Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: Proposals for DNELs have been made following current ECHA guidance but also referring to the ECETOC Technical Report No.110 issued in October 2010: "Guidance on Assessment Factors to Derive a DNEL".
Overall assessment factor (AF):
9
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
152 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
1
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
1
Dose descriptor starting point:
other: acute NOAEC (weight of evidence)

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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

Proposals for DNELs have been made following current ECHA guidance but also referring to the ECETOC Technical Report No.110 issued in October 2010: "Guidance on Assessment Factors to Derive a DNEL". In particular, based on the justifications provided in the report, an intraspecies assessment factor of 3 is used for workers.

INHALATION EXPOSURE

Systemic

Long term exposure

The DNEL may be calculated considering two different starting points. The first considers derivation from the systemic NOEL of 53 mg/kg bw/d from the repeat dose rat study. This is considered valid since the target organ of the liver is considered which results from systemic exposure to furfural. In contrast, the RAR (2008) considered mortality in the 28 day inhalation toxicity study. The mortalities could be viewed to be a consequence of the local, nasal irritation effects and, as also concluded by the EPA, could be considered to not represent a 'true' systemic effect. The latter approach produces the lower DNEL value and this is used for the risk assessment as precautionary, although clearly the overall risk assessment is driven by the local effects for furfural.

Dose descriptor

In sub-chronic studies the NOAEL for systemic effects was 53 mg/kg bw/d in the rat (as current dossier).

Modification of dose descriptor

Convert the rat oral NOAEL (mg/kg bw/d) into a human inhalation NOAEC (mg/m3) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.3).

It is assumed that uptake of furfural after ingestion is 90% and after inhalation exposure, is 100% (EC RAR, 2008).

NOAECinhalation  =Oral NOAEL x [1/ sRVrat[1]] x [ABSoral-rat/ABSinhal-human] x [sRVhuman/wRV]

NOAECinhalation =53 x [1/0.343] x [90/100] x [6.7/10]

                                       = 93 mg/m3

Assessment factors

 

Uncertainty

AFs

Justification

Interspecies differences

1

differences in metabolic rate

remaining differences

Intraspecies differences

3

default AF for workers (ECETOC)

Differences in duration of exposure

1

normally a factor 2 is applied for extrapolation of subchronic to chronic exposure. However, given the results of the oral sub-chronic and chronic gavage study for furfural, no effect of exposure duration was found on the NOAEL and the effects observed.  Therefore, no correction for differences between experimental conditions and exposure pattern of the worker is made (EC RAR, 2008)

Dose response and endpoint specific/ severity issues

1

default AF; clear NOAEC

Quality of database

1

default; GLP-compliant guideline study; additional factor not appropriate for as furfural is the proximate metabolite

Overall AF

3

 

 

DNELl-t inhal     = 93 mg/m3/ 3

= 31 mg/m3

alternatively

Taking the NOAEC based on the EC RAR (2008) conclusion and as included in the current REACH dossier, this is 320 mg/m3The DNEL calculation is as follows:

Correcting the rat inhalation NOAEC for duration of exposure and worker respiratory volume:

NOAECinhalation  =320 x [6/8] x [6.7/10]

                       = 160 mg/m3

Assessment factors

 

Uncertainty

AFs

Justification

Interspecies differences

1

differences in metabolic rate

Intraspecies differences

3

default AF for workers (ECETOC)

Differences in duration of exposure

3

Normally, and according to ECETOC and ECHA guidance, a factor of 6 should be applied for extrapolation from a sub-acute (28 day) to chronic exposure.  However according to the EC RAR 2008; a factor of 3 is applied for extrapolation of sub-acute to chronic exposure. A chronic inhalation study with rats is not available.  However the results of the oral subchronic and chronic study in hamsters, show no effect of exposure duration on the NOAEL and the effects observed.

