Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.26 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
37.5
Dose descriptor starting point:
NOAEC
Value:
320 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
160 mg/m³
Explanation for the modification of the dose descriptor starting point:

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

AF for dose response relationship:
1
Justification:
default, clear NOAEC
AF for differences in duration of exposure:
3
Justification:
Normally a factor 6 is applied for extrapolation from a subacute (28 days) 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. The results of the oral subchronic and chronic study in hamsters, show no effect of exposure duration on the NOAEL and the effects observed.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling is applicable when setting an inhalation DNEL based on an inhalation animal study
AF for other interspecies differences:
2.5
Justification:
default AF
AF for intraspecies differences:
5
Justification:
default AF for workers
AF for the quality of the whole database:
1
Justification:
default, GLP compliant guideline study;
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
36.48 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):
25
Dose descriptor starting point:
NOAEC
Value:
540 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
912 mg/m³
Explanation for the modification of the dose descriptor starting point:

The acute inhalation NOAEC (mortality) of furfural 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=4)3x 4      = (Ct=0.25)3x 0.25

(Ct=0.25)3      = (362)3x 16

Ct=0.25           = 912 mg/m3

AF for dose response relationship:
2
Justification:
NOAEC from an acute study
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling is applicable when setting an inhalation DNEL based on an inhalation animal study
AF for other interspecies differences:
2.5
Justification:
default AF for workers
AF for intraspecies differences:
5
Justification:
default AF for workers
AF for the quality of the whole database:
1
Justification:
recent GLP study

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
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor:
NOAEC
Value:
8 mg/m³
AF for dose response relationship:
1
Justification:
Dose response clearly demonstrated in 28d study (Staal et al, 2018) , and clear NOAEL identified.
AF for differences in duration of exposure:
1
Justification:
local effect not relevant
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling is applicable when setting an inhalation DNEL based on an inhalation animal study.
AF for other interspecies differences:
1
Justification:
The AF of 1 is based on local irritant property, induced by an elevated concentration of furfural, with little difference in toxicodynamic/ toxicokinetic effect across species.

Supporting this position is that there is comparability of effects between golden Syrian hamsters and rats following inhalation exposure, where no differences in response to local effects of inhalation of furfural were seen (Feron 1984).

A residual AF of 2.5 is not applicable since furfural induces a direct physical effect at the site of entry, an effect expected to occur in all exposed species when a threshold exposure concentration is exceeded, and this is supported by the fact that there are no adverse effects reported in the lower respiratory tract/lungs in any inhalation studies conducted.

Correction for differing respiratory rates is not applicable for local irritant effects in the nasal cavity.
AF for intraspecies differences:
1
Justification:
Local irritant property induced by an elevated concentration of furfural with no differences in toxicodynamic/ toxicokinetic effect between/within species.
AF for the quality of the whole database:
1
Justification:
default AF
AF for remaining uncertainties:
1
Justification:
Data from the 28d sub-acute inhalation toxicity study with furfural in rats (Staal et al, 2008) confirms the NOAEL as 8 mg/m3 for the purposes of risk assessment.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
24 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.66 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
AF for dose response relationship:
1
Justification:
default AF, clear NOAEL
AF for differences in duration of exposure:
3
Justification:
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, the results of the oral subchronic and chronic study in hamsters, show no effect of exposure duration on the NOAEL and the effects observed.
AF for interspecies differences (allometric scaling):
4
Justification:
default AF
AF for other interspecies differences:
2.5
Justification:
default AF
AF for intraspecies differences:
5
Justification:
default AF for workers
AF for the quality of the whole database:
1
Justification:
default, GLP compliant study
AF for remaining uncertainties:
1
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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.067 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
NOAEC
Value:
320 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
80 mg/m³
Explanation for the modification of the dose descriptor starting point:

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.

