Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
63.5 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
Dose descriptor starting point:
NOAEL
Value:
900 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 562.5 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
450 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
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Acute Effects

LCCPs demonstrate a low order of acute toxicity. No mortalities were observed and the reported oral LD50values all exceeded 5,000 mg/kg bwt in the rat, mouse and dog. This conclusion is also supported by additional acute intraperitoneal (i.p.) studies in rats and mice that showed no mortality at 5,000 mg/kg bwt (i.p.) with several different LCCP test substances. The lack of acute toxicology data via inhalation or dermal exposure routes for LCCPs is not expected to be an important data gap as these routes of exposure are insignificant for LCCPs, which have very low vapour pressure and are absorbed very poorly through the skin.

DNELs for acute toxicity should be derived if an acute toxicity hazard, leading to classification and labelling (e.g. under EU CLP or DSD regulations), has been identified and there is a potential for high peak exposures (this is only usually relevant for inhalation exposures). As no acute hazard has been identified, then a DNEL for acute toxicity is unnecessary as the long-term DNEL will normally be sufficient to ensure that adverse effects do not occur. Consequently, no worker-DNELs for acute toxicity have been calculated.

Irritation/Sensitisation

LCCPs are not classified as skin or respiratory irritants or sensitisers. As such, there is no basis to establish DNELs based on localised effects.

Derivation of the DNELs

There are three sets of DNELs for LCCPs to cover the three main classes of LCCP:

- C18 -C20 Liquid LCCP

- C20 -C30 Liquid LCCP

- C20 -C30 Solid LCCP

The derivation of these DNELs is provided below:

C18-C20 LCCP (liquid)

 

Workers

 

Dermal - Long-Term Systemic Effects

 

Key Study: MCCP Repeat-Dose Study (Elcombe 2005b), Oral (gavage) exposure in rats

 

Dose Descriptor: NOAEL (systemic toxicity) = 23 mg/kg/day

 

Corrected Dermal NOAEL = Oral NOAEL x (ABSoral-rat/ABSdermal-human)

 

= 23 mg/kg/day x (0.5/0.01)[a]

 

Corrected Dermal NOAEL = 1150.0 mg/kg/day

 

Assessment Factors:   Interspecies               4 (allometric scaling)

                                                                       2.5 (remaining differences)

                                   Intraspecies                5 (REACH guidance)

                                   Exposure Duration     2 (subchronic to chronic)

                                   Dose Response           1

                                   Quality of Database   1

 

Total Assessment Factor:                               100

 

DNELDermal - Long-Term Systemic= 1150.0 mg/kg/day ÷ 100

 

DNELDermal - Long-Term Systemic= 11.5 mg/kg/day

 

 

Inhalation - Long-Term Systemic Effects

 

Key Study: MCCP Repeat-Dose Study (Elcombe 2005b), Oral (gavage) exposure in rats

 

Dose Descriptor: NOAEL (systemic toxicity) = 23 mg/kg/day

 

Corrected Inhalation NOAEL = Oral NOAEL x (1/sRVrat)[b]x (ABSoral-rat/ ABSinhl-human)

 

= 23 mg/kg/day x (1 / 0.38m3kg-18hr-1) x (0.5/0.5)[c]

 

Corrected Inhalation NOAEL = 60.5 mg/m3 for 8hr

 

Corrected Inhalation NOAEL (workers) = 60.5 x (sRVhuman/ wRV)[d]

 

= 60.5 x (6.7 / 10)

 

Corrected Inhalation NOAEL (workers) = 40.5 mg/m3 for 8hr

 

Assessment Factors:   Interspecies                2.5 (remaining differences)

                                   Intraspecies                5 (REACH)

                                   Exposure Duration     2 (subchronic to chronic)

                                   Dose Response           1

                                   Quality of Database   1

 

Total Assessment Factor:                               25

 

DNELInhl - Long-Term Systemic= 40.5 mg/m3 for 8hr ÷ 25

 

DNELInhl - Long-Term Systemic= 1.62 mg/m3 for 8hr

 

 