Dose response and endpoint specific/ severity issues

1

default AF; clear NOAEC

Quality of database

1

default; GLP-compliant guideline study

Overall AF

9

 

 

DNELl-t inhal     = 160 mg/m3/ 9

= 17.8 mg/m3

Acute/short-term exposure

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e. g. C&L) has been identified and there is a potential for high peak exposures. These “peaks” are normally associated with inhalation exposure but are less common for skin contact and ingestion (TGD Guidance Appendix R.8-8).  Furfural is classified for acute inhalation toxicity, hence an acute DNEL will be proposed for the inhalation route.

Dose descriptor

The acute inhalation NOAEC (mortality) of furfuryl alcohol in the rat (4 hr exposure) of 540 mg/m3.

Modification of dose descriptor

Initial modification of NOAEC of 540 mg/m3for light work (6.7 m3/ 10 m3) gives 362 mg/m3.

Adjust for duration only applying Haber’s law to derive the equivalent 15 min exposure:

(Ct=6)3x 4      = (Ct=0.25)3x 0.25

(Ct=0.25)3      = (362)3x 16

Ct=0.25           = 912 mg/m3

Assessment factors

 

Uncertainty

AFs

Justification

Interspecies differences

1

differences in metabolic rate

no AF for remaining differences

Intraspecies differences

3

deafult workers (ECETOC)

Differences in duration of exposure

1

default AF

Dose response and endpoint specific/ severity issues

2

NOEC from an acute study

Quality of database

1

Recent, GLP study

Overall AF

6

 

 

Inhalation DNELacute    = 912 mg/m3/ 6

                                   = 152 mg/m3

Local effects

Long-term exposure

Dose descriptor

In a 28 day study the NOAEC for local effects was 8 mg/m3 (Staal et al., 2008) 

Modification of dose descriptor

No modification since this is a local effect.

Assessment factors

 

Uncertainty

AFs

Justification

Interspecies differences

1

local irritant property induced by an elevated concentration of furfural with little if any difference in toxicodynamic/toxicokinetic effect across species. 

Intraspecies differences

1

local irritant property induced by an elevated concentration of furfural with little if any difference in toxicodynamic/toxicokinetic effect within species. 

Differences in duration of exposure

1

Local effect, not relevant. 

Dose response and endpoint specific/ severity issues

1

NOAEC. 

Quality of database

1

Default AF

Overall AF

1

 

 

local DNELl-t inhal                                 = 8 mg/m3/ 1

                                                        = 8 mg/m3

Acute/short-term exposure

Corrosive and irritant effects on the skin and eye are local, concentration-dependent phenomena.  No dose/response information can be derived from animal study data available for furfural and DNELs cannot therefore be derived from these data. For respiratory tract irritation, considering a weight of evidence assessment of both repeat dose toxicity studies and human data, 20 mg/m3 is concluded to be protective for acute effects.

Past decisions from the European Commission Working Group on Classification and Labelling of Dangerous Substances indicate that furfural is irritating to eyes, skin and respiratory tract hence appropriate RMM and OCs should be employed.  This is consistent with the conclusions of the EC RAR (2008).

DERMAL EXPOSURE

Systemic effects

Long term exposure

The potential of a substance to cause long-term systemic effects can judged based on the results of repeated dose toxicity and reproductive (fertility, developmental) testing.

Oral: sub-chronic effects: rat 13 wk NOAEL = 53 mg/kg bw/d developmental toxicity: rat 13 wk NOAEL = 100 mg/kg bw/d

Dose descriptor

In sub-chronic studies the NOAEL for systemic effects was 53 mg/kg bw/d in the rat.  It is noted that from EPA review (2010) that there is information available demonstrating that the 28 day dermal study NOAEL is 250 mg/kg bw/d.  The use of the NOAEL of 53 mg/kg bw/d to derive the DNEL long term for dermal exposure is therefore precautionary and conservative.

Modification of dose descriptor

Convert the rat oral NOAEL (mg/kg bw/d) into a human dermal NOAEL (mg/kg bw/d) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.5).

