Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 056 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC

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:
1.65 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
512 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL

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:
no hazard identified

Additional information - workers

This substance is of complex composition by process that meets the criteria of a UVCB. It contains (1) multiplePhenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc species (neutral dimeric, trimeric, and tetrameric dithiophosphate forms), (2) their basic salt compliments, (3)Tetrapropenyl phenol (residual starting material), and (4) base oil (solvent). The substance as a whole does not have repeat dose test data to calculate the long-term systemic derived no effect levels (DNEL). However, a DNEL for the material as a whole can be derived by calculating the DNEL for the main constituents as follows:

 

-         The DNEL for phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc is based on read across from the most sensitive endpoint (repeat dose toxicity) with an analog substance (see CASRN: 4259-15-8, EINECS: 224-235-5). See the repeat dose data waiver for read across justification.

-         The DNEL for tetrapropenyl phenol (TPP) is based on the NOAEL from a two generation reproductive toxicity study with TPP (the most sensitive endpoint). As the zinc salt as manufactured contains 9.1% TPP, a dose of 165 mg/kg/day (15 mg/kg bw/day divided by 9.1%) would be the projected NOAEL since it would deliver no more than 15 mg/kg/day of TPP. This correction is also used to calculate the inhalation DNEL. The assessment factors used in the calculation of the DNEL are based on the properties of TPP.

 

The long-term DNELs for both chemicals are then applied to the chemical safety assessment to calculate the risk characterization ratios (see appendix).

 

Justification for 10% dermal absorption correction forphenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc

 

No ADME, toxicokinetic, or repeat dose dermal toxicity data are available for the substance. However, the physicochemical properties in combination with the available toxicity studies in animals provide strong support in determining the expected dermal absorption of this substance. This substanceis not expected to be absorbed via the GI tract or through the skin.This substancehas a molecular weight of roughly 1301, a water solubility of < 1mg/L, log Kowof >7, and vapor pressure < 0.013 Pa at 25oC. Low bioavailability is supported by the low systemic toxicity observed following oral and dermal administration. Based on this information as a whole and theGuidance Document on Dermal Absorption by the European Commission (2004), a default value of 10% for dermal absorption is considered appropriate.

The long-term systemic DNELs for Phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc are calculated as follows:

 

Worker

Route

Dose descriptor

Corrected dose descriptor

Most sensitive endpoint

DNEL

Justification

Dermal

NOAEL: 125.0 mg/kg bw/day

1250 mg/kg bw/day (corrected for 10% dermal absorption)

Repeated dose toxicity

10.4 mg/kg bw/day

An assessment factor of 120 is based on the following:4 for allometric scale, 1 for remaining difference, intraspecies difference (5 for workers), duration extrapolation (6 for subacute to chronic exposure), and quality of the data (1 for a reliable study).

Inhalation

NOAEL: 125.0 mg/kg bw/day

220 mg/m3

Repeated dose toxicity

7.3 mg/m3(0.14 ppm)

Using a correction factor of 1.7621((1/sRVrat(0.38))x(ABSoral-rat(100)/ABSinh-human(100))x(sRVhuman(6.7)/wRV(10))) giving a corrected inhalation NOAEC value of 220mg/m3.An assessment factor of 30 is based on the following:1 for interspecies difference, intraspecies difference (5 for workers), duration extrapolation (6 for subacute to chronic exposure), and quality of the data (1 for a reliable study).

 

General Population

Route

Dose descriptor

Corrected dose descriptor

Most sensitive endpoint

DNEL

Justification

Oral

NOAEL: 125.0 mg/kg bw/day

125 mg/kg bw/ day

Repeated dose toxicity

0.21 mg/kg bw/day

An assessment factor of 600 is based on the following:4 for allometric scale, 2.5 for remaining difference, intraspecies difference (10 for general population), duration extrapolation (6 for subacute to chronic exposure), and quality of the data (1 for a reliable study).

Dermal

NOAEL: 125.0 mg/kg bw/day

1250 mg/kg bw/day (corrected for 10% dermal absorption)

Repeated dose toxicity

5.2 mg/kg bw/day

An assessment factor of 240 is based on the following:4 for allometric scale, 1 for remaining difference, intraspecies difference (10 for general population), duration extrapolation (6 for subacute to chronic exposure), and quality of the data (1 for a reliable study).

