2-chloropropane

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

91.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEC

Value:

3 252 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

2 287.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

A NOAEC of 3252 mg/m³, resulting from a 90d inhalation exposure repeated dose toxicity study was considered for the derivation of the DNEL. This NOAEC was corrected for DNEL derivation by considering difference in daily exposure (6 h/d in study, 8 h/d for workers) and considering differences in respiratory volume between rats as used in study and workers performing lightweight activities in line with ECHA guidance for derivation of DNELs.

Worker – Inhalation = 3252 mg/m3 x 6/8 x 7/5 x 6.7/10 = 2287.8 mg/m3

AF for dose response relationship:

1

Justification:

dose descriptor is a NOAEC from reliable study

AF for differences in duration of exposure:

2

Justification:

sub-chronic to chronic assessment factor

AF for interspecies differences (allometric scaling):

1

Justification:

rat - systemic effect (inhalation route) - not applicable for setting inhalation DNEL

AF for other interspecies differences:

2.5

Justification:

systemic effect remaining differences according to guidance

AF for intraspecies differences:

5

Justification:

workers default according to guidance

AF for the quality of the whole database:

1

Justification:

good quality, subchronic data, supported by read-across reproductive data

AF for remaining uncertainties:

1

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

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

132 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEC

Value:

3 252 mg/m³

Modified dose descriptor starting point:

NOAEL

Value:

13 200 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A NOAEC of 3252 mg/m³, resulting from a 90d inhalation exposure repeated dose toxicity study was considered for the derivation of the DNELdermal for workers. This NOAEC was corrected for DNEL derivation by considering difference in daily exposure (6 h/d in study, 8 h/d for workers) and considering conversion from NOAEC to NOAEL by multiplying with 0.29 m³/kg bw in line with ECHA guidance for derivation of DNELs and correcting by 100%/10% considering differences in absorption.

NOAEC of 3252 mg/m³ * 7/5 *(0.29 m³/kg bw) * 100%/10% = 13200 mg/m³ (corrected NOAEL dermal)

AF for dose response relationship:

1

Justification:

dose descriptor is a NOAEL

AF for differences in duration of exposure:

2

Justification:

sub-chronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

rat - systemic effect (dermal route)

AF for other interspecies differences:

2.5

Justification:

systemic effect

AF for intraspecies differences:

5

Justification:

workers

AF for the quality of the whole database:

1

Justification:

good quality

AF for remaining uncertainties:

1

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:

low hazard (no threshold derived)

Additional information - workers

Acute DNELs:

Worker: Production of isopropyl chloride (IPC) is in excess of 10 t/y. According to REACh guidance “Guidance on Information Requirement and Chemical Safety Assessment Part B: Hazard Assessment”, above 10t/y, the establishment of acute toxicity DNEL is unnecessary in most cases, as the DNEL based on long-term exposure is normally sufficient to ensure that adverse effects do not occur. Thus, as long-term DNELs are available for IPC and this substance is not classified for acute toxicity via any route of exposure, separate acute DNELs were not derived. As IPC is not a skin irritant; for local effects the systemic DNEL may be used as default.

Long term DNELs:

DNELs are based on the inhalation rat study (key study selected) entitled "Inhalation Toxicity of Isopropyl Chloride: 90-Day Study on Rats". Starting Dose for DNEL Calculation = 996 ppm (NOAEC) = 3252 mg/m3 at 20 degrees Celsius and 1 atm.

Modified doses for DNEL Calculations:

Worker – Inhalation = 3252 mg/m3 x 6/8 x 7/5 x 6.7/10 = 2287.8 mg/m3

Worker – Dermal = 3252 mg/m3 x 7/5 x 0.29 m3/kg bw/d = 1320 mg/kg bw

Absorption: IPC is expected to be absorbed intact via all relevant routes of exposure [1, 2]. The low molecular weight (78.5413 g/mol), log POW value (1.9), and physical state of IPC favour its absorption via various routes of exposure (i.e., oral, dermal, and inhalation). The high vapour pressure of IPC, however, limits its absorption following dermal exposure, and renders inhalation the most relevant route of exposure. Based on this information and according to REACh guidance “Guidance on Information Requirement and Chemical Safety Assessment Part B: Hazard Assessment”, the oral, dermal, and inhalational absorption was determined to be 100%. Given the VP value of IPC, the dermal absorption was assessed to be 10%.

Modified doses for DNEL Calculations with Absorption Values:

Worker – Inhalation = 2287.8 mg/m3

Worker – Dermal = 1320 mg/kg bw x 10 = 13200 mg/kg bw

Assessment Factors (AF):

Worker – Inhalation = 2.5 (for non-metabolic species differences) x 5 for (intraspecies difference); no scaling factor required (as per REACh guidance) x 2 for duration from subchronic to chronic; no assessment factor for dose-response; no assessment factor for quality of database = 25

Worker – Dermal = 4 (rat scaling factor) x 2.5 (for non-metabolic species differences) x 5 for (intraspecies difference) x 2 for duration from subchronic to chronic; no assessment factor for dose-response; no assessment factor for quality of database = 100

Final DNELs:

Worker – Inhalation = 91.5 mg/m3

Worker – Dermal = 132 mg/kg bw

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

16.3 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEC

Value:

3 252 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

813 mg/m³

Explanation for the modification of the dose descriptor starting point:

A NOAEC of 3252 mg/m³, resulting from a 90d inhalation exposure repeated dose toxicity study was considered for the derivation of the DNEL. This NOAEC was corrected for DNEL derivation by considering difference in daily exposure (6 h/d in study, 24 h/d for general population) in line with ECHA guidance for derivation of DNELs.

