Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
44.43 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
Value:
450 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 110.79 mg/m³
Explanation for the modification of the dose descriptor starting point:

 This DNEL was derived using the NOAEL for systemic effects of 450 mg/kg/day from the 90-day repeated toxicity study by oral route (CIT 1999), after a route to route extrapolation (oral-to-inhalation) and after correction for difference in exposure conditions and between respiratory rates under standard conditions and under conditions of light activity (1/0.38 m3/kg x 7d/5d x 6.7 m3/10 m3).  


The absorption by inhalation is expected to be of the same order than the absorption by oral route (see section 7.1).


Modified NOAEC= 450x1/0.38 m3/kg x 7d/5d x 6.7 m3/10m3=1110.79 mg/m3


DNEL =1110.79/25=44.43 mg/m3 

AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEC.
AF for differences in duration of exposure:
2
Justification:
DNEL is based on a subchronic study (90-day).
AF for interspecies differences (allometric scaling):
1
Justification:
not needed for an inhalation DNEL
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining differences.
AF for intraspecies differences:
5
Justification:
A factor of 5 is applied for worker DNELs.
AF for the quality of the whole database:
1
Justification:
The key study chosen for DNEL calculation is considered as a reliable study.
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
49 mg/m³
DNEL related information
DNEL derivation method:
other: German MAK value
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
98 mg/m³
DNEL related information
DNEL derivation method:
other: German MAK value

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
63 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:
450 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
6 300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

 This DNEL was derived using the NOAEL for systemic effects of 450 mg/kg/day from a OECD 408 (CIT 1999), after a route to route extrapolation (oral-to-dermal) and after correction for difference in absorption and in exposure conditions (50%/5% x 7d/5d). The oral and dermal absorptions are estimated to be 50% and 5% respectively.


Corrected NOAEL= 450 x(50/5)x 1,4= 6300 mg/kg/j


DNEL = 6300/100 = 63 mg/kg/j

AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEL.
AF for differences in duration of exposure:
2
Justification:
DNEL is based on a subchronic study (90-day).
AF for interspecies differences (allometric scaling):
4
Justification:
An allometric scaling factor of 4 must be applied because the key study was performed on rats.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining differences.
AF for intraspecies differences:
5
Justification:
A factor of 5 is applied for worker DNELs.
AF for the quality of the whole database:
1
Justification:
The key study chosen for DNEL calculation is considered as a reliable study.
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Justification of Point of departure


DNELs were calculated based on two studies :


-the 90-day repeated toxicity study (OECD 408) with a NOAEL for systemic effects of 450 mg/kg/day,


-the extended one generation reproduction toxicity study (OECD 443) with a NOAEL for development toxicity of 250 mg/kg/day (pups mortality).*


The DNELs based on the 90-day repeated toxicity study were selected for risk assessment because there are lower values than the DNELs derived from the OECD 443 study.


*Assessment factors used for DNELs based on reproduction effects (OECD 443 study) :


AF for dose response relationship: 1 (based on a NOAEL)


AF for differences in duration of exposure : 1  ("A lower factor (minimum 1) may for instance be used if there is specific evidence that increasing exposure duration does not increase the incidence or severity of adverse effects." ECHA guidance R8, 2012, page 29)


AF for interspecies differences (allometric scaling): 4 (based on rat study)


AF for other interspecies differences: 2.5 (default factor)


AF for intraspecies differences: 5 (default factor for workers DNELs)


AF for the quality of the whole database: 1 (sufficient database)


AF for remaining uncertainties : 1 (not needed)


 


Explanation of DNELs (local effects)


Occupational exposure limits (8-h time weighted average) of 10 ppm (49 mg/m3) have been adopted in Austria and Germany (DFG) or of 25 ppm (125 mg/m3) in Belgium, Denmark and Great Britain. Short-term OEL of 10 ppm is in force in Austria, of 20 ppm in Germany (DFG) and of 25 ppm in Denmark, France, Spain, Sweden and UK.


The scientific background for setting the OEL (MAK value) of 10 ppm by Germany (DFG) has been published in “Occupational toxicants, Critical data evaluation for MAK values and classification of carcinogens, volume 16, pp 233-246, WILEY-VCH Ed. ”. The rational to set the MAK value was summarized as followed:


“Carcinogenicity studies with hexylene glycol are not available. However, the genotoxicity studies provide no evidence of a carcinogenic potential. In animal studies of limited validity, 40 mg/kg body weight and day was found to be the NOEL for systemic toxicity after oral administration of the substance. The critical effect of hexylene glycol, however, is the eye irritation, which was observed in animals treated with the undiluted substance. Hexylene glycol does not seem to be a very powerful eye irritant as 25 % solutions were not irritating. In an early study, eye irritation developed in most of the 12 male and female test persons exposed for 15 minutes to hexylene glycol vapour in a concentration of 50 ppm (approximately equivalent to the saturation concentration at 25°C). No NOEL was determined in this study. The eye irritation seems not to have been very severe, a fact which is also suggested by the steepness of the dose-response curve seen in the Draize test data. The MAK value was established provisionally at 10 ml/m3. Because the eye irritation was not severe, for the restriction of exposure peaks hexylene glycol was classified in Peak limitation category I with an excursion factor of 2. Then, even during the permissible peak concentrations up to 20 ml/m3, no marked irritation is expected. Because of the lack of adequate data for the irritant potential of hexylene glycol, the MAK value must be considered provisional and requires confirmation in further studies. Assuming that 100 % of the inhaled substance is absorbed, exposure to concentrations in the range of the MAK value could result in a daily dose of 7.5 mg/kg body weight which is still below the NOEL determined in animal studies with oral administration, assuming 100 % absorption here too. As there are no reproductive toxicity studies, hexylene glycol is listed in Section II of the List of MAK and BAT Values. The sensitizing potential is low and so the substance is not designated with an "Sh". The solubility of the substance suggests that it would be readily absorbed through the skin, but as the toxicity after repeated dermal application to experimental animals is low, the substance is not designated with an "H"”.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.83 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Value:
450 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
391.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