C20-C30 LCCP (liquid)

 

Workers

 

Dermal - Long-Term Systemic Effects

 

Key Study: IRDC (1984b). IRDC Report No. 438-028/438-021 August 22, 1984 13-week oral gavage with combined excretion, tissue level and elimination study

 

Dose Descriptor: LOAEL (systemic toxicity) = 100 mg/kg/day (based on female LOAEL)

 

Corrected Dermal LOAEL = Oral LOAEL x (ABSoral-rat/ ABSdermal-human)

 

= 100 mg/kg/day x (0.5/0.01)[f]

 

Corrected Dermal LOAEL = 5,000.0 mg/kg/day

 

Assessment Factors:   Interspecies                4 (allometric scaling)

                                                                       2.5 (remaining differences)

                                   Intraspecies                5 (REACH guidance)

                                   Exposure Duration     2 (subchronic to chronic)

                                   Dose Response           3 (using LOAEL)

                                   Quality of Database   1

 

Total Assessment Factor:                               250

 

DNELDermal - Long-Term Systemic= 5,000.0 mg/kg/day ÷ 250

 

DNELDermal - Long-Term Systemic= 20.0 mg/kg/day

 

Inhalation - Long-Term Systemic Effects

 

Key Study: IRDC (1984b). IRDC Report No. 438-028/438-021 August 22, 1984 13-week oral gavage with combined excretion, tissue level and elimination study

 

Dose Descriptor: LOAEL (systemic toxicity) = 100 mg/kg/day (based on female LOAEL)

 

Corrected Inhalation LOAEL = Oral LOAEL x (1/sRVrat)[g]x (ABSoral-rat/ ABSinhl-human)

 

= 100 mg/kg/day x (1 / 0.38m3kg-18hr-1) x (0.5/0.5)[h]

 

Corrected Inhalation LOAEL = 263.2 mg/m3 for 8hr

 

Corrected Inhalation LOAEL (workers) = 263.2 x (sRVhuman/ wRV)[i]

 

= 263.2 x (6.7 / 10)

 

Corrected Inhalation LOAEL (workers) = 176.3 mg/m3 for 8hr

 

Assessment Factors:   Interspecies                2.5 (remaining differences)

                                  Intraspecies                5 (REACH guidance)

                                   Exposure Duration     2 (subchronic to chronic)

                                   Dose Response           3 (LOAEL used)

                                   Quality of Database   1

 

Total Assessment Factor:                               75

 

DNELInhl - Long-Term Systemic= 176.3 mg/m3 for 8hr ÷ 75

 

DNELInhl - Long-Term Systemic= 2.35 mg/m3 for 8hr

 

  

C20-C30 LCCP (solid)

 

Workers

 

Dermal - Long-Term Systemic Effects

 

Key Study: LCCP Study IRDC (1984a). Report No. 438-027 / 438-024, Oral (gavage) exposure in rats

 

Dose Descriptor: NOAEL (systemic toxicity) = 900 mg/kg/day

 

Corrected Dermal NOAEL = Oral NOAEL x (ABSoral-rat/ ABSdermal-human)

 

= 900 mg/kg/day x (0.5/0.01)[k]

 

Corrected Dermal NOAEL = 45,000.0 mg/kg/day

 

Assessment Factors:   Interspecies                4 (allometric scaling)

                                                                       2.5 (remaining differences)

                                   Intraspecies                5 (REACH guidance)

                                   Exposure Duration     2 (subchronic to chronic)

                                   Dose Response           1

                                   Quality of Database   1

 

Total Assessment Factor:                               100

 

DNELDermal - Long-Term Systemic= 45,000.0 mg/kg/day ÷ 100

 

DNELDermal - Long-Term Systemic= 450.0 mg/kg/day

 

 

Inhalation - Long-Term Systemic Effects

 

Key Study: LCCP Study IRDC (1984a). Report No. 438-027 / 438-024, Oral (gavage) exposure in rats

 

Dose Descriptor: NOAEL (systemic toxicity) = 900 mg/kg/day

 

