Furfuryl alcohol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

31 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

3

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

143 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:

LOAEC

Acute/short 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 starting point:

LOAEC

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:

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

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.

HAZARD VIA INHALATION ROUTE

Systemic effects

Long-term exposure

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

For furfuryl alcohol, the following NOAECs are presented in the IUCLID dossier. For oral dosing these are based on data for the proximate metabolite, furfural (2-furaldehyde):

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:
sub-chronic effects: rat 14 wk NOAEC = 64 mg/m³
sub-chronic effects: mouse 14 wk NOAEC = 128 mg/m³
chronic effects: rat NOAEC = 32 mg/m³
chronic effects: mouse NOAEC = 32 mg/m³

The inhalation NOAEC in rats relates to effects (lower body weight and poorer survival) which are considered to be secondary consequences of the nasal irritation/tumours and in the mouse kidney damage which is considered to be exacerbation of an age-related phenomenon). Since there are no target organ effects in the 14 wk inhalation studies it is concluded that the DNEL for repeat dose exposure local effects will be protective for systemic effects. 

The systemic NOAEL of 53 mg/kg bw/d will be referenced from the furfural study and an inhalation and dermal DNELs derived for systemic effects. The rationale is that, even though the NOAEC could be taken from the 14 wk inhalation studies, the doses were not sufficient to administer a systemic dose of 53 mg/kg bw/d i. e. the systemic dose resulting from 64 mg/m³is 16.5 mg/kg bw/d. The local effects reported, preclude the ability to carry out a repeat dose inhalation study at a dose which would produce systemic toxicity (i. e. liver toxicity).

Dose descriptor 

In sub-chronic studies the NOAEL for systemic effects for the proximate metabolite, furfural, 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 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 furfuryl alcohol after ingestion is 90% and after inhalation exposure, is 100%.

NOAEC_inhalation   =Oral NOAEL x [1/ sRV_rat^[1]] x [ABS_oral-rat/ABS_inhal-human] x [sRV_human/wRV]

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

                                  = 93 mg/m³

[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)

Assessment factors

Uncertainty	AFs	Justification
Interspecies differences	1	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	3

 

DNEL_{l-t inhal}      = 93 mg/m³/ 3

= 31 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). Furfuryl alcohol is classified for acute oral, dermal and inhalation toxicity. Acute hazard via the oral route is not relevant for workers. Hence an acute DNEL will be considered for the dermal and inhalation routes only.

Dose descriptor

The acute inhalation NOAEC for furfuryl alcohol in the rat (4 hr exposure) is 510 mg/m³.

Modification of dose descriptor

Initial modification of NOAEC of 510 mg/m³for light work (6.7 m³/ 10 m³) gives 340 mg/m³.

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

(C_t=6)³x 4       = (C_t=0.25)³x 0.25

(C_t=0.25)³       = (340)³x 16

C_t=0.25            = 857 mg/m³

Assessment factors

Uncertainty	AFs	Justification
Interspecies differences	1	differences in metabolic rate no AF for remaining differences
Intraspecies differences	3	default workers (ECETOC)
Differences in duration of exposure	1	default AF
Dose response and endpoint specific/ severity issues	2	NOAEC from an acute study
Quality of database	1	Recent, GLP study
Overall AF	6

 Inhalation DNEL_acute  = 857 mg/m³/ 6

                                     = 143 mg/m³

Local effects

Long term exposure

After chronic exposure, extensive non-neoplastic alterations in the respiratory and olfactory epithelia and hyperplastic Bowman’s glands were observed in both rats and mice (NTP, 1999). Sustained extensive chronic damage was necessary for tumour development and the NTP (1999) study report notes that the hyperplasia and squamous cell metaplasia in the rat represent conversion of highly specialised nasal tissue into more resistant types of epithelium, representing an adaptive response to chronic irritation. Based on these observations, furfuryl alcohol is considered to have respiratory irritating properties.

In humans it appears that furfuryl alcohol in combination with dust and formaldehyde or other chemicals, or exposure to various fumes and vapour might cause slight irritation and or acute restrictiveness of the lungs. However, a direct correlation with furfuryl alcohol exposure levels could not be clearly established since, in these studies, humans were exposed to mixtures and/or reactions products and not to furfuryl alcohol alone.