Inhalation

NOAEL: 125.0 mg/kg bw/day

328.75 mg/m3

Repeated dose toxicity

5.5 mg/m3(0.10 ppm)

Using a correction factor of2.63 ((1/sRVrat(0.38)) x (ABSoral-rat(100)/ABSinh-human(100))x(ABSinh-rat(100)/ABSinh-human(100))) yields acorrected inhalation NOAEC value of 328.75mg/m3. An assessment factor of 60 is based on the following:1 for interspecies difference, intraspecies difference (10 for general population), duration extrapolation (6 for subacute to chronic exposure), and quality of the data (1 for a reliable study).

 

 

The long-term systemic DNELs for tetrapropenyl phenol are calculated as follows:

 

Worker

Route

Dose descriptor

Corrected dose descriptor

Most sensitive endpoint

DNEL

Justification

Dermal

NOAEL: 15.0 mg/kg bw/day

165 mg/kg bw/day

Reproductive toxicity

1.65 mg/kg bw/day

The NOAEL of 15 mg/kg bw/day is divided by 9.1% to correct for the amount of TPP to obtain the corrected dose descriptor. An assessment factor of 100 is based on the following:4 for allometric scale, 2.5 for remaining difference, intraspecies difference (5 for workers), duration extrapolation (2 for subchronic to chronic exposure), and quality of the data (1 for a reliable study).

Inhalation

NOAEL: 15.0 mg/kg bw/day

290 mg/m3

Reproductive toxicity

11.6 mg/m3(0.93 ppm)

Using a correction factor of 1.7621((1/sRVrat(0.38))x(ABSoral-rat(100)/ABSinh-human(100))x(sRVhuman(6.7)/wRV(10))) giving a corrected inhalation NOAEC value of 26.43mg/m3.26.43 mg/m3is divided by 9.1% to correct for the amount of TPP to obtain the corrected dose descriptor. An assessment factor of 25 is based on the following:2.5 for interspecies difference (remaining difference), intraspecies difference (5 for workers), duration extrapolation (2 for subchronic to chronic exposure), and quality of the data (1 for a reliable study).

 

General Population

Route

Dose descriptor

Corrected dose descriptor

Most sensitive endpoint

DNEL

Justification

Oral

NOAEL: 15.0 mg/kg bw/day

165 mg/kg bw/day

Reproductive toxicity

0.825 mg/kg bw/day

The NOAEL of 15 mg/kg bw/day is divided by 9.1% to correct for the amount of TPP to obtain the corrected dose descriptor. An assessment factor of 200 is based on the following:4 for allometric scale, 2.5 for remaining difference, intraspecies difference (10 for general population), duration extrapolation (2 for subchronic to chronic exposure), and quality of the data (1 for a reliable study).

Dermal

NOAEL: 15.0 mg/kg bw/day

165 mg/kg bw/day

Reproductive toxicity

0.825 mg/kg bw/day

The NOAEL of 15 mg/kg bw/day is divided by 9.1% to correct for the amount of TPP to obtain the corrected dose descriptor. An assessment factor of 200 is based on the following:4 for allometric scale, 2.5 for remaining difference, intraspecies difference (10 for general population), duration extrapolation (2 for subchronic to chronic exposure), and quality of the data (1 for a reliable study).

Inhalation

NOAEL: 15.0 mg/kg bw/day

433 mg/m3

Reproductive toxicity

8.67 mg/m3(0.70 ppm)

Using a correction factor of2.63 ((1/sRVrat(0.38)) x (ABSoral-rat(100)/ABSinh-human(100))x(ABSinh-rat(100)/ABSinh-human(100))) yields acorrected inhalation NOAEC value of 39.45mg/m3. 39.45 mg/m3is divided by 9.1% to correct for the amount of TPP to obtain the corrected dose descriptor. An assessment factor of 50 is based on the following:2.5 for interspecies difference (remaining difference), intraspecies difference (10 for general population), duration extrapolation (2 for subchronic to chronic exposure), and quality of the data (1 for a reliable study).

