Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.34 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:
617.8 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:
4.17 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
299 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

Composition

This substance is of complex composition by process that meets the criteria of a UVCB. It contains

      i.         multiple Phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc species (neutral dimeric, trimeric, and tetrameric dithiophosphate forms)

    ii.         their basic salt compliments,

   iii.         Tetrapropenyl phenol (residual starting material),

   iv.         base oil (solvent).

 

Dermal Absorption:

 

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

 Physicochemical properties:

MW: 1301

Measured water solubility: <5mg/L

Measured Log Kow:> 2.59 (the upper limit is estimated to be < 3.6 by read across to an analog substance, EC 224-235-5)

Vapor pressure: 4.1 x10-3Pa at 25oC

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 relatively high molecular weight, low water solubility, low Log Kow, and low vapor pressure, suggested low absorption via dermal, oral or inhalative administration routes. 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 (details see Toxicokinetic).

 

Justification for 100% dermal absorption for TPP

Physicochemical properties:

MW: <500

Measured water solubility: 1.54 mg/L

Measured Log Kow:7.73 

Vapor pressure: 1.1 x10-2Pa at 25oC

Based on discussion on TPP toxicokinetic (reference: CSR for CAS 121158-58-5, EC 310-154-3), dermal penetration is expected for this substance due to its small molecular weight/size and lipophilicity and 100% dermal absorption was assumed for DNEL derivation. Therefore, same parameters were used in the current communication.

 

 

DNEL - short term local effect

Exposure based waiver.

 

DNEL - short term, systemic effect

Dermal route:

  • Descriptor: Acute dermal study, NOAEL is 25600 mg/kg in rats
  • AF:

4 for allometric scale,

2.5 for remaining difference,

5 for intraspecies difference (workers)

  • Correct for concentration of 58.4%

 

Inhalation route:

  • Descriptor: the acute oral NOAEL of 7500 mg/kg
  • Corrected descriptor: 1.76((1/sRVrat(0.38) x (ABSoral-rat(100)/ABSinh-rat(100)) x (sRVhuman (0.67)/wRV (10))) to give a corrected acute inhalation NOAEC of 13,200 mg/m3
  • AF:1 for allometric scale,2.5 for remaining differen5 for intraspecies difference (workers),
  • Correct for concentration of 58.4%

DNEL - long term local effect:

Exposure based waiver.

 

DNEL - long term, systemic effect

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:  

  • Repeat dose toxicity study is not available for phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc, but an OECD 407 (NOAEL = 125 mg/kg/d) and OECD 422 (NOAEL = 160 mg/kg/d) toxicity study in rats were available for category substances EC 224-235-5 and EC270-608-0, respectively. These substances show similarities in structure and chemistry, presumably toxicological effects. Therefore the lowest NOAEL from the two studies were used to derive DNEL for the current registration substance.   See the repeat dose data waiver for read across justifications.

DNEL calculation is present in Table 1. 

 

  • 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 8.27% TPP, a dose of 181.4 mg/kg/day (15 mg/kg bw/day divided by 8.27%) 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.

DNEL calculation is present in Table 2. 

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

 

 

Table 1. The long-term systemic DNELs for Phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc are calculated as follows (workers):

 

Route

Dose descriptor

Corrected dose descriptor

Most sensitive endpoint

DNEL

Justification

Dermal

NOAEL: 125.0 mg/kg bw/day, oral study

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

Repeated dose toxicity

4.17 mg/kg bw/day

An assessment factor of 300 is based on the following:

4 for allometric scale,

2.5 for remaining difference,

5 for intraspecies difference (workers),

6 for duration extrapolation (subacute to chronic exposure),

1 for quality of the data (a reliable study).

 

Inhalation

NOAEL: 125.0 mg/kg bw/day

220 mg/m3

Repeated dose toxicity

7.34 mg/m3

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 220.4mg/m3.

 

An assessment factor of 30 is based on the following:

1 for interspecies difference,

5 for intraspecies difference (workers),

6 for duration extrapolation (subacute to chronic exposure),

1 for quality of the data (a reliable study).