In most European countries, a national OEL of 5 or 2 ppm has been established for exposure to furfuryl alcohol on the workplace. In the present dossier on furfuryl alcohol, the limit value of 2 ppm is considered for risk assessment purposes. As discussed above, in repeated dose inhalation toxicity studies in rat, local effects on the nasal epithelium have been reported. These local effects have warranted classification of furfuryl alcohol under DSD as "irritating for the respiratory system" (Xi, R37). However, these irritating local effects on the nasal epithelium after repeated exposure have not been reported in the workplace over the 60 plus years that furfural alcohol has been manufactured and used. To confirm this, a statement ("no nasal irritation has been reported in workers exposed to furfuryl alcohol in a plant which could be attributed to fufuryl acohol") from a production plant is available (see attachment). Based on the absence of adverse effects reported in workers at the OEL of 2 ppm, equivalent to 8 mg/m³, this limit value is considered as a realistic limit value for assessment of safe use. 

Dose descriptor 

In chronic studies the reported LOAEC for local effects was 8 mg/m³. However, as relates to DNEL derivation, this LOAEC is actually regarded as a NOAEC (see justification under Section 5.3.4 of the CSR).

Modification of dose descriptor

No modification since this is a local effect.

Assessment factors

Uncertainty	AF	Justification
Interspecies differences	1	Local irritant property induced by an elevated concentration of furfuryl alcohol with little if any difference in toxicodynamic/toxicokinetic effect across species Supporting this position is that there is comparability of effects between rats and mice in the NTP study, with no clear species difference in response at the lowest dose. Residual AF of 2.5 is not applicable since this is a physical effect at the site of entry and this is supported by the fact that there are no adverse effects reported in lower respiratory tract/lungs, at any dose level.  In addition, metabolism could be argued to be not implicated since an NOAEC for the proximate metabolite, furfural, has been established at 8 mg/m^3(28 day study [2]) with reported LOAEC of 20 mg/m^3(furfural RAR, 2008).
Intraspecies differences	1	local irritant property induced by an elevated concentration of furfuryl alcohol 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’ (see rationale in main text, CSR section 5.8.3)
Quality of database	1	Default AF
Overall AF	1

[2] Reference to the NOAEC is from a more recent study (Staal et al., 2008). 

DNEL_{l-t inhal}     = 8 mg/m³ 

Acute/short-term exposure

Corrosive and irritant effects on the skin are local, concentration-dependent phenomena. No dose/response information can be derived from data available for furfuryl alcohol and a DNEL cannot therefore be determined.  It is proposed that furfuryl alcohol should be classified as irritating to the respiratory tract hence appropriate RMM and OCs should be employed.

HAZARD VIA DERMAL ROUTE

Systemic effects

Long term exposure

Dose descriptor 

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

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 furfuryl alcohol after ingestion is 90% and after dermal exposure, is 100%.

_correctedDermal NOAEL = NOAEL_oralx [ABS_oral-rat/ABS_dermal-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 NOAEL
Quality of database	1	default; GLP-compliant guideline study; additional factor not appropriate for as furfural is the proximate metabolite
Overall AF	12

 

DNEL_{l-t dermal}     = 47.7 mg/kg bw/d / 12

= 4.0 mg/kg bw/d

Acute toxicity

The available acute dermal data, although regarded as sufficient for classification purposes, is not considered suitable for quantitative, DNEL determination. It is proposed that the long-term dermal DNEL for systemic effects is, by default, sufficiently protective for acute effects (see below).

Local effects

Long term exposure

No information is available to characterise the repeated local effects of furfuryl alcohol 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.

Acute/short term exposure

Corrosive and irritant effects on the skin are local, concentration-dependent phenomena. No dose/response information can be derived from data available for furfuryl alcohol and a DNEL cannot therefore be determined.  It is proposed that furfuryl alcohol should be classified as irritating to skin hence appropriate RMM and OCs should be employed.

HAZARD FOR THE EYES

Local effects

Furfuryl alcohol is classified as an eye irritant (CLD Category 2 H319). No dose response information can be derived and therefore it is concluded to be of low hazard (ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

9.3 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

5

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

128.5 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

10

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:

LOAEC

Acute/short 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 starting point:

LOAEC

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:

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:

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.

