: physiologically based pharmacokinetic modelling to predict uptake and metabolism in rats and humans”. Report No: CTL/R/1275, ICI Central Toxicology Laboratory, 1995. Derivation of the DNEL for long-term effects in the general population

AF Description	AF Gen Pop
Route to route extrapolation	1
Scaling factor animal to man	1
Other interspecies differences	2.5
Intraspecies variability	6
Duration extrapolation	1
Dose-response	1
Quality database	1
Total Assessment Factor	15
Gen Pop - Long-term inhalation
Point of Departure	208000 mg/m3
Test exposure time adjustment	6/24 x 5/7
Adjusted Starting Point	37142 mg/m3
DNEL	2476 mg/m3
DNEL	594 ppm