Taking the NOAEC based on the EC RAR (2008) conclusion and as included in the current REACH dossier, this is 320 mg/m3

The DNEL calculation is as follows:

Correcting the rat inhalation NOAEC for duration of exposure:

NOAECinhalation  =320 x [6/24]

                      = 80 mg/m3

AF for dose response relationship:
1
Justification:
default
AF for differences in duration of exposure:
3
Justification:
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.)(in accordance to the conclusion of RAR 2008)
AF for interspecies differences (allometric scaling):
1
Justification:
no allometric scaling is applicable when setting an inhalation DNEL based on an inhalation animal study
AF for other interspecies differences:
2.5
Justification:
default AF
AF for intraspecies differences:
10
Justification:
default AF for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
27.22 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):
50
Dose descriptor starting point:
NOAEC
Value:
540 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
1 361 mg/m³
Explanation for the modification of the dose descriptor starting point:

NOAEC acute inhalation toxicity 540 mg/m3

Adjusted for duration only applyingd Habers law to derive 15 min exp;  (1361 mg/m3).

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

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

Ct=0.25                         = 1361 mg/m3

AF for dose response relationship:
2
Justification:
NOAEC from an acute study
AF for interspecies differences (allometric scaling):
1
Justification:
no allometric scaling is applicable when setting an inhalation DNEL based on an inhalation animal study
AF for other interspecies differences:
2.5
Justification:
default AF
AF for intraspecies differences:
10
Justification:
default AF for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

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
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor:
NOAEC
Value:
8 mg/m³
AF for dose response relationship:
1
Justification:
Dose response clearly demonstrated in 28d study (Staal et al, 2018) , and clear NOAEL identified.
AF for differences in duration of exposure:
1
Justification:
local effect not relevant
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling is applicable when setting an inhalation DNEL based on an inhalation animal
study.
AF for other interspecies differences:
1
Justification:
The AF of 1 is based on local irritant property, induced by an elevated concentration of furfural, with
little difference in toxicodynamic/ toxicokinetic effect across species.
Supporting this position is that there is comparability of effects between golden Syrian hamsters and
rats following inhalation exposure, where no differences in response to local effects of inhalation of
furfural were seen (Feron 1984).
A residual AF of 2.5 is not applicable since furfural induces a direct physical effect at the site of e
ntry, an effect expected to occur in all exposed species when a threshold exposure concentration is
exceeded, and this is supported by the fact that there are no adverse effects reported in the lower
respiratory tract/lungs in any inhalation studies conducted.
Correction for differing respiratory rates is not applicable for local irritant effects in the nasal cavity.
AF for intraspecies differences:
1
Justification:
Local irritant property induced by an elevated concentration of furfural with no differences in toxi
codynamic/ toxicokinetic effect between/within species.
AF for the quality of the whole database:
1
Justification:
default AF
AF for remaining uncertainties:
1
Justification:
Data from the 28d sub-acute inhalation toxicity study with furfural in rats (Staal et al, 2008) confirms
the NOAEL as 8 mg/m3 for the purposes of risk assessment.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
24 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
AF for dose response relationship:
1
Justification:
default AF, clear NOAEL
AF for differences in duration of exposure:
3
Justification:
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, the results of the oral subchronic and chronic study in hamsters, show no effect of exposure duration on the NOAEL and the effects observed.
AF for interspecies differences (allometric scaling):
4
Justification:
default AF
AF for other interspecies differences:
2.5
Justification:
default AF
AF for intraspecies differences:
10
Justification:
default AF for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
0.47 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
53 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
47.7 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

NOAEL for systemic effects was 53 mg/kg bw/d in the rat. (90% intake)

correctedOral NOAEL = NOAELoralx [ABSoral-rat]

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

AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
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 general population (EC RAR, 2008) )
AF for interspecies differences (allometric scaling):
4
Justification:
default AF
AF for other interspecies differences:
2.5
Justification:
default AF
AF for intraspecies differences:
10
Justification:
default AF for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.47 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population