Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 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
DNEL value:
88.2 mg/m³
Explanation for the modification of the dose descriptor starting point:
No dose descriptor for the inhalation route is available; therefore route to route extrapolation is used to convert the oral NOAEL. Detailed information is given in the discussion.
AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL, therefore the default assessment factor of 1 for a standard procedure is considered appropriate.
AF for differences in duration of exposure:
2
Justification:
Default factor for extrapolation sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
It is not necessary to apply an allometric scaling factor because the starting point has been corrected for differences in respiratory volume and this takes account of differences in metabolic rates.
AF for other interspecies differences:
2.5
Justification:
Due to the absence of toxicokinetic data an additional factor of 2.5 for other interspecies differences is applied according to TGD 8.
AF for intraspecies differences:
5
Justification:
The default factor of 5 for workers is used to take account of intraspecies variability.
AF for the quality of the whole database:
1
Justification:
The key studies were conducted according to modern regulatory standards and were adequately reported.
AF for remaining uncertainties:
1
Justification:
No additional AF was deemed necessary.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.5 mg/m³
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
Explanation for the modification of the dose descriptor starting point:
No dose descriptor for the inhalation route is available; therefore route to route extrapolation is used to convert the oral NOAEL. Detailed information is given in the discussion.

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 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
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No dose descriptor for the dermal route is available; therefore route to route extrapolation is used to convert the oral NOAEL. Detailed information is given in the discussion.
AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL, therefore the default assessment factor of 1 for a standard procedure is considered appropriate.
AF for differences in duration of exposure:
2
Justification:
Default factor for extrapolation sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
The starting point is an oral dose descriptor from a rat study. It is therefore necessary to include an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.
AF for other interspecies differences:
2.5
Justification:
Due to the absence of toxicokinetic data an additional factor of 2.5 for other interspecies differences is applied according to TGD 8.
AF for intraspecies differences:
5
Justification:
The default factor of 5 for workers is used to take account of intraspecies variability.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

General considerations

Acute toxicity

For Guanidine hydrochloride an acute toxicity hazard leading to a classification according to CLP (EU-GHS) Regulation (EC) No1272/2008 acute toxicity Category 4 for the oral and inhalation route has been identified. The findings from acute oral toxicity studies suggest that the Guanidine ion exhibits a primary effect on the central nervous / neuromuscular system. However, effects were observed in the range of classification Hazard Category 4, no clear NOAEL could be identified.

No hazard leading to classification was identified for dermal acute toxicity. 

 

Long-term data

Data relevant for long-term toxicity are available from an oral sub-chronic toxicity study and a developmental toxicity study, both in rats.

For Developmental toxicity a NOAEL of 350 mg/kg bw/day was established, no effects on prenatal data, litter data, foetal external, visceral, skeletal and craniofacial parameters were observed up to the highest dose level. Maternal toxicity was observed at 450 and 350 mg/kg bw/day based on mortality (450 mg/kg bw/day) and statistically significantly reduced body weight gain and food consumption. The NOAEL for maternal toxicity was 150 mg/kg bw/day.

A NOAEL of 100 mg/kg bw/day was derived from sub-chronic toxicity study, based on a nephropathy observed at 300 mg/kg bw/day. A (NOEL) could not be established, due to the local irritant effects of Guanidine hydrochloride in the glandular stomach of all dose groups.

Taken together the relevant dose descriptor used as starting point for DNEL derivation is the lowest NOAEL of 100 mg/kg bw/day.

 

Irritation/ corrosion

Based on the available in vivo data from a skin irritation study Guanidine hydrochloride is classified irritating to the skin (Category 2).

The substance is classified as irritating to the eye by legal binding classification. Respiratory irritation was not reported from an acute toxicity study by inhalation route.

 

Sensitization:

No skin sensitisation potential of Guanidine hydrochloride has been identified in a skin sensitisation study according to the Buehler method.

 

Genetic toxicity:

The results from gene mutation assays in bacteria and mammalian cells, as well as chromosome aberration in mammalian cells are consistently negative. Thus, there is no evidence for a genotoxic potential of Guanidine hydrochloride.

  

Allocated hazard category for qualitative assessment:  

The most critical effect of guanidine hydrochloride for the allocation of a hazard category to be used for qualitative assessment is the classification as skin and eye irritating with Hazard statements H315 “Causes skin irritation” and H319 “Causes serious eye irritation” according to CLP (EU-GHS) Regulation (EC) No 1272/2008. Hence the low hazard category has to be assigned according to TGD part E. 

 

Derivation of DNELs: 

DNELlong –term systemic inhalation

Route to route extrapolation oral to inhalation

Starting point: NOAEL (rat) of 100 mg/kg bw/day from sub-chronic toxicity study

 

For the derivation of a NOAEC for worker the following corrections have to be applied to the oral NOAEL (rat).

