Reaction mass of divinylbenzene and ethylstyrene

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

29 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL for reproductive and developmental effects was 100 mg/kg bw/day which is the lowest NOAEL observed with DVB and considered the critical dose descriptor for deriving the long-term DNELs. Based on available PBPK data for the structural analogue styrene, it is assumed that DVB is well absorbed when administered orally in rabbits as it is in rats and mice. A value of 50% absorption is assumed for derivation of the DNELs and represents a conservative value for DNEL derivation based on data in experimental animals. Similarly, available data in experimental animals and humans show that inhaled styrene vapor is well-absorbed across the respiratory tract and 100% absorption via the inhalation route of exposure is assumed. Therefore, no additional assessment factor was applied to account for differences in the absorption rate via oral and inhalation exposure.

AF for dose response relationship:

1

Justification:

The dose response was unremarkable (no additiona factor needed).

AF for differences in duration of exposure:

1

Justification:

No additional assessment factor for exposure duration needs to be applied as the critical endpoint is the developmental toxicity and the exposure duration of the study covers the critical time period.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling factor has been applied as the oral dose is converted into an air concentration.

AF for other interspecies differences:

1

Justification:

For remaining interspecies differences it is considered justified to use an assessment factor of 1 instead of the default factor of 2.5 based on an extensive database on the toxicokinetics for the structural analogue styrene. The metabolism of styrene is considered to occur largely in the liver. It is clear that metabolism involving styrene oxide as an intermediate is a major route in rodents and humans as well. The kinetics of styrene in human liver are predicted to be similar to those of rats and rabbits. Several studies have been conducted to show that the major routes of DVB hepatic metabolism are comparable to styrene.

AF for intraspecies differences:

5

Justification:

For intra-species differences the default factor of 5 (according to the ECHA Guidance Document, Chapter R.8) has been applied.

AF for the quality of the whole database:

1

Justification:

For quality of the whole database the default factor of 1 (according to the ECHA Guidance Document, Chapter R.8) has been applied.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

20 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

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:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL for reproductive and developmental effects was 100 mg/kg bw/day in an OECD 414 oral gavage study in rabbits. Based on available PBPK data for the structural analogue styrene it is assumed that DVB is well-absorbed (100% absorption) when administered orally in rats or rabbits, whereas absorption in humans via dermal exposure is considered to be very low (only 2% dermal absorption was concluded for styrene in the EU risk assessment report). Therefore, the oral NOAEL has been corrected for dermal absorption assuming that less than 10% of DVB is being absorbed via dermal exposure. This is a conservative value taking into account that the PBPK data from a structural analogue is used.

AF for dose response relationship:

1

Justification:

The dose response was unremarkable (no additional factor needed).

AF for differences in duration of exposure:

1

Justification:

No additional assessment factor for exposure duration needs to be applied as the critical endpoint is the developmental toxicity and the exposure duration of the study covers the critical time period.

AF for interspecies differences (allometric scaling):

4

Justification:

For inter-species differences the default factors (according to the ECHA Guidance Document, Chapter R.8) have been applied.

AF for other interspecies differences:

2.5

Justification:

For inter-species differences the default factors (according to the ECHA Guidance Document, Chapter R.8) have been applied.

AF for intraspecies differences:

5

Justification:

For intra-species differences the default factors (according to the ECHA Guidance Document, Chapter R.8) have been applied.

AF for the quality of the whole database:

1

Justification:

For quality of the database the default factors (according to the ECHA Guidance Document, Chapter R.8) have been applied.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

The reaction mass of divinylbenzene and ethylstyrene (DVB) is not classified for acute toxicity for any route of exposure. Therefore, no short-term DNELs have been derived for workers and the general population.

 

DVB-55 is a weak skin sensitizer based on the results of an LLNA (EC3 > 10). Therefore, appropriate risk management measures will be identified based on assigned classification for handling all grades of the reaction mass of divinylbenzene and ethylstyrene.

 

Worker-DNEL long-term for the inhalation route:

 

For long-term exposure only systemic DNELs were derived. The DNELs for systemic effects are considered to be sufficiently protective for any potential local effects like skin and eye irritation. Adverse effects observed in a number of repeated dose inhalation studies were reduced body and thymus weights, increased organ weights (liver & kidney), nephropathy and renal tubule hyperplasia and necrosis of liver and kidney at higher concentrations. In addition, nasal effects including necrosis of the olfactory epithelium were observed at all dose levels in rats and mice. The read-across to styrene indicates that these nasal effects are rodent-specific (related to P450-2F2-mediated metabolism), and therefore not relevant to human health risk assessment. The OECD 414 study was selected as most relevant study for determining the long-term DNELs because of the reproductive toxicity effects (reduced pup body weight) seen in this study. The NOAEL for reproductive and developmental effects was 100 mg/kg bw/day (equivalent to 27 ppm assuming 50% oral absorption in rabbits) which is the lowest NOAEL observed with DVB and considered the critical dose descriptor for deriving the long-term DNELs.

 

Worker-DNEL long-term for the dermal route:

 

DVB has the potential to be absorbed across the skin and there is the potential for adverse systemic effects to arise as a result of skin exposure. No studies have been undertaken by the dermal route to characterise the dose-response relationship for systemic effects therefore it is necessary to obtain a long-term dermal DNEL by route-to-route extrapolation. Since developmental toxicity has been identified as the critical health endpoint for long-term inhalation exposure, this endpoint will also be the critical endpoint for long-term dermal exposure. The NOAEL for reproductive and developmental effects was 100 mg/kg bw/day in an OECD 414 oral gavage study in rabbits. Based on available PBPK data for the structural analogue styrene it is assumed that DVB is well absorbed (100%) when administered orally in rats and rabbits, whereas absorption in humans via dermal exposure is considered to be very low (only 2% dermal absorption was concluded for styrene in the EU risk assessment report). Therefore, the oral NOAEL has been corrected for dermal absorption assuming that less than 10% of DVB is being absorbed via dermal exposure. This is a conservative value taking into account that the PBPK data from a structural analogue is used.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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:

no hazard identified

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

No DNELs for consumer exposure to DVB/EVB have been derived as no consumer uses of DVB/EVB are known.