NOAEC of 3252 mg/m³ * (6 h/d / 24 h/d) = 813 mg/m³ (corrected NOAEC)

AF for dose response relationship:

1

Justification:

dose descriptor is a NOAEC

AF for differences in duration of exposure:

2

Justification:

sub-chronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

rat - systemic effect (inhalation route)

AF for other interspecies differences:

2.5

Justification:

systemic effect

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

good quality

AF for remaining uncertainties:

1

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

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

47.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEC

Value:

3 252 mg/m³

Modified dose descriptor starting point:

NOAEL

Value:

9 430 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A NOAEC of 3252 mg/m³, resulting from a 90d inhalation exposure repeated dose toxicity study was considered for the derivation of the DNELdermal for workers. This NOAEC was corrected for DNEL derivation by considering difference in daily exposure (6 h/d in study, 24 h/d for general population) and considering conversion from NOAEC to NOAEL by multiplying with 1.15 m³/kg bw in line with ECHA guidance for derivation of DNELs (total factor of 0.29) in line with ECHA guidance for derivation of DNELs and correcting by 100%/10% considering differences in absorption.

NOAEC of 3252 mg/m³ * 0.29 m³/kg bw/d * 100%/10% = 9430 mg/kg bw/d (corrected NOAEL dermal)

AF for dose response relationship:

1

Justification:

dose descriptor is a NOAEL corr.

AF for differences in duration of exposure:

2

Justification:

sub-chronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

rat - systemic effect (dermal route)

AF for other interspecies differences:

2.5

Justification:

systemic effect

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

good quality

AF for remaining uncertainties:

1

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:

4.7 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Value:

943 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A NOAEC of 3252 mg/m³, resulting from a 90d inhalation exposure repeated dose toxicity study was considered for the derivation of the DNELdermal for workers. This NOAEC was corrected for DNEL derivation by considering difference in daily exposure (6 h/d in study, 24 h/d for general population) and considering conversion from NOAEC to NOAEL by multiplying with 1.15 m³/kg bw in line with ECHA guidance for derivation of DNELs (total factor of 0.29).

NOAEC of 3252 mg/m³ * 0.29 m³/kg bw/d = 943 mg/kg bw/d (corrected NOAEL dermal)

AF for dose response relationship:

1

Justification:

dose descriptor is a NOAEL

AF for differences in duration of exposure:

2

Justification:

sub-chronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

rat - systemic effect (oral route)

AF for other interspecies differences:

2.5

Justification:

systemic effect

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

good quality

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

Acute DNELs:

General Population: Production of isopropyl chloride (IPC) is in excess of 10 t/y. According to REACh guidance “Guidance on Information Requirement and Chemical Safety Assessment Part B: Hazard Assessment”, above 10t/y, the establishment of acute toxicity DNEL is unnecessary in most cases, as the DNEL based on long-term exposure is normally sufficient to ensure that adverse effects do not occur. Thus, as long-term DNELs are available for IPC and this substance is not classified for acute toxicity via any route of exposure, separate acute DNELs were not derived. As IPC is not a skin irritant; for local effects the systemic DNEL may be used as default.

Long term DNELs:

DNELs are based on the inhalation rat study (key study selected) entitled "Inhalation Toxicity of Isopropyl Chloride: 90-Day Study on Rats". Starting Dose for DNEL Calculation = 996 ppm (NOEC) = 3252 mg/m3

Modified doses for DNEL Calculations:

General Population – Oral = 3252 mg/m3 x 0.29 m3/kg bw/d = 943 mg/kg bw/day

General Population – Inhalation = 3252 mg/m3 x 6/24 = 813 mg/m3

General Population – Dermal = 1606 mg/m3 x 0.29 m3/kg bw/day = 943 mg/kg bw/day

Absorption: IPC is expected to be absorbed intact via all relevant routes of exposure [1, 2]. The low molecular weight (78.5413 g/mol), log POW value (1.9), and physical state of IPC favour its absorption via various routes of exposure (i.e., oral, dermal, and inhalation). The high vapour pressure of IPC, however, limits its absorption following dermal exposure, and renders inhalation the most relevant route of exposure. Based on this information and according to REACh guidance “Guidance on Information Requirement and Chemical Safety Assessment Part B: Hazard Assessment”, the oral and inhalational absorption was determined to be 100%. Given the VP value of IPC, the dermal absorption was assessed to be 10%.

Modified doses for DNEL Calculations with Absorption Values:

General Population – Oral = 943 mg/kg bw/day

General Population – Inhalation = 813 mg/m3

General Population – Dermal = 943 mg/kg bw/day x 10 = 9430 mg/kg bw/day

Assessment Factors (AF):

General Population – Oral = 4 (rat scaling factor) x 2.5 (for non-metabolic species differences) x 10 for (intraspecies difference) x 2 for duration from subchronic to chronic; no assessment factor for dose-response; no assessment factor for quality of database = 200

General Population – Inhalation = 2.5 (for non-metabolic species differences) x 10 for (intraspecies difference); no scaling factor required (as per REACh guidance) x 2 for duration from subchronic to chronic; no assessment factor for dose-response; no assessment factor for quality of database = 50

General Population – Dermal = 4 (rat scaling factor) x 2.5 (for non-metabolic species differences) x 10 for (intraspecies difference) x 2 for duration from subchronic to chronic; no assessment factor for dose-response; no assessment factor for quality of database = 200

Final DNELs:

General Population – Oral = 4.7 mg/kg bw

General Population – Inhalation = 16.3 mg/m3

General Population – Dermal = 47.2 mg/kg bw