Corrected Inhalation NOAEL = Oral NOAEL x (1/sRVrat)[l]x (ABSoral-rat/ ABSinhl-human)

 

= 900 mg/kg/day x (1 / 0.38m3kg-18hr-1) x (0.5/0.5)[m]

 

Corrected Inhalation NOAEL = 2368.4 mg/m3 for 8hr

 

Corrected Inhalation NOAEL (workers) = 2368.4 x (sRVhuman/ wRV)[n]

 

= 2368.4 x (6.7 / 10)

 

Corrected Inhalation NOAEL (workers) = 1586.8 mg/m3 for 8hr

 

Assessment Factors:   Interspecies                2.5 (remaining differences)

                                   Intraspecies                5 (REACH guidance)

                                   Exposure Duration     2 (subchronic to chronic)

                                   Dose Response           1

                                   Quality of Database   1

 

Total Assessment Factor:                               25

 

DNELInhl - Long-Term Systemic= 1586.8 mg/m3 for 8hr ÷ 25

 

DNELInhl - Long-Term Systemic= 63.5 mg/m3 for 8hr

 

  


[a]Based on MCCP oral and skin absorption efficiencies of 50% and 1.0%, respectively (MCCP Annex XV Report 2009).

[b]Standard respiratory volume (rat) = 0.38 m3/kg for 8 hours.

[c]Based on MCCP oral and inhalation absorption efficiencies of 50% (MCCP Annex XV Report 2009).

[d]Standard respiratory volume (human) = 6.7 m3for 8 hours; worker respiratory volume = 10 m3for 8 hours

[e]Based on MCCP oral and skin absorption efficiencies of 50% and 1.0%, respectively (MCCP Annex XV Report 2009).

[f]Based on MCCP oral and skin absorption efficiencies of 50% and 1.0%, respectively (MCCP Annex XV Report 2009).

[g]Standard respiratory volume (rat) = 0.38 m3/kg for 8 hours.

[h]Based on MCCP oral and inhalation absorption efficiencies of 50% (MCCP Annex XV Report 2009).

[i]Standard respiratory volume (human) = 6.7 m3for 8 hours; worker respiratory volume = 10 m3for 8 hours

[j]Based on MCCP oral and skin absorption efficiencies of 50% and 1.0%, respectively (MCCP Annex XV Report 2009).

[k]Based on MCCP oral and skin absorption efficiencies of 50% and 1.0%, respectively (MCCP Annex XV Report 2009).

[l]Standard respiratory volume (rat) = 0.38 m3/kg for 8 hours.

[m]Based on MCCP oral and inhalation absorption efficiencies of 50% (MCCP Annex XV Report 2009).

[n]Standard respiratory volume (human) = 6.7 m3for 8 hours; worker respiratory volume = 10 m3for 8 hours

[o]Based on MCCP oral and skin absorption efficiencies of 50% and 1.0%, respectively (MCCP Annex XV Report 2009).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Not applicable. Inhalation exposure not expected to the general population.  LCCP have very low vapour pressure.

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
225 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:
900 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.5 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
Dose descriptor starting point:
NOAEL
Value:
900 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Acute Effects

LCCPs demonstrate a low order of acute toxicity. No mortalities were observed and the reported oral LD50values all exceeded 5,000 mg/kg bwt in the rat, mouse and dog. This conclusion is also supported by additional acute intraperitoneal (i.p.) studies in rats and mice that showed no mortality at 5,000 mg/kg bwt (i.p.) with several different LCCP test substances. The lack of acute toxicology data via inhalation or dermal exposure routes for LCCPs is not expected to be an important data gap as these routes of exposure are insignificant for LCCPs, which have very low vapour pressure and are absorbed very poorly through the skin.

DNELs for acute toxicity should be derived if an acute toxicity hazard, leading to classification and labelling (e.g. under EU CLP or DSD regulations), has been identified and there is a potential for high peak exposures (this is only usually relevant for inhalation exposures). As no acute hazard has been identified, then a DNEL for acute toxicity is unnecessary as the long-term DNEL will normally be sufficient to ensure that adverse effects do not occur. Consequently, no worker-DNELs for acute toxicity have been calculated.