It is assumed that uptake of furfural after ingestion is 90% and after dermal exposure, is 100% (EC RAR, 2008).

correctedDermal NOAEL = NOAELoralx [ABSoral-rat/ABSdermal-human]

correctedDermal NOAEL = 53 x [90/100] = 47.7 mg/kg bwt/d

Assessment factors

 

Uncertainty

AFs

Justification

Interspecies differences

4

differences in metabolic rate

no AF for remaining differences

Intraspecies differences

3

default AF for workers (ECETOC)

Differences in duration of exposure

1

normally a factor 2 is applied for extrapolation of subchronic to chronic exposure. However, given the results of the oral sub-chronic and chronic gavage study for furfural, no effect of exposure duration was found on the NOAEL and the effects observed.  Therefore, no correction for differences between experimental conditions and exposure pattern of the worker is made (EC RAR, 2008).

Dose response and endpoint specific/ severity issues

1

default AF; clear NOAEC

Quality of database

1

default; GLP-compliant guideline study; additional factor not appropriate for as furfural is the proximate metabolite

Overall AF

12

 

 

DNELl-t dermal     = 47.7 mg/kg bw/d / 12

= 4.0 mg/kg bw/d

Acute/short term exposure

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e. g. C&L) has been identified and there is a potential for high peak exposures. These “peaks” are normally associated with inhalation exposure but are less common for skin contact and ingestion (TGD Guidance Appendix R.8-8).  Furfural does not warrant classification for acute dermal toxicity.  

Dose descriptor

The acute dermal LD50 of furfural could be considered to be >2000 mg/kg and therefore no DNEL for dermal systemic effects should be required. 

Local effects

No information is available to characterise the repeated local effects of furfural on the skin, while route-to-route extrapolation (respiratory tract to skin) is not appropriate. However, risk management measures and other occupational controls are designed to limit skin irritation will also protect against long term local skin effects.  This conclusion is consistent with the EC RAR (2008) for furfural.

It is of note that there was no significant dermal irritation reported in the 28 day dermal toxicity study (EPA review, 2010).

 

[1] 8 hour value calculated from TGD Table R.8-17 values (as per guidance Appx R.8-2, example B.4) – sRV for rat (mean male/female) is 1.43 L/min/kg bw = 0.343 m3/kg bw for 8 hours (same duration of exposure as worker).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
1
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
136 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
10

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
1
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
1
Dose descriptor starting point:
other: acute NOAEC (weight of evidence)

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
DNEL (Derived No Effect Level)
Value:
2.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Proposals for DNELs have been made following current ECHA guidance but also referring to the ECETOC Technical Report No.110 issued in October 2010: "Guidance on Assessment Factors to Derive a DNEL". In particular, based on the justifications provided in the report, an intraspecies assessment factor of 5 is used for the general population.

INHALATION EXPOSURE

Systemic effects

Long term exposure

The potential of a substance to cause long-term systemic effects can judged based on the results of repeated dose toxicity and reproductive (fertility, developmental) testing.

Oral: sub-chronic effects: rat 13 wk NOAEL = 53 mg/kg bw/d developmental toxicity: rat 13 wk NOAEL = 100 mg/kg bw/d

Inhalation: repeat dose effects: rat 28 day NOAEC = 320 mg/m3This NOAEC for systemic effects is that reported (concluded) in the EC RAR 2008.  It is interesting to note that the recent US EPA review (docket EPA-HQ-OPP-2009-0722-0005; p23 of 86) concluded there were no significant systemic effects in either 28 day study.

It is clear that a systemic NOAEL (oral route) has been established as 53 mg/kg bw/d and this could be used to extrapolate a systemic DNEL following inhalation exposure.  This is also considered below and demonstrates that the value calculated from the inhalation study NOAEC of 320 mg/m3 is precautionary and conservative, but is it acknowledged that this was the point of departure used in the EC RAR for furfural (2008).