HAZARD VIA INHALATION ROUTE

Systemic effects

Long-term exposure

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

For furfuryl alcohol, the following NOAECs are presented in the IUCLID dossier. For oral dosing these are based on data for the proximate metabolite, furfural (2-furaldehyde):

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:
sub-chronic effects: rat 14 wk NOAEC = 64 mg/m³
sub-chronic effects: mouse 14 wk NOAEC = 128 mg/m³
chronic effects: rat NOAEC = 32 mg/m³
chronic effects: mouse NOAEC = 32 mg/m³

The inhalation NOAEC in rats relates to effects (lower body weight and poorer survival) which are considered to be secondary consequences of the nasal irritation/tumours and in the mouse kidney damage which is considered to be exacerbation of an age-related phenomenon). Since there are no target organ effects in the 14 wk inhalation studies it is concluded that the DNEL for repeat dose exposure local effects will be protective for systemic effects. 

The systemic NOAEL of 53 mg/kg bw/d will be referenced from the furfural study and an inhalation and dermal DNELs derived for systemic effects. The rationale is that, even though the NOAEC could be taken from the 14 wk inhalation studies, the doses were not sufficient to administer a systemic dose of 53 mg/kg bw/d i. e. the systemic dose resulting from 64 mg/m³is 16.5 mg/kg bw/d.  The local effects reported, preclude the ability to carry out a repeat dose inhalation study at a dose which would produce systemic toxicity (i. e. liver toxicity).

Dose descriptor 

In sub-chronic studies the NOAEL for systemic effects for the proximate metabolite, furfural, 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 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 furfuryl alcohol after ingestion is 90% and after inhalation exposure, is 100%.

NOAEC_inhalation   =Oral NOAEL x [1/ sRV_rat^[1]] x [ABS_oral-rat/ABS_inhal-human] x [sRV_human/wRV]

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

= 46.3 mg/m³

[1] 24 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 = 1.03 m³/kg bw for 24 hours (same duration of exposure as worker)

Assessment factors

Uncertainty	AFs	Justification
Interspecies differences	1	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	5

 

DNEL_{l-t inhal}     = 46.3 mg/m³/ 5

= 9.3 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). Furfuryl alcohol is classified for acute inhalation toxicity.   Hence an acute DNEL is considered .

Dose descriptor

The acute inhalation NOAEC for furfuryl alcohol in the rat (4 hr exposure) of 510 mg/m³.

Modification of dose descriptor

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

(C_t=4)³x 4       = (C_t=0.25)³x 0.25

(C_t=0.25)³`         = (510)³x 16

C_t=0.25                        = 1285 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	NOAEC from an acute study
Quality of database	1	Recent, GLP study
Overall AF	10

 

DNELacute     = 1285 mg/m³/ 10

                       = 128.5 mg/m³

Local effects

Long term exposure

After chronic exposure, extensive non-neoplastic alterations in the respiratory and olfactory epithelia and hyperplastic Bowman’s glands were observed in both rats and mice (NTP, 1999). Sustained extensive chronic damage was necessary for tumour development and the NTP (1999) study report notes that the hyperplasia and squamous cell metaplasia in the rat represent conversion of highly specialised nasal tissue into more resistant types of epithelium, representing an adaptive response to chronic irritation.  Based on these observations, furfuryl alcohol is considered to have respiratory irritating properties.

In humans it appears that furfuryl alcohol in combination with dust and formaldehyde or other chemicals, or exposure to various fumes and vapour might cause slight irritation and or acute restrictiveness of the lungs. However, a direct correlation with furfuryl alcohol exposure levels could not be clearly established since, in these studies, humans were exposed to mixtures and/or reactions products and not to furfuryl alcohol alone.

In most European countries, a national OEL of 5 or 2 ppm has been established for exposure to furfuryl alcohol on the workplace. In the present dossier on furfuryl alcohol, the limit value of 2 ppm is considered for risk assessment purposes.  As discussed above, in repeated dose inhalation toxicity studies in rat, local effects on the nasal epithelium have been reported.  These local effects have warranted classification of furfuryl alcohol under DSD as "irritating for the respiratory system" (Xi, R37).  However, these irritating local effects on the nasal epithelium after repeated exposure have not been reported in the workplace over the 60 years and more that furfural alcohol is manufactured and used. To confirm this, a statement ("no nasal irritation has been reported in workers exposed to furfuryl alcohol in a plant which could be attributed to fufuryl acohol") from a production plant is available (see attachment). Based on the absence of adverse effects reported in workers at the OEL of 2 ppm, equivalent to 8 mg/m³, this limit value is considered as a realistic limit value for assessment of safe use. 