Irritation/Sensitisation

LCCPs are not classified as skin or respiratory irritants or sensitisers. As such, there is no basis to establish DNELs based on localised effects.

Derivation of the DNELs

There are three sets of DNELs for LCCPs to cover the three main classes of LCCP:

- C18 -C20 Liquid LCCP

- C20 -C30 Liquid LCCP

- C20 -C30 Solid LCCP

The derivation of these DNELs is provided below:

C18-C20 LCCP (liquid)

 

General Population

 

Dermal - Long-Term Systemic Effects

 

Key Study: MCCP Repeat-Dose Study (Elcombe 2005b), Oral (gavage) exposure in rats

 

Dose Descriptor: NOAEL (systemic toxicity) = 23 mg/kg/day

 

Corrected Dermal NOAEL = Oral NOAEL x (ABSoral-rat/ ABSdermal-human)

 

= 23 mg/kg/day x (0.5/0.01)[e]

 

Corrected Dermal NOAEL = 1150.0 mg/kg/day

 

Assessment Factors:   Interspecies                4 (allometric scaling)

                                                                       2.5 (remaining differences)

                                   Intraspecies                10 (REACH guidance)

                                   Exposure Duration     2 (subchronic to chronic)

                                   Dose Response           1

                                   Quality of Database   1

 

Total Assessment Factor:                               200

 

DNELDermal - Long-Term Systemic= 1150.0 mg/kg/day ÷ 200

 

DNELDermal - Long-Term Systemic= 5.75 mg/kg/day

 

 

Oral - Long-Term Systemic Effects

 

Key Study: MCCP Repeat-Dose Study (Elcombe 2005b), Oral (gavage) exposure in rats

 

Dose Descriptor: NOAEL (systemic toxicity) = 23 mg/kg/day

 

Assessment Factors:   Interspecies                4 (allometric scaling)

                                                                       2.5 (remaining differences)

                                   Intraspecies                10 (REACH guidance)

                                   Exposure Duration     2 (subchronic to chronic)

                                   Dose Response           1

                                   Quality of Database   1

 

Total Assessment Factor:                               200

 

DNELOral - Long-Term Systemic= 23.0 mg/kg/day ÷ 200

 

DNELOral - Long-Term Systemic= 0.115 mg/kg/day

 

 

C20-C30 LCCP (liquid)

 

General Population

 

Dermal - Long-Term Systemic Effects

 

Key Study: IRDC (1984b). IRDC Report No. 438-028/438-021 August 22, 1984 13-week oral gavage with combined excretion, tissue level and elimination study

 

Dose Descriptor: LOAEL (systemic toxicity) = 100 mg/kg/day (based on female LOAEL)

 

Corrected Dermal LOAEL = Oral LOAEL x (ABSoral-rat/ ABSdermal-human)

 

= 100 mg/kg/day x (0.5/0.01)[j]

 

Corrected Dermal LOAEL = 5,000.0 mg/kg/day

 

Assessment Factors:   Interspecies                4 (allometric scaling)

                                                                       2.5 (remaining differences)

                                   Intraspecies                10 (REACH guidance)

                                   Exposure Duration     2 (subchronic to chronic)

                                   Dose Response           3 (LOAEL used)

                                   Quality of Database   1

 

Total Assessment Factor:                               600

 

DNELDermal - Long-Term Systemic= 5,000.0 mg/kg/day ÷ 600

 

DNELDermal - Long-Term Systemic= 8.3 mg/kg/day

 

Oral - Long-Term Systemic Effects

 

Key Study: IRDC (1984b). IRDC Report No. 438-028/438-021 August 22, 1984 13-week oral gavage with combined excretion, tissue level and elimination study

 

Dose Descriptor: LOAEL (systemic toxicity) = 100 mg/kg/day (based on female LOAEL)

 

Assessment Factors:   Interspecies                4 (allometric scaling)

                                                                       2.5 (remaining differences)

                                   Intraspecies                10 (REACH guidance)