The DNEL may be calculated considering two different starting points. The first considers derivation from the systemic NOEL of 53 mg/kg bw/d from the repeat dose rat study. This is considered valid since the target organ of the liver is considered which results from systemic exposure to furfural. In contrast, the RAR (2008) considered mortality in the 28 day inhalation toxicity study. The mortalities could be viewed to be a consequence of the local, nasal irritation effects and, as also concluded by the EPA, could be considered to not represent a 'true' systemic effect.

The latter approach produces the lower DNEL value and this is not considered appropriate for the risk assessment and therefore the inhalation DNEL of 8 mg/m3 is used which is considered appropriately protective.

Dose descriptor

In sub-chronic studies the NOAEL for systemic effects was 53 mg/kg bw/d in the rat (as current dossier).

Modification of dose descriptor

Convert the rat oral NOAEL (mg/kg bw/d) into a human inhalation NOAEC (mg/m3) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.3).

It is assumed that uptake of furfural after ingestion is 90% and after inhalation exposure, is 100% (EC RAR, 2008).

NOAECinhalation                = Oral NOAEL x [1/ sRVrat[1]] x [ABSoral-rat/ABSinhal-human]

NOAECinhalation               =53 x [1/1.03] x [90/100]

                                       = 46.3 mg/m3

Assessment factors

 

Uncertainty

AFs

Justification

Interspecies differences

1

differences in metabolic rate

remaining differences

Intraspecies differences

5

default AF for general population

Differences in duration of exposure

1

normally a factor 2 is applied for extrapolation of subchronic to chronic exposure. However, given the results of the oral sub-chronic and chronic gavage study for furfural, no effect of exposure duration was found on the NOAEL and the effects observed.  Therefore, no correction for differences between experimental conditions and exposure pattern of the worker is made (EC RAR, 2008)

Dose response and endpoint specific/ severity issues

1

default AF; clear NOAEC

Quality of database

1

default; GLP-compliant guideline study; additional factor not appropriate for as furfural is the proximate metabolite

Overall AF

5

 

 

DNELl-t inhal     = 46.3 mg/m3/ 5

= 9.3 mg/m3

alternatively

Taking the NOAEC based on the EC RAR (2008) conclusion and as included in the current REACH dossier, this is 320 mg/m3The DNEL calculation is as follows:

Correcting the rat inhalation NOAEC for duration of exposure:

NOAECinhalation  =320 x [6/24]

                       = 80 mg/m3

Assessment factors

 

Uncertainty

AFs

Justification

Interspecies differences

1

differences in metabolic rate

Intraspecies differences

5

default AF for general population (ECETOC)

Differences in duration of exposure

3

Normally, and according to ECETOC and ECHA guidance, a factor of 6 should be applied for extrapolation from a sub-acute (28 day) to chronic exposure.  However according to the EC RAR 2008; a factor of 3 is applied for extrapolation of sub-acute to chronic exposure. A chronic inhalation study with rats is not available.  However the results of the oral subchronic and chronic study in hamsters, show no effect of exposure duration on the NOAEL and the effects observed.

Dose response and endpoint specific/ severity issues

1

default AF; clear NOAEC

Quality of database

1

default; GLP-compliant guideline study

Overall AF

10

 

 

DNELl-t inhal     = 80 mg/m3/ 10

= 8 mg/m3

 

Acute/short-term exposure

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e. g. C&L) has been identified and there is a potential for high peak exposures. These “peaks” are normally associated with inhalation exposure but are less common for skin contact and ingestion (TGD Guidance Appendix R.8-8).  Furfural is classified for acute inhalation toxicity therefore a DNEL is derived.

Dose descriptor

The acute inhalation NOAEC (mortality) of furfuryl alcohol in the rat (4 hr exposure) of 540 mg/m3.

