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:
3.31 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
Modified dose descriptor starting point:
NOAEC
Value:
82.9 mg/m³
Explanation for the modification of the dose descriptor starting point:
8 h exposure time, extrapolation from 50 % bioavailability oral to 100 % bioavailability inhalation, no inhalation study available
AF for dose response relationship:
1
Justification:
not required, starting point is NOAEL
AF for differences in duration of exposure:
2
Justification:
extrapolation from sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
allometric scaling is already applied in route-to-route extrapolation
AF for other interspecies differences:
2.5
Justification:
default factor for remaining differences
AF for intraspecies differences:
5
Justification:
default factor for worker
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.93 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):
8.33
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEC
Value:
82.9 mg/m³
Explanation for the modification of the dose descriptor starting point:
15 min. exposure time, extrapolation from DNEL systemic long term based on Haber's law.

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.88 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
Modified dose descriptor starting point:
NOAEL
Value:
188 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
extrapolation from 50 % bioavailability oral to 25 % bioavailability dermal, no dermal study available
AF for dose response relationship:
1
Justification:
starting point is NOAEL
AF for differences in duration of exposure:
2
Justification:
Extrapolation from subchornic to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
allometric scaling factor rat-human
AF for other interspecies differences:
2.5
Justification:
default factor for remaining differences
AF for intraspecies differences:
5
Justification:
default for worker
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

As Guanidine is the major component for systemic toxicity, the fractions of carbonate and chloride are not taken into account. Based on the molecular weight, following conversion factor is derived to extrapolate NOAELs from Guanidine chloride to Guanidine carbonate:

-       Fraction of Guanidine in Guanidine carbonate = (2 x59.0715)/180.167 = 0.66.

-       Fraction of Guanidine in Guanidine chloride =59.0715/95.5324= 0.62

-       Conversion factor from Guanidine chloride to Guanidine carbonate = 0.62/0.66 =0.94.

For the subchronic oral NOAEL, following corrections are therefore applied:

-       NOAEL systemic: 100 mg/kg x 0.94 = 94 mg/kg

For the modification of systemic long term NOAELs, following absorption rates are applied :

-       Inhalation: 100 % (worst case assumption)

-       Oral: 50% (this can be considered as a conservative value, based on the comparison between the LD50subcutaneous versus oral in rats for Guanidine, which is at least 3 times lower); currently in the dossier 50% absorption after oral application was described.

-       Dermal: 25% (this can be considered as a conservative value, based on the comparison between the LD50oral versus dermal in rats for Guanidine carbonate and Guanidine chloride, which is at least 2 times lower).

For theroute-to-route extrapolation, following modifications are therefore proposed based on the above differences in absorption:

-       For inhalation long term DNELS: oral NOAEL :2

-       For dermal long term DNELS: oral NOAEL x2

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.82 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
Modified dose descriptor starting point:
NOAEC
Value:
40.9 mg/m³
Explanation for the modification of the dose descriptor starting point:
8 h exposure time, extrapolation from 50 % bioavailability oral to 100 % bioavailability inhalation, no inhalation study available
AF for dose response relationship:
1
Justification:
not required, starting point is NOAEL
AF for differences in duration of exposure:
2
Justification:
extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
allometric scaling is already applied in route-to-route extrapolation
AF for other interspecies differences:
2.5
Justification:
default factor for remaining differences
AF for intraspecies differences:
10
Justification:
default factor for the general population
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.46 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):
16.7
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEC
Value:
40.9 mg/m³
Explanation for the modification of the dose descriptor starting point:
15 min. exposure time, extrapolation from DNEL systemic long term based on Haber's law.

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.94 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
Modified dose descriptor starting point:
NOAEL
Value:
188 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
extrapolation from 50 % bioavailability oral to 25 % bioavailability dermal, no dermal study available
AF for dose response relationship:
1
Justification:
not required, starting point is NOAEL
AF for differences in duration of exposure:
2
Justification:
Extrapolation from subchronic to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
default factor rat-human
AF for other interspecies differences:
2.5
Justification:
default factor for remaining differences
AF for intraspecies differences:
10
Justification:
default factor for general population
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

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):
200
Modified dose descriptor starting point:
NOAEL
Value:
94 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route to route extrapolation required
AF for dose response relationship:
1
Justification:
not required
AF for differences in duration of exposure:
2
Justification:
Extrapolation from subchronic to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
default factor rat-human
AF for other interspecies differences:
2.5
Justification:
default factor for remaining differences
AF for intraspecies differences:
10
Justification:
default factor general population
AF for the quality of the whole database:
1
Justification:
not required
AF for remaining uncertainties:
1
Justification:
not required
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.41 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):
66.7
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEL
Value:
94 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
extrapolation from DNEL systemic long term based on Haber's law.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

As Guanidine is the major component for systemic toxicity, the fractions of carbonate and chloride are not taken into account. Based on the molecular weight, following conversion factor is derived to extrapolate NOAELs from Guanidine chloride to Guanidine carbonate:

-       Fraction of Guanidine in Guanidine carbonate = (2 x59.0715)/180.167 = 0.66.

-       Fraction of Guanidine in Guanidine chloride =59.0715/95.5324= 0.62

-       Conversion factor from Guanidine chloride to Guanidine carbonate = 0.62/0.66 =0.94.

For the subchronic oral NOAEL, following corrections are therefore applied:

-       NOAEL systemic: 100 mg/kg x 0.94 = 94 mg/kg

For the modification of systemic long term NOAELs, following absorption rates are applied :

-       Inhalation: 100 % (worst case assumption)

-       Oral: 50% (this can be considered as a conservative value, based on the comparison between the LD50subcutaneous versus oral in rats for Guanidine, which is at least 3 times lower); currently in the dossier 50% absorption after oral application was described.

-       Dermal: 25% (this can be considered as a conservative value, based on the comparison between the LD50oral versus dermal in rats for Guanidine carbonate and Guanidine chloride, which is at least 2 times lower).

For theroute-to-route extrapolation, following modifications are therefore proposed based on the above differences in absorption:

-       For inhalation long term DNELS: oral NOAEL :2

-       For dermal long term DNELS: oral NOAEL x2