                                   Exposure Duration     2 (subchronic to chronic)

                                   Dose Response           3 (LOAEL used)

                                   Quality of Database   1

 

Total Assessment Factor:                               600

 

DNELOral - Long-Term Systemic= 100.0 mg/kg/day ÷ 600

 

DNELOral - Long-Term Systemic= 0.167 mg/kg/day

 

C20-C30 LCCP (solid)

 

General Population

 

Dermal - Long-Term Systemic Effects

 

Key Study: LCCP Study IRDC (1984a). Report No. 438-027 / 438-024, Oral (gavage) exposure in rats

 

Dose Descriptor: NOAEL (systemic toxicity) = 900 mg/kg/day

 

Corrected Dermal NOAEL = Oral NOAEL x (ABSoral-rat/ ABSdermal-human)

 

= 900 mg/kg/day x (0.5/0.01)[o]

 

Corrected Dermal NOAEL = 45,000.0 mg/kg/day

 

Assessment Factors:   Interspecies                4 (allometric scaling)

                                                                       2.5 (remaining differences)

                                   Intraspecies                10 (REACH guidance)

                                   Exposure Duration     2 (subchronic to chronic)

                                   Dose Response           1

                                   Quality of Database   1

 

Total Assessment Factor:                               200

 

DNELDermal - Long-Term Systemic= 45,000.0 mg/kg/day ÷ 200

 

DNELDermal - Long-Term Systemic= 225.0 mg/kg/day

 

Oral - Long-Term Systemic Effects

 

Key Study: LCCP Study IRDC (1984a). Report No. 438-027 / 438-024, Oral (gavage) exposure in rats

 

Dose Descriptor: NOAEL (systemic toxicity) = 900 mg/kg/day

 

Assessment Factors:   Interspecies                4 (allometric scaling)

                                                                       2.5 (remaining differences)

                                   Intraspecies                10 (REACH guidance)

                                   Exposure Duration     2 (subchronic to chronic)

                                   Dose Response           1

                                   Quality of Database   1

 

Total Assessment Factor:                               200

 

DNELOral - Long-Term Systemic= 900.0 mg/kg/day ÷ 200

 

DNELOral - Long-Term Systemic= 4.5 mg/kg/day

 

 


[a]Based on MCCP oral and skin absorption efficiencies of 50% and 1.0%, respectively (MCCP Annex XV Report 2009).

[b]Standard respiratory volume (rat) = 0.38 m3/kg for 8 hours.

[c]Based on MCCP oral and inhalation absorption efficiencies of 50% (MCCP Annex XV Report 2009).

[d]Standard respiratory volume (human) = 6.7 m3for 8 hours; worker respiratory volume = 10 m3for 8 hours

[e]Based on MCCP oral and skin absorption efficiencies of 50% and 1.0%, respectively (MCCP Annex XV Report 2009).

[f]Based on MCCP oral and skin absorption efficiencies of 50% and 1.0%, respectively (MCCP Annex XV Report 2009).

[g]Standard respiratory volume (rat) = 0.38 m3/kg for 8 hours.

[h]Based on MCCP oral and inhalation absorption efficiencies of 50% (MCCP Annex XV Report 2009).

[i]Standard respiratory volume (human) = 6.7 m3for 8 hours; worker respiratory volume = 10 m3for 8 hours

[j]Based on MCCP oral and skin absorption efficiencies of 50% and 1.0%, respectively (MCCP Annex XV Report 2009).

[k]Based on MCCP oral and skin absorption efficiencies of 50% and 1.0%, respectively (MCCP Annex XV Report 2009).

[l]Standard respiratory volume (rat) = 0.38 m3/kg for 8 hours.

[m]Based on MCCP oral and inhalation absorption efficiencies of 50% (MCCP Annex XV Report 2009).

[n]Standard respiratory volume (human) = 6.7 m3for 8 hours; worker respiratory volume = 10 m3for 8 hours

[o]Based on MCCP oral and skin absorption efficiencies of 50% and 1.0%, respectively (MCCP Annex XV Report 2009).