Modification of dose descriptor

Adjust for duration only applying Haber’s law to derive the equivalent 15 min exposure:

(Ct=6)3x 4                       = (Ct=0.25)3x 0.25

(Ct=0.25)3                       = (540)3x 16

Ct=0.25                         = 1361 mg/m3

Assessment factors

 

Uncertainty

AFs

Justification

Interspecies differences

1

differences in metabolic rate

no AF for remaining differences

Intraspecies differences

5

default general population (ECETOC)

Differences in duration of exposure

1

default AF

Dose response and endpoint specific/ severity issues

2

NOEC from an acute study

Quality of database

1

Recent, GLP study

Overall AF

10

 

 

Inhalation DNELacute    = 1361 mg/m3/ 10

                                   = 136 mg/m3

 

Local effects

Long term exposure

Dose descriptor

In a 28 day study the NOAEC for local effects was 8 mg/m3(Staal et al., 2008)

Modification of dose descriptor

No modification since this is a local effect.

Assessment factors

 

Uncertainty

AFs

Justification

Interspecies differences

1

local irritant property induced by an elevated concentration of furfural with little if any difference in toxicodynamic/toxicokinetic effect across species. 

Intraspecies differences

1

local irritant property induced by an elevated concentration of furfural with little if any difference in toxicodynamic/toxicokinetic effect within species. 

Differences in duration of exposure

1

Local effect, not relevant. 

Dose response and endpoint specific/ severity issues

1

NOAEC. 

 

Quality of database

1

Default AF

Overall AF

1

 

 

local DNELl-t inhal                                 = 8 mg/m3/ 1

                                                           = 8 mg/m3

Acute/short-term exposure

Corrosive and irritant effects on the skin and eye are local, concentration-dependent phenomena.  No dose/response information can be derived from animal study data available for furfural and DNELs cannot therefore be derived from these data. For respiratory tract irritation, considering a weight of evidence assessment of both repeat dose toxicity studies and human data, 20 mg/m3 is concluded to be protective for acute effects.

Past decisions from the European Commission Working Group on Classification and Labelling of Dangerous Substances indicate that furfural is irritating to eyes, skin and respiratory tract hence appropriate RMM and OCs should be employed.  This is consistent with the conclusions of the EC RAR (2008).

DERMAL EXPOSURE

Systemic effects

Long term exposure

The potential of a substance to cause long-term systemic effects can judged based on the results of repeated dose toxicity and reproductive (fertility, developmental) testing.

Oral: sub-chronic effects: rat 13 wk NOAEL = 53 mg/kg bw/d developmental toxicity: rat 13 wk NOAEL = 100 mg/kg bw/d

Dose descriptor

In sub-chronic studies the NOAEL for systemic effects was 53 mg/kg bw/d in the rat.  It is noted that from EPA review (2010) that there is information available demonstrating that the 28 day dermal study NOAEL is 250 mg/kg bw/d.  The use of the NOAEL of 53 mg/kg bw/d to derive the DNEL long term for dermal exposure is therefore precautionary and conservative.

Modification of dose descriptor

Convert the rat oral NOAEL (mg/kg bw/d) into a human dermal NOAEL (mg/kg bw/d) after adjusting for differences in uptake between the two routes of exposure (TGD, Appendix R.8-2, Example B.5).

It is assumed that uptake of furfural after ingestion is 90% and after dermal exposure, is 100% (EC RAR, 2008).

correctedDermal NOAEL = NOAELoralx [ABSoral-rat/ABSdermal-human]

correctedDermal NOAEL = 53 x [90/100] = 47.7 mg/kg bwt/d

Assessment factors

 

Uncertainty

AFs

Justification

Interspecies differences

4

differences in metabolic rate

no AF for remaining differences

Intraspecies differences

5

default AF for general population (ECETOC)

Differences in duration of exposure

1

normally a factor 2 is applied for extrapolation of subchronic to chronic exposure. However, given the results of the oral sub-chronic and chronic gavage study for furfural, no effect of exposure duration was found on the NOAEL and the effects observed.  Therefore, no correction for differences between experimental conditions and exposure pattern of the worker is made (EC RAR, 2008).