 

 

Table 2. 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

181.4 mg/kg bw/day

 

(concentration in the registered substance is 8.27%)

Reproductive toxicity

1.81 mg/kg bw/day

Ø The NOAEL of 15 mg/kg bw/day is divided by 8.27% to correct for the amount of TPP to obtain the corrected dose descriptor.

Ø An assessment factor of 100 is based on:

4 for allometric scale,

2.5 for remaining difference,

5 for intraspecies difference (workers),

2 for duration extrapolation (subchronic to chronic exposure),

1 for quality of the data (a reliable study).

Inhalation

NOAEL: 15.0 mg/kg bw/day

290 mg/m3

Reproductive toxicity

12.7 mg/m3

Ø The NOAEL of 15 mg/kg bw/day is divided by 8.27% to correct for the amount of TPP to obtain the corrected dose descriptor.

Ø Using a correction factor of 181.4 mg/kg/d((1/sRVrat(0.38))x(ABSoral-rat(100)/ABSinh-human(100))x(sRVhuman(6.7)/wRV(10))) giving a corrected inhalation NOAEC value of 319.8 mg/m3/d.

Ø An assessment factor of 25 is based on

2.5 for interspecies difference (remaining difference),

5 for intraspecies difference (workers),

2 for duration extrapolation (subchronic to chronic exposure),

1 for quality of the data (a reliable study).

 

 

 

 

 

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.81 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:
152.3 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
25
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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.1 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:
149.5 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:
43.8 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Composition

This substance is of complex composition by process that meets the criteria of a UVCB. It contains

    i.          multiple Phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc species (neutral dimeric, trimeric, and tetrameric dithiophosphate forms)

    ii.         their basic salt compliments,

   iii.         Tetrapropenyl phenol (residual starting material),

   iv.         base oil (solvent).

 

Dermal Absorption:

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

 Physicochemical properties:

MW: 1301

Measured water solubility: <5mg/L

Measured Log Kow:> 2.59 (the upper limit is estimated to be < 3.6 by read across to an analog substance, EC 224-235-5)

Vapor pressure: 4.1 x10-3Pa at 25oC

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 relatively high molecular weight, low water solubility, low Log Kow, and low vapor pressure, suggested low absorption via dermal, oral or inhalative administration routes. 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 (details see Toxicokinetic).

 

Justification for 100% dermal absorption for TPP

     Physicochemical properties:

MW: <500

Measured water solubility: 1.54 mg/L

Measured Log Kow:7.73 

Vapor pressure: 1.1 x10-2Pa at 25oC

Based on discussion on TPP toxicokinetic (reference: CSR for CAS 121158-58-5, EC 310-154-3), dermal penetration is expected for this substance due to its small molecular weight/size and lipophilicity and 100% dermal absorption was assumed for DNEL derivation. Therefore, same parameters were used in the current communication.

 

 

DNEL - short term local effect

Exposure based waiver.

 

DNEL - short term, systemic effect

Dermal route:

  • Descriptor: Acute dermal study, NOAEL is 25600 mg/kg in rats
  • AF:

4 for allometric scale,

2.5 for remaining difference,

10 for intraspecies difference (general populations)

  • Correct for concentration of 58.4%

 

Inhalation route:

  • Descriptor: the acute oral NOAEL of 7500 mg/kg
  • Corrected descriptor: 1.76((1/sRVrat(0.38) x (ABSoral-rat(100)/ABSinh-rat(100)) x (sRVhuman (0.67)/wRV (10))) to give a corrected acute inhalation NOAEC of 13,200 mg/m3
  • AF: 1 for allometric scale, 2.5 for remaining different 10 for intraspecies difference (general populations),
  • Correct for concentration of 58.4%

Oral route:

  • Descriptor: the acute oral NOAEL of 7500 mg/kg
  • AF: 4 for allometric scale, 2.5 for remaining different 10 for intraspecies difference (general populations),
  • Correct for concentration of 58.4%

 

DNEL - long term local effect:

Exposure based waiver.