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
60
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
528 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
LOAEC

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:
0.825 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
256 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL

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:
0.21 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
75 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
LOAEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

This substance is of complex composition by process that meets the criteria of a UVCB. It contains (1) multiplePhenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc species (neutral dimeric, trimeric, and tetrameric dithiophosphate forms), (2) their basic salt compliments, (3)Tetrapropenyl phenol (residual starting material), and (4) base oil (solvent). The substance as a whole does not have repeat dose test data to calculate the long-term systemic derived no effect levels (DNEL). However, a DNEL for the material as a whole can be derived by calculating the DNEL for the main constituents as follows:

 

-         The DNEL for phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc is based on read across from the most sensitive endpoint (repeat dose toxicity) with an analog substance (see CASRN: 4259-15-8, EINECS: 224-235-5). See the repeat dose data waiver for read across justification.

-         The DNEL for tetrapropenyl phenol (TPP) is based on the NOAEL from a two generation reproductive toxicity study with TPP (the most sensitive endpoint). As the zinc salt as manufactured contains 9.1% TPP, a dose of 165 mg/kg/day (15 mg/kg bw/day divided by 9.1%) would be the projected NOAEL since it would deliver no more than 15 mg/kg/day of TPP. This correction is also used to calculate the inhalation DNEL. The assessment factors used in the calculation of the DNEL are based on the properties of TPP.

 

The long-term DNELs for both chemicals are then applied to the chemical safety assessment to calculate the risk characterization ratios (see appendix).

 

Justification for 10% dermal absorption correction forphenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc

 

No ADME, toxicokinetic, or repeat dose dermal toxicity data are available for the substance. However, the physicochemical properties in combination with the available toxicity studies in animals provide strong support in determining the expected dermal absorption of this substance. This substanceis not expected to be absorbed via the GI tract or through the skin.This substancehas a molecular weight of roughly 1301, a water solubility of < 1mg/L, log Kowof >7, and vapor pressure < 0.013 Pa at 25oC. Low bioavailability is supported by the low systemic toxicity observed following oral and dermal administration. Based on this information as a whole and theGuidance Document on Dermal Absorption by the European Commission (2004), a default value of 10% for dermal absorption is considered appropriate.

The long-term systemic DNELs for Phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc are calculated as follows:

 

Worker

Route

Dose descriptor

Corrected dose descriptor

Most sensitive endpoint

DNEL

Justification

Dermal

NOAEL: 125.0 mg/kg bw/day

1250 mg/kg bw/day (corrected for 10% dermal absorption)

Repeated dose toxicity

10.4 mg/kg bw/day

An assessment factor of 120 is based on the following:4 for allometric scale, 1 for remaining difference, intraspecies difference (5 for workers), duration extrapolation (6 for subacute to chronic exposure), and quality of the data (1 for a reliable study).

Inhalation

NOAEL: 125.0 mg/kg bw/day

220 mg/m3

Repeated dose toxicity

7.3 mg/m3(0.14 ppm)

Using a correction factor of 1.7621((1/sRVrat(0.38))x(ABSoral-rat(100)/ABSinh-human(100))x(sRVhuman(6.7)/wRV(10))) giving a corrected inhalation NOAEC value of 220mg/m3.An assessment factor of 30 is based on the following:1 for interspecies difference, intraspecies difference (5 for workers), duration extrapolation (6 for subacute to chronic exposure), and quality of the data (1 for a reliable study).

 

General Population

Route

Dose descriptor

Corrected dose descriptor

Most sensitive endpoint

DNEL

Justification

Oral

NOAEL: 125.0 mg/kg bw/day

125 mg/kg bw/ day

Repeated dose toxicity

0.21 mg/kg bw/day

An assessment factor of 600 is based on the following:4 for allometric scale, 2.5 for remaining difference, intraspecies difference (10 for general population), duration extrapolation (6 for subacute to chronic exposure), and quality of the data (1 for a reliable study).

Dermal

NOAEL: 125.0 mg/kg bw/day

1250 mg/kg bw/day (corrected for 10% dermal absorption)

Repeated dose toxicity

5.2 mg/kg bw/day

An assessment factor of 240 is based on the following:4 for allometric scale, 1 for remaining difference, intraspecies difference (10 for general population), duration extrapolation (6 for subacute to chronic exposure), and quality of the data (1 for a reliable study).

