thiourea; thiocarbamide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 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):

12.5

Dose descriptor starting point:

NOAEC

Value:

6.88 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

169.83 mg/m³

Explanation for the modification of the dose descriptor starting point:

Standard respiratory volume, human (sRVhuman) for 8 h per person (70 kg): 6.7 m³

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw

Worker respiratory volume (wRV) for 8 hours with light physical activity per person: 10 m³

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh.-human): 1/2

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

 

Corrected NOAEC (inhalation) for workers:

NOAEC_corr = NOAEL_oral x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x ABS_oral/ABS_inh

NOAEC_corr = 6.88 mg/kg bw/day x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x 1/2

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

As a dose descriptor starting point is used from a chronic repeated dose toxicity study, no further extrapolation regarding duration is required.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The chronic toxicity study equivalent to OECD No. 452 is considered to be conducted according to regulatory standards and not considered to contribute to uncertainty, hence it is not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties 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:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.81 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):

50

Dose descriptor starting point:

NOAEL

Value:

6.88 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

240.8 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral absorption of the rat/ dermal absorption of humans (ABS oral-rat / ABS derm-human): 1/0.04

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEL (dermal) for workers:

NOAEL_corr = NOAEL_oral x 7d/5d x ABS_oral/ABS_inh

NOAEL_corr = 6.88 mg/kg bw/day x 7d/5d x 1/0.04

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

As a dose descriptor starting point is used from a chronic repeated dose toxicity study, no further extrapolation regarding duration is required.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is applied.

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied. The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The chronic toxicity study equivalent to OECD No. 452 is considered to be conducted according to regulatory standards and not considered to contribute to uncertainty, hence it is not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties 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:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Systemic long-term DNEL for inhalation exposure

The respective NOAEC is based on a NOAEL of 6.88 mg/kg bw/day from a chronic oral rat (24 month drinking water) study equivalent to OECD No. 452, considering an oral bioavailability of 100%. It was modified using a human standard respiratory volume (sRVhuman) of 6.7 m³ for 8 hours per person (70 kg), a rat standard respiratory volume (sRVrat) of 0.38 m³/kg bw for 8 hours, a worker respiratory volume (wRV) of 10 m³ for 8 hours with light physical activity, the default quotient of ½ for oral absorption of the rat and inhalation absorption of humans (ABS oral-rat / ABS inh-human) and a correction for difference between human and experimental exposure conditions (7 days exposure of the rats/5 days exposure of worker per week) to 169.83 mg/m³ using the equation provided in the Guidance Document on Information Requirement, Chapter R8:

NOEC_corr = NOAEL_oral x 1/0.38 m³/kg bw/day x 6.7 m³/10m³ x 7d/5d x ABS_oral/ABS_inh

Using assessment factors of (i) 2.5 for remaining species differences and (ii) 5 for intraspecies extrapolation, a DNEL of 1 mg/m³ for long-term, systemic inhalative exposure was calculated.

 

 

Systemic acute DNEL for inhalation exposure

In accordance with column 2 of REACH Annex VIII, an acute inhalation toxicity study was conducted equivalent to OECD Guideline No 403. The 4 h LC50 of thiourea in rats was higher than 195 mg/m³ air. Higher concentrations could not be attained. Due to the physico-chemical properties of the substance (especially the low volatility; vapour pressure =9.9*10^-5 Pa), high peak-inhalation exposure is not considered relevant. The long-term DNEL of 1 mg/m³ is considered sufficient to ensure that acute effects do not occur.

 

 

Local long-term and acute DNELs for inhalation exposure

No study on respiratory irritation is available, but, due to the negative outcomes in in vivo skin irritation and eye irritation studies and further physico-chemical properties of the substance (especially the low volatility; vapour pressure = 9.9*10^-5 Pa), inhalation exposure is considered unlikely. Thus, long-term and acute local effects in the respiratory tract are not expected.

 

 

Systemic long-term DNEL for dermal exposure

The NOAEL of 6.88 mg/kg bw/day from a chronic oral rat (24 month drinking water) study equivalent to OECD guideline 452 was used as POD. It was modified using a correction for difference between human and experimental exposure conditions (7 days exposure of the rats/5 days exposure of worker per week) to 299.6 mg/kg bw/day using the equation provided in the Guidance Document on Information Requirement, Chapter R8:

NOAEL_corr = NOAEL_dermal x 7d/5d

Using assessment factors of (i) 4 for interspecies differences (allometric scaling), (ii) 2.5 for remaining interspecies differences and (iii) 5 for intraspecies extrapolation, a DNEL of 4.81 mg/kg bw/day for long-term, systemic dermal exposure was calculated.

 

 

Systemic acute DNEL for dermal exposure

In an acute dermal toxicity study, the NOAEL was >2000 mg/kg bw/day. Therefore no hazard could be identified so that the determination of a DNEL for acute oral toxicity was not triggered.

 

 

Local long-term and acute DNELs for dermal exposure

No hazard was identified in skin sensitisation studies. Thus, long-term and acute local dermal effects are not likely to occur. The long-term inhalation and dermal DNELs for local effects were not derived.