 

DNEL - long term, systemic effect

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:  

  • Repeat dose toxicity study is not available for phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc, but an OECD 407 (NOAEL = 125 mg/kg/d) and OECD 422 (NOAEL = 160 mg/kg/d) toxicity study in rats were available for category substances EC 224-235-5 and EC270-608-0, respectively. These substances show similarities in structure and chemistry, presumably toxicological effects. Therefore the lowest NOAEL from the two studies were used to derive DNEL for the current registration substance.   See the repeat dose data waiver for read across justifications.

DNEL calculation is present in Table 1. 

 

  • 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 8.27% TPP, a dose of 1181.4 mg/kg/day (15 mg/kg bw/day divided by 8.27%) 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.

DNEL calculation is present in Table 2. 

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

 

Table 1. The long-term systemic DNELs for Phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc are calculated as follows (general populations):

 

Route

Dose descriptor

Corrected dose descriptor

Most sensitive endpoint

DNEL

Justification

Dermal

NOAEL: 125.0 mg/kg bw/day, oral study

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

Repeated dose toxicity

2.1 mg/kg bw/day

An assessment factor of 600 is based on the following:

4 for allometric scale,

2.5 for remaining difference,

10 for intraspecies difference (general populations),

6 for duration extrapolation (subacute to chronic exposure),

1 for quality of the data (a reliable study).

 

Corrected for concentration: 58.4%

Inhalation

NOAEL: 125.0 mg/kg bw/day

108.7 mg/m3

Repeated dose toxicity

1.81 mg/m3

Using a correction factor of 0.87((1/sRVrat(1.15))x(ABSoral-rat(100)/ABSinh-human(100))) giving a corrected inhalation NOAEC value of 108.7mg/m3.

 

An assessment factor of 60 is based on the following:

1 for interspecies difference,

10 for intraspecies difference (general populations),

6 for duration extrapolation (subacute to chronic exposure),

1 for quality of the data (a reliable study).

Oral

NOAEL: 125.0 mg/kg bw/day

NOAEL: 125.0 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 since QSAR modeling predicated no metabolic activities occurred in the skin,

10 for intraspecies difference (general populations),

6 for duration extrapolation (subacute to chronic exposure),

1 for quality of the data (a reliable study).

 

Corrected for concentration: 58.4%

 

Table 2. The long-term systemic DNELs for tetrapropenyl phenol are calculated as follows (general population):

 

Route

Dose descriptor

Corrected dose descriptor

Most sensitive endpoint

DNEL

Justification

Dermal

NOAEL: 15.0 mg/kg bw/day

181.4 mg/kg bw/day

 

(concentration in the registered substance is 8.27%)

Reproductive toxicity

0.907 mg/kg bw/day

The NOAEL of 15 mg/kg bw/day is divided by 8.27% to correct for the amount of TPP to obtain the corrected dose descriptor.

 

An assessment factor of 200 is based on:

4 for allometric scale,

2.5 for remaining difference,

5 for intraspecies difference (general populations),

2 for duration extrapolation (subchronic to chronic exposure),

1 for quality of the data (a reliable study).

Inhalation

NOAEL: 15.0 mg/kg bw/day

108.7 mg/m3

Reproductive toxicity

3.154 mg/m3

The NOAEL of 15 mg/kg bw/day is divided by 8.27% to correct for the amount of TPP to obtain the corrected dose descriptor of 181.4 mg/kg/d.

 

Using a correction factor 0.87((1/sRVrat(1.15))x(ABSoral-rat(100)/ABSinh-human(100))) giving a corrected inhalation NOAEC value of 108.7 mg/m3/d.

 

An assessment factor of 50 is based on

2.5 for interspecies difference (remaining difference),

10 for intraspecies difference (general populations),

2 for duration extrapolation (subchronic to chronic exposure),

1 for quality of the data (a reliable study).

Oral

NOAEL: 15.0 mg/kg bw/day

181.4 mg/kg bw/day

 

(concentration in the registered substance is 8.27%)

Reproductive toxicity

0.907 mg/kg bw/day

The NOAEL of 15 mg/kg bw/day is divided by 8.27% to correct for the amount of TPP to obtain the corrected dose descriptor.

 

An assessment factor of 200 is based on:

4 for allometric scale,

2.5 for remaining difference,

10 for intraspecies difference (general populations),

2 for duration extrapolation (subchronic to chronic exposure),

1 for quality of the data (a reliable study).