The oral NOAEL (rat) is multiplied with 1/0.38 m³/kg bw/8h (default respiratory volume in rat, table R.8.2 of CSR guidance) to give the corresponding rat inhalation 8h-NOAEC (no-observed adverse effect concentration).

 

To obtain the starting point for workers, a factor of 0.67 is applied to the NOAEC to account for the differences in inhalation rates between animals at rest and humans involved in light activity.

Due to the absence of route specific information a default factor of 2 is included by assuming 50 % for oral absorption (ABS oral-rat) and 100 % absorption after inhalation (ABS inh-human).

For workers the corrected inhalation NOAEC is calculated according to the following equation:

corrected inhalation NOAEC = oral NOAEL x 1/sRVratx ABSoral-rat/ ABSinh-humanx sRVhuman/ wRV1

= 100 x 1/0.38 x 50/100 x 6.7/10

 

The corrected inhalation NOAECworker(8h) is therefore:

= 88.2 mg/m3(8h-TWA)

  

DNELshort –term systemic inhalation

For guanidine hydrochloride an acute toxicity hazard leading to a classification according to CLP (EU-GHS) Regulation (EC) No1272/2008 acute toxicity Category 4 for the inhalation route has been identified. However, a reliable dose descriptor for acute systemic effects could not be derived from the available inhalation studies.

High peak exposure cannot be entirely excluded as guanidine hydrochloride is a solid and particle size distribution value D10 is 48.08 µm and D50 value is 139.26 µm. According to the definition of EN 481 particles of≤100 µm belong to the inhalable fraction.

Considering high peak exposure the DNEL for acute toxicity was set for a reference period of 15 minutes at 3 times the value (default 3) of the long-term DNEL. This approach is appropriate because similar mechanisms of actions are probably involved in the responses to single and repeated exposure (TGD R8). 

 

DNELlong –term systemic dermal

Route to route extrapolation oral to dermal

Starting point: NOAEL (rat) of 100 mg/kg bw/day from sub-chronic toxicity study

 

No toxicokinetic studies are available for guanidine hydrochloride. Guanidine hydrochloride is soluble in water and has a log P value of -1.7, therefore absorption has to be expected. After oral exposure signs of systemic toxicity including death were observed in acute toxicity studies, thus absorption of guanidine hydrochloride has occurred. As a consequence it is likely that the substance will also be absorbed if inhaled. This assumption is supported by data from an acute inhalation toxicity study, were systemic effects and death were observed.

As data from a dermal acute toxicity study show no systemic effects at the limit dose of 2000 mg/kg bw/d, guanidine hydrochloride is expected to be not favourable for dermal absorption. The stratum corneum provides its greatest barrier function against hydrophilic compounds. If water solubility is above 10,000 mg/L and the log P value below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for guanidine hydrochloride is considered to be low, due to the water solubility of 2150 g/L and the log P value of -1.7.

Based on these findings and as a worst case assumption the dermal NOAEL is determined to be equal to the oral NOAEL.

Thus no additional assessment factor deemed necessary for oral-to-dermal extrapolation.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.87 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
DNEL value:
43.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
No dose descriptor for the inhalation route is available; therefore route to route extrapolation is used to convert the oral NOAEL. Detailed information is given in the discussion.
AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL, therefore the default assessment factor of 1 for a standard procedure is considered appropriate.
AF for differences in duration of exposure:
2
Justification:
Default factor for extrapolation sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
It is not necessary to apply an allometric scaling factor because the starting point has been corrected for differences in respiratory volume and this takes account of differences in metabolic rates.
AF for other interspecies differences:
2.5
Justification:
Due to the absence of toxicokinetic data an additional factor of 2.5 for other interspecies differences is applied according to TGD 8.
AF for intraspecies differences:
10
Justification:
The default factor of 10 for general population is used to take account of intraspecies variability.
AF for the quality of the whole database:
1
Justification:
The key studies were conducted according to modern regulatory standards and were adequately reported.
AF for remaining uncertainties:
1
Justification:
No additional AF was deemed necessary.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No dose descriptor for the dermal route is available; therefore route to route extrapolation is used to convert the oral NOAEL. Detailed information is given in the discussion.
AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL, therefore the default assessment factor of 1 for a standard procedure is considered appropriate.
AF for differences in duration of exposure:
2
Justification:
Default factor for extrapolation sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
The starting point is an oral dose descriptor from a rat study. It is therefore necessary to include an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.
AF for other interspecies differences:
2.5
Justification:
Due to the absence of toxicokinetic data an additional factor of 2.5 for other interspecies differences is applied according to TGD 8.
AF for intraspecies differences:
10
Justification:
The default factor of 10 for general population is used to take account of intraspecies variability.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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:
0.5 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL, therefore the default assessment factor of 1 for a standard procedure is considered appropriate.
AF for differences in duration of exposure:
2
Justification:
Default factor for extrapolation sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
The starting point is an oral dose descriptor from a rat study. It is therefore necessary to include an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.
AF for other interspecies differences:
2.5
Justification:
Due to the absence of toxicokinetic data an additional factor of 2.5 for other interspecies differences is applied according to TGD 8.
AF for intraspecies differences:
10
Justification:
The default factor of 10 for general population is used to take account of intraspecies variability.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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

General considerations

Acute toxicity

For Guanidine hydrochloride an acute toxicity hazard leading to a classification according to CLP (EU-GHS) Regulation (EC) No1272/2008 acute toxicity Category 4 for the oral and inhalation route has been identified. The findings from acute oral toxicity studies suggest that the Guanidine ion exhibits a primary effect on the central nervous / neuromuscular system. However, effects were observed in the range of classification Hazard Category 4, no clear NOAEL could be identified.