 

 

Hazard for the eyes

No hazards were identified in an eye irritation study. Thus, local effects on the eyes are unlikely. 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.1 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:

NOAEC

Value:

6.88 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

2.99 mg/m³

Explanation for the modification of the dose descriptor starting point:

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m³/kg bw/day

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 1/2 (default)

Corrected NOAEC (inhalation) for general population:

NOAEC_corr = NOAEL_oral x 1/1.15 m³/kg bw/day x ABS_oral/ABS_inh

NOAEC_corr = 6.88 mg/kg bw/day x 0.87 m³/kg bw/day x 1/2

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

As a dose descriptor starting point is used from a chronic repeated dose toxicity study, no further extrapolation regarding duration is required.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

10

Justification:

The default value for the relatively heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The chronic toxicity study equivalent to OECD No. 452 is considered to be conducted according to regulatory standards and not considered to contribute to uncertainty, hence it is not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties 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:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.7 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:

6.88 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

172 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Available data do not suggest a pronounced difference between oral and dermal route.

Oral absorption of the rat/ dermal absorption of humans (ABS oral-rat / ABS derm-human): 1/0.04

Corrected NOAEL (dermal) for general population:

NOAEL_corr = NOAEL_oral x ABS_oral/ABS_derm

NOAEL_corr = 6.88 mg/kg bw/day x 1/0.04

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

As a dose descriptor starting point is used from a chronic repeated dose toxicity study, no further extrapolation regarding duration is required.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is applied.

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied. The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The chronic toxicity study equivalent to OECD No. 452 is considered to be conducted according to regulatory standards and not considered to contribute to uncertainty, hence it is not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties 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:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.1 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

Dose descriptor starting point:

NOAEL

Value:

6.88 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

As a dose descriptor starting point is used from an oral chronic repeated dose toxicity study, no further modification is required.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

As a dose descriptor starting point is used from a chronic repeated dose toxicity study, no further extrapolation regarding duration is required.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is applied.

AF for other interspecies differences:

2.5

Justification:

The recommended AF for other interspecies differences is applied. The recommended AF for other interspecies differences is applied.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The chronic toxicity study equivalent to OECD No. 452 is considered to be conducted according to regulatory standards and not considered to contribute to uncertainty, hence it is not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties 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:

no hazard identified

Additional information - General Population

Systemic long-term DNEL for inhalation exposure

The respective NOAEC is based on a NOAEL of 6.88 mg/kg bw/day from a chronic oral rat (24 month drinking water) study equivalent to OECD No. 452, considering an oral bioavailability of 100%. It was modified  using a rat standard respiratory volume (sRVrat) of 1.15 m³/kg bw/day for 24 hours and the default quotient of ½ for oral absorption of the rat and inhalation absorption of humans (ABS oral-rat / ABS inh-human) to 0.1 mg/m³ using the equation provided in the Guidance Document on Information Requirement, Chapter R8.

NOEC_corr = NOAEL_oral x 1/1.15 m³/kg bw/day x ABS_oral/ABS_inh

Using assessment factors of (i) 2.5 for remaining species differences and (ii) 10 for intraspecies extrapolation, a DNEL of 3.7 mg/m³ for long-term, systemic inhalative exposure was calculated.

 

Systemic acute DNEL for inhalation exposure

In accordance with column 2 of REACH Annex VIII, an acute inhalation toxicity study was conducted equivalent to OECD Guideline No 403. The 4 h LC50 of thiourea in rats was higher than 195 mg/m³ air. Higher concentrations could not be attained. Due to the physico-chemical properties of the substance (especially the low volatility; vapour pressure =9.9*10^-5 Pa), high peak-inhalation exposure is not considered relevant. The long-term DNEL of 1 mg/m³ is considered sufficient to ensure that acute effects do not occur.

 

Local long-term and acute DNELs for inhalation exposure

No study on respiratory irritation is available, but, due to the negative outcomes in in vivo skin irritation and eye irritation studies and further physico-chemical properties of the substance (especially the low volatility; vapour pressure = 9.9*10^-5 Pa), inhalation exposure is considered unlikely. Thus, long-term and acute local effects in the respiratory tract are not expected.

 

Systemic long-term DNEL for dermal exposure

The NOAEL of 6.88 mg/kg bw/day from a chronic oral rat (24 month drinking water) study equivalent to OECD No. 452 was used as POD. It does not have to be modified according to Guidance Document on Information Requirement, Chapter R8 as a similar absorption through the oral and dermal route is assumed.

Using assessment factors of (i) 4 for interspecies differences (allometric scaling), (iii) 2.5 for remaining interspecies differences and (iiii) 10 for intraspecies extrapolation, a DNEL of 1.7  mg/kg bw/day for long-term, systemic dermal exposure of the general population was calculated.

 

Systemic acute DNEL for dermal exposure

In an acute dermal toxicity study, the NOAEL was >2000 mg/kg bw/day. Therefore no hazard could be identified so that the determination of a DNEL for acute oral toxicity was not triggered.

 

Local long-term and acute DNELs for dermal exposure

No hazard was identified in skin sensitisation studies. Thus, long-term and acute local dermal effects are not likely to occur. The long-term inhalation and dermal DNELs for local effects were not derived.

 

Systemic long-term DNEL for oral exposure

The NOAEL 6.88 mg/kg bw/day from a chronic oral rat (24 month drinking water) study equivalent to OECD No. 452 was used as POD. It does not have to be modified according to Guidance Document on Information Requirement, Chapter R8.

Using assessment factors of (i) 4 for interspecies differences (allometric scaling), (ii) 2.5 for remaining interspecies differences and (iii) 10 for intraspecies extrapolation, a DNEL of 0.1 mg/kg bw/day for long-term, systemic oral exposure was calculated.

 

Systemic acute DNEL for oral exposure

In an acute oral toxicity study, the NOAEL was >2000 mg/kg bw/day. Therefore no hazard could be identified so that the determination of a DNEL for acute oral toxicity was not triggered.

 

Hazard for the eyes

No hazards were identified in an eye irritation study. Thus, local effects on the eyes are unlikely.