Inhalation

NOAEL: 125.0 mg/kg bw/day

328.75 mg/m3

Repeated dose toxicity

5.5 mg/m3(0.10 ppm)

Using a correction factor of2.63 ((1/sRVrat(0.38)) x (ABSoral-rat(100)/ABSinh-human(100))x(ABSinh-rat(100)/ABSinh-human(100))) yields acorrected inhalation NOAEC value of 328.75mg/m3. An assessment factor of 60 is based on the following:1 for interspecies difference, intraspecies difference (10 for general population), duration extrapolation (6 for subacute to chronic exposure), and quality of the data (1 for a reliable study).

 

 

The long-term systemic DNELs for tetrapropenyl phenol are calculated as follows:

 

Worker

Route

Dose descriptor

Corrected dose descriptor

Most sensitive endpoint

DNEL

Justification

Dermal

NOAEL: 15.0 mg/kg bw/day

165 mg/kg bw/day

Reproductive toxicity

1.65 mg/kg bw/day

The NOAEL of 15 mg/kg bw/day is divided by 9.1% to correct for the amount of TPP to obtain the corrected dose descriptor. An assessment factor of 100 is based on the following:4 for allometric scale, 2.5 for remaining difference, intraspecies difference (5 for workers), duration extrapolation (2 for subchronic to chronic exposure), and quality of the data (1 for a reliable study).

Inhalation

NOAEL: 15.0 mg/kg bw/day

290 mg/m3

Reproductive toxicity

11.6 mg/m3(0.93 ppm)

Using a correction factor of 1.7621((1/sRVrat(0.38))x(ABSoral-rat(100)/ABSinh-human(100))x(sRVhuman(6.7)/wRV(10))) giving a corrected inhalation NOAEC value of 26.43mg/m3.26.43 mg/m3is divided by 9.1% to correct for the amount of TPP to obtain the corrected dose descriptor. An assessment factor of 25 is based on the following:2.5 for interspecies difference (remaining difference), intraspecies difference (5 for workers), duration extrapolation (2 for subchronic to chronic exposure), and quality of the data (1 for a reliable study).

 

General Population

Route

Dose descriptor

Corrected dose descriptor

Most sensitive endpoint

DNEL

Justification

Oral

NOAEL: 15.0 mg/kg bw/day

165 mg/kg bw/day

Reproductive toxicity

0.825 mg/kg bw/day

The NOAEL of 15 mg/kg bw/day is divided by 9.1% to correct for the amount of TPP to obtain the corrected dose descriptor. An assessment factor of 200 is based on the following:4 for allometric scale, 2.5 for remaining difference, intraspecies difference (10 for general population), duration extrapolation (2 for subchronic to chronic exposure), and quality of the data (1 for a reliable study).

Dermal

NOAEL: 15.0 mg/kg bw/day

165 mg/kg bw/day

Reproductive toxicity

0.825 mg/kg bw/day

The NOAEL of 15 mg/kg bw/day is divided by 9.1% to correct for the amount of TPP to obtain the corrected dose descriptor. An assessment factor of 200 is based on the following:4 for allometric scale, 2.5 for remaining difference, intraspecies difference (10 for general population), duration extrapolation (2 for subchronic to chronic exposure), and quality of the data (1 for a reliable study).

Inhalation

NOAEL: 15.0 mg/kg bw/day

433 mg/m3

Reproductive toxicity

8.67 mg/m3(0.70 ppm)

Using a correction factor of2.63 ((1/sRVrat(0.38)) x (ABSoral-rat(100)/ABSinh-human(100))x(ABSinh-rat(100)/ABSinh-human(100))) yields acorrected inhalation NOAEC value of 39.45mg/m3. 39.45 mg/m3is divided by 9.1% to correct for the amount of TPP to obtain the corrected dose descriptor. An assessment factor of 50 is based on the following:2.5 for interspecies difference (remaining difference), intraspecies difference (10 for general population), duration extrapolation (2 for subchronic to chronic exposure), and quality of the data (1 for a reliable study).