No hazard leading to classification was identified for dermal acute toxicity. 

 

Long-term data

Data relevant for long-term toxicity are available from an oral sub-chronic toxicity study and a developmental toxicity study, both in rats.

For Developmental toxicity a NOAEL of 350 mg/kg bw/day was established, no effects on prenatal data, litter data, foetal external, visceral, skeletal and craniofacial parameters were observed up to the highest dose level. Maternal toxicity was observed at 450 and 350 mg/kg bw/day based on mortality (450 mg/kg bw/day) and statistically significantly reduced body weight gain and food consumption. The NOAEL for maternal toxicity was 150 mg/kg bw/day.

A NOAEL of 100 mg/kg bw/day was derived from sub-chronic toxicity study, based on a nephropathy observed at 300 mg/kg bw/day. A (NOEL) could not be established, due to the local irritant effects of Guanidine hydrochloride in the glandular stomach of all dose groups.

Taken together the relevant dose descriptor used as starting point for DNEL derivation is the lowest NOAEL of 100 mg/kg bw/day.

 

Irritation/ corrosion

Based on the available in vivo data from a skin irritation study Guanidine hydrochloride is classified irritating to the skin (Category 2).

The substance is classified as irritating to the eye by legal binding classification. Respiratory irritation was not reported from an acute toxicity study by inhalation route.

 

Sensitization:

No skin sensitisation potential of Guanidine hydrochloride has been identified in a skin sensitisation study according to the Buehler method.

 

Genetic toxicity:

The results from gene mutation assays in bacteria and mammalian cells, as well as chromosome aberration in mammalian cells are consistently negative. Thus, there is no evidence for a genotoxic potential of Guanidine hydrochloride.

  

Allocated hazard category for qualitative assessment:  

The most critical effect of guanidine hydrochloride for the allocation of a hazard category to be used for qualitative assessment is the classification as skin and eye irritating with Hazard statements H315 “Causes skin irritation” and H319 “Causes serious eye irritation” according to CLP (EU-GHS) Regulation (EC) No 1272/2008. Hence the low hazard category has to be assigned according to TGD part E.  

 

DNELlong –term systemic inhalation

Route to route extrapolation oral to inhalation

Starting point: NOAEL (rat) of 100 mg/kg bw/day from sub-chronic toxicity study

 

For the derivation of a NOAEC for the general population the following corrections have to be applied to the oral NOAEL (rat). Due to the absence of route specific information a default factor of 2 is included by assuming 50 % for oral absorption (ABS oral-rat) and 100 % absorption after inhalation (ABS inh-human).

For general population in case of 24h exposure/d the corrected inhalation NOAEC is calculated according to the following equation:

 

corrected inhalation NOAEC = oral NOAEL x 1/sRVrat1 x ABSoral-rat/ ABSinh-human

= 100 x 1/1.15 x 50/100

 

The corrected inhalation NOAECgeneral population(24h) is therefore:

= 43.5 mg/m3

 

 

DNELlong –term systemic dermal

Route to route extrapolation oral to dermal

Starting point: NOAEL (rat) of 100 mg/kg bw/day from sub-chronic toxicity study

  

No toxicokinetic studies are available for guanidine hydrochloride. Guanidine hydrochloride is soluble in water and has a log P value of -1.7, therefore absorption has to be expected. After oral exposure signs of systemic toxicity including death were observed in acute toxicity studies, thus absorption of guanidine hydrochloride has occurred. As a consequence it is likely that the substance will also be absorbed if inhaled. This assumption is supported by data from an acute inhalation toxicity study, were systemic effects and death were observed.

As data from a dermal acute toxicity study show no systemic effects at the limit dose of 2000 mg/kg bw/d, guanidine hydrochloride is expected to be not favourable for dermal absorption. The stratum corneum provides its greatest barrier function against hydrophilic compounds. If water solubility is above 10,000 mg/L and the log P value below 0 the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for guanidine hydrochloride is considered to be low, due to the water solubility of 2150 g/L and the log P value of -1.7.

Based on these findings and as a worst case assumption the dermal NOAEL is determined to be equal to the oral NOAEL.

Thus no additional assessment factor deemed necessary for oral-to-dermal extrapolation.