 

Dose descriptor 

In chronic studies the reported LOAEC for local effects was 8 mg/m³. However, as relates to DNEL derivation, this LOAEC is actually regarded as a NOAEC (see justification under Section 5.3.4 of the CSR).

Modification of dose descriptor

No modification since this is a local effect.

Assessment factors

Uncertainty	AF	Justification
Interspecies differences	1	Local irritant property induced by an elevated concentration of furfuryl alcohol with little if any difference in toxicodynamic/toxicokinetic effect across species Supporting this position is that there is comparability of effects between rats and mice in the NTP study, with no clear species difference in response at the lowest dose. Residual AF of 2.5 is not applicable since this is a physical effect at the site of entry and this is supported by the fact that there are no adverse effects reported in lower respiratory tract/lungs, at any dose level.  In addition, metabolism could be argued to be not implicated since an NOAEC for the proximate metabolite, furfural, has been established at 8 mg/m^3(28 day study [2]) with reported LOAEC of 20 mg/m^3(furfural RAR, 2008).
Intraspecies differences	1	local irritant property induced by an elevated concentration of furfuryl alcohol 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’ (see rationale in main text, CSR section 5.8.3)
Quality of database	1	Default AF
Overall AF	1

 

[2] Reference to the NOAEC is from a more recent study (Staal et al., 2008). 

DNEL_{l-t inhal}     = 8 mg/m³ 

 

Acute/short-term exposure

Corrosive and irritant effects on the skin are local, concentration-dependent phenomena. No dose/response information can be derived from data available for furfuryl alcohol and a DNEL cannot therefore be determined.  It is proposed that furfuryl alcohol should be classified as irritating to the respiratory tract hence appropriate RMM and OCs should be employed.

HAZARD VIA DERMAL ROUTE

Systemic effects

Long term exposure

Dose descriptor 

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

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 furfuryl alcohol after ingestion is 90% and after dermal exposure, is 100%.

_correctedDermal NOAEL = NOAEL_oralx [ABS_oral-rat/ABS_dermal-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 NOAEL
Quality of database	1	default; GLP-compliant guideline study; additional factor not appropriate for as furfural is the proximate metabolite
Overall AF	20

 

DNEL_{l-t dermal}     = 47.7 mg/kg bw/d / 20

= 2.4 mg/kg bw/d

 

Acute toxicity

The available acute dermal data, although regarded as sufficient for classification purposes, is not considered suitable for quantitative, DNEL determination. It is proposed that the long-term dermal DNEL for systemic effects is, by default, sufficiently protective for acute effects (see below).

Local effects

Long term exposure

No information is available to characterise the repeated local effects of furfuryl alcohol on the skin, while route-to-route extrapolation (respiratory tract to skin) is not appropriate. However, classification and labelling are designed to limit skin irritation will also protect against long term local skin effects.

Acute/short term exposure

Corrosive and irritant effects on the skin are local, concentration-dependent phenomena. No dose/response information can be derived from data available for furfuryl alcohol and a DNEL cannot therefore be determined.  It is proposed that furfuryl alcohol should be classified as irritating to skin hence appropriate RMM and OCs should be employed.

 

HAZARD VIA ORAL ROUTE

Systemic effects

Long term exposure

Dose descriptor 

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

 

Modification of dose descriptor

Adjustment for 90% absorption is proposed to 47.7 mg/kg bw/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

 

DNEL_{l-t oral}        = 47.7 mg/kg bwt/d / 20

                         = 2.4 mg/kg bw/d

 

Acute/short term exposure

In the absence of specific dose response information for acute oral toxicity, the DNEL_{l-t oral} will be used for the acute DNEL.

 

HAZARD FOR THE EYES

Local effects

Furfuryl alcohol is classified as an eye irritant (CLD Category 2 H319). No dose response information can be derived and therefore it is concluded to be of low hazard (ECHA Guidance on information requirements and chemical safety assessment Part E: Risk Characterisation).