This DNEL was derived using the NOAEL for systemic effects of 450 mg/kg/day from a OECD 408 in rats conducted by gavage route (CIT 1999), after a route to route extrapolation (oral-to-inhalation x 1/1.15 m3/kg). The absorption by inhalation is expected to be of the same order than the absorption by oral route. 


NOAEC = 450x 1/1.15=450x0,86=391.3 mg/m3


DNEL = 391.3 /50= 7.83 mg/m3 

AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEC.
AF for differences in duration of exposure:
2
Justification:
DNEL is based on a subchronic study (90-day).
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation. Allometric scaling is implicitly taken into account in the factor for remaining differences.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining differences.
AF for intraspecies differences:
10
Justification:
A factor of 10 is applied for the general population DNELs.
AF for the quality of the whole database:
1
Justification:
The key study chosen for DNEL calculation is considered as a reliable study.
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
25 mg/m³
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor:
LOAEC
AF for dose response relationship:
2
Justification:
The eye irritation seems not to have been very severe
AF for differences in duration of exposure:
1
Justification:
not needed for a local effect
AF for interspecies differences (allometric scaling):
1
Justification:
not needed for a local effect
AF for other interspecies differences:
1
Justification:
not needed for a local effect
AF for intraspecies differences:
5
Justification:
sufficient for a local effect
AF for the quality of the whole database:
1
Justification:
not needed
AF for remaining uncertainties:
1
Justification:
not needed
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
49 mg/m³
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor starting point:
LOAEC
AF for intraspecies differences:
5
Justification:
for intraspecies differences and extrapolation of NOAEL

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
22.5 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):
200
Dose descriptor starting point:
NOAEL
Value:
450 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
4 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

 This DNEL was derived using the NOAEL of 450 mg/kg/day from a OECD 408 oral toxicity study in rats (CIT 1999), after a route to route extrapolation (oral-to-dermal, x 50%/5%). The oral and dermal absorptions are estimated to be 50 and 5% respectively. 


Corrected NOAEL= 450x (0/5)= 4500 mg/kg/j


DNEL = 4500/200=22.5 mg/kg/day 

AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEL.
AF for differences in duration of exposure:
2
Justification:
DNEL is based on a subchronic study (90-day).
AF for interspecies differences (allometric scaling):
4
Justification:
An allometric scaling factor of 4 must be applied because the key study was performed on rats.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining differences.
AF for intraspecies differences:
10
Justification:
A factor of 10 is applied for the general population DNELs.
AF for the quality of the whole database:
1
Justification:
The key study chosen for DNEL calculation is considered as a reliable study.
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.25 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):
200
Dose descriptor starting point:
NOAEL
Value:
450 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
450 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

This DNEL was derived using the NOAEL for systemic effects of 450 mg/kg/day from the OECD 408 oral toxicity study in rats (CIT 1999).

AF for dose response relationship:
1
Justification:
This factor is applied because the dose-descriptor starting point is a NOAEL.
AF for differences in duration of exposure:
2
Justification:
DNEL is based on a subchronic study (90-day).
AF for interspecies differences (allometric scaling):
4
Justification:
An allometric scaling factor of 4 must be applied because the key study was performed on rats.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is applied for remaining differences.
AF for intraspecies differences:
10
Justification:
A factor of 10 is applied for the general population DNELs.
AF for the quality of the whole database:
1
Justification:
The key study chosen for DNEL calculation is considered as a reliable study.
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Justification of Point of departure


DNELs were calculated based on two studies :


-the 90-day repeated toxicity study (OECD 408) with a NOAEL for systemic effects of 450 mg/kg/day,


-the extended one generation reproduction toxicity study (OECD 443) with a NOAEL for development toxicity of 250 mg/kg/day (pups mortality).*


The DNELs based on the 90-day repeated toxicity study were selected for risk assessment because there are lower values than the DNELs derived from the OECD 443 study.


*Assessment factors used for DNELs based on reproduction effects (OECD 443 study) :


AF for dose response relationship: 1 (based on a NOAEL)


AF for differences in duration of exposure : 1  ("A lower factor (minimum 1) may for instance be used if there is specific evidence that increasing exposure duration does not increase the incidence or severity of adverse effects." ECHA guidance R8, 2012, page 29)


AF for interspecies differences (allometric scaling): 4 (based on rat study)


AF for other interspecies differences: 2.5 (default factor)


AF for intraspecies differences: 10 (default factor for general population DNELs)


AF for the quality of the whole database: 1 (sufficient database)


AF for remaining uncertainties : 1 (not needed)