Dose response and endpoint specific/ severity issues

1

default AF; clear NOAEC

Quality of database

1

default; GLP-compliant guideline study; additional factor not appropriate for as furfural is the proximate metabolite

Overall AF

20

 

 

DNELl-t dermal     = 47.7 mg/kg bw/d / 20

= 2.4 mg/kg bw/d

Acute/short-term exposure

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e. g. C&L) has been identified and there is a potential for high peak exposures. These “peaks” are normally associated with inhalation exposure but are less common for skin contact and ingestion (TGD Guidance Appendix R.8-8).  Furfural does not warrant classification for acute dermal toxicity.

Dose descriptor

The acute dermal LD50 of furfural could be considered to be >2000 mg/kg and therefore no DNEL for dermal systemic effects should be required. 

Local effects

Long term exposure

No information is available to characterise the repeated local effects of furfural on the skin, while route-to-route extrapolation (respiratory tract to skin) is not appropriate. However, risk management measures and other occupational controls are designed to limit skin irritation will also protect against long term local skin effects.  This conclusion is consistent with the EC RAR (2008) for furfural.

It is of note that there was no significant dermal irritation reported in the 28 day dermal toxicity study (EPA review, 2010).

Acute/short-term exposure

Corrosive and irritant effects on the skin and eye are local, concentration-dependent phenomena.  No dose/response information can be derived from animal study data available for furfural and a DNEL cannot therefore be derived from these data.

Past decisions from the European Commission Working Group on Classification and Labelling of Dangerous Substances indicate that furfural is irritating to eyes, skin and respiratory tract hence appropriate RMM and OCs should be employed.  This is consistent with the conclusions of the EC RAR (2008).

ORAL EXPOSURE

Systemic effects

Long term exposure

The potential of a substance to cause long-term systemic effects can judged based on the results of repeated dose toxicity and reproductive (fertility, developmental) testing.

Oral: sub-chronic effects: rat 13 wk NOAEL = 53 mg/kg bw/d developmental toxicity: rat 13 wk NOAEL = 100 mg/kg bw/d

Dose descriptor

In sub-chronic studies the NOAEL for systemic effects was 53 mg/kg bw/d in the rat. 

Modification of dose descriptor

Convert the rat oral NOAEL (mg/kg bw/d) into a human oral NOAEL (mg/kg bw/d) after adjusting for differences in uptake (TGD, Appendix R.8-2, Example B.5).

It is assumed that uptake of furfural after ingestion is 90% (EC RAR, 2008).

correctedOral NOAEL = NOAELoralx [ABSoral-rat]

correctedOral NOAEL = 53 x [0.90] = 47.7 mg/kg bwt/d

Assessment factors

 

Uncertainty

AFs

Justification

Interspecies differences

4

differences in metabolic rate

no AF for remaining differences

Intraspecies differences

5

default AF for general population (ECETOC)

Differences in duration of exposure

1

normally a factor 2 is applied for extrapolation of subchronic to chronic exposure. However, given the results of the oral sub-chronic and chronic gavage study for furfural, no effect of exposure duration was found on the NOAEL and the effects observed.  Therefore, no correction for differences between experimental conditions and exposure pattern of the worker is made (EC RAR, 2008).

Dose response and endpoint specific/ severity issues

1

default AF; clear NOAEC

Quality of database

1

default; GLP-compliant guideline study; additional factor not appropriate for as furfural is the proximate metabolite

Overall AF

20

 

 

DNELl-t oral        = 47.7 mg/kg bw/d / 20

= 2.4 mg/kg bw/d

Acute/short-term exposure

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e. g. C&L) has been identified and there is a potential for high peak exposures. These “peaks” are normally associated with inhalation exposure but are less common for skin contact and ingestion (TGD Guidance Appendix R.8-8).  Furfural is classified for acute oral toxicity and so a DNEL is considered for the oral route of exposure.

The acute oral LD50 of furfural could be considered to be 100 mg/kg.  However it is clear from repeat dose studies that the NOAEL is 53 mg/kg bw/d (Jonker 2000a, b).  It is proposed that the DNEL long term value for systemic exposure via the oral route will be protective for any acute effects.  Deriving an acute oral DNEL following guidance would give a lower value than the long term DNEL which is considered inappropriate.