Guanidinium thiocyanate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.092 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:

31 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

27.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

Reflecting differences in molecular weight between the source substance Ammonium thiocyanate and the target substance Guanidine Thiocyanate a factor of 1.55 was applied to the NOAEL 20 mg/kg bw/d obtained from a sub-chronic toxicity study with Ammonium Thiocyanate resulting in a NOAEL of 31 mg/kg bw/d, which is used for derivation of Guanidine Thiocyanate DNELs.

Route to route extrapolation oral to inhalation

Starting point: NOAEL (rat) of 31 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

= 31 x 1/0.38 x 50/100 x 6.7/10

The corrected inhalation NOAECworker(8h) is therefore:

= 27.3 mg/m³(8h-TWA)

The applied total assessment factor is 25. The relevant dose descriptor, NOAEC of 27.3 mg/m³ (8h-TWA) was calculated by route-to-route extrapolation from the derived NOAEL of 31 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):

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 is deemed necessary.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.28 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:

Considering high peak exposure the DNEL for acute inhalation 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). 

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.31 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:

31 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

31 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The dermal NOAEL is determined to be equal to the oral NOAEL. Based on the assumption, that dermal absorption will not be higher than oral absorption, no additional assessment factor deemed necessary for oral-to-dermal extrapolation.

Reflecting differences in molecular weight between the source substance Ammonium thiocyanate and the target substance Guanidine Thiocyanate a factor of 1.55 was applied to the NOAEL 20 mg/kg bw/d obtained from a sub-chronic toxicity study with Ammonium Thiocyanate resulting in a NOAEL of 31 mg/kg bw/d, which is used for derivation of Guanidine Thiocyanate DNELs.

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 studies were conducted according to modern regulatory standards and were adequately reported.

AF for remaining uncertainties:

1

Justification:

No additional AF is deemed necessary.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

According to harmonised classification and labelling for salts of thiocyanic acid, (status 2016-09-09, ECHA homepage, https://echa.europa.eu/information-on-chemicals/annex-vi-to-clp) Guanidine Thiocyanate has to be classified for acute toxicity Category 4 for all routes.

According to TGD part E no hazard category has to be allocated to substances classified in category 4 for acute toxicity, therefore “no hazard identified” was chosen.

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.27 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:

31 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

13.48 mg/m³

Explanation for the modification of the dose descriptor starting point:

Reflecting differences in molecular weight between the source substance Ammonium thiocyanate and the target substance Guanidine Thiocyanate a factor of 1.55 was applied to the NOAEL 20 mg/kg bw/d obtained from a sub-chronic toxicity study with Ammonium Thiocyanate resulting in a NOAEL of 31 mg/kg bw/d, which is used for derivation of Guanidine Thiocyanate DNELs.

To assess consumer inhalation exposure, the oral NOAEL (rat) is multiplied with 1/1.15 m³/kg bw (Table R.8.2 of CSR guidance) to give the corresponding 24h-NOAEC (no-observed adverse effect concentration). 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 consumers the corrected inhalation NOAEC is calculated according to the following equation:

corrected inhalation NOAEC = oral NOAEL x 1/sRV rat x ABS oral-rat/ ABS inh-rat x ABS oral-human/ ABS inh-human

= 31 x 1/1.15 x50/100

The corrected inhalation NOAEC consumer (24h) is therefore:

= 13.48 mg/m³(24-h)

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 consumers is used to take account of intraspecies variability.

AF for the quality of the whole database:

1

Justification:

The key studies were conducted to modern regulatory standards and were adequately reported.

AF for remaining uncertainties:

1

Justification:

No additional AF is deemed necessary.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.155 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:

31 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The dermal NOAEL is determined to be equal to the oral NOAEL. Based on the assumption, that dermal absorption will not be higher than oral absorption, no additional assessment factor deemed necessary for oral-to-dermal extrapolation.

Reflecting differences in molecular weight between the source substance Ammonium thiocyanate and the target substance Guanidine Thiocyanate a factor of 1.55 was applied to the NOAEL 20 mg/kg bw/d obtained from a sub-chronic toxicity study with Ammonium Thiocyanate resulting in a NOAEL of 31 mg/kg bw/d, which is used for derivation of Guanidine Thiocyanate DNELs.

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 consumers will be used to take account of intraspecies variability.

AF for the quality of the whole database:

1

Justification:

The key studies were conducted 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:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

According to harmonised classification and labelling for salts of thiocyanic acid, (status 2016-09-09, ECHA homepage, https://echa.europa.eu/information-on-chemicals/annex-vi-to-clp) Guanidine Thiocyanate has to be classified for acute toxicity Category 4 for all routes.

According to TGD part E no hazard category has to be allocated to substances classified in category 4 for acute toxicity, therefore “no hazard identified” was chosen.

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.155 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:

31 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Reflecting differences in molecular weight between the source substance Ammonium thiocyanate and the target substance Guanidine Thiocyanate a factor of 1.55 was applied to the NOAEL 20 mg/kg bw/d obtained from a sub-chronic toxicity study with Ammonium Thiocyanate resulting in a NOAEL of 31 mg/kg bw/d, which is used for derivation of Guanidine Thiocyanate DNELs.

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 consumers is used to take account of intraspecies variability.

AF for the quality of the whole database:

1

Justification:

The key studies were conducted to modern regulatory standards and were adequately reported.

AF for remaining uncertainties:

1

Justification:

No additional AF is deemed necessary.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

For Guanidine Thiocyanate there are no consumer uses, the DNELs for general population are solely derived to cover the exposure scenario man via environment.