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:

11 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:

other: NOEL

Value:

30 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOEL for reproductive and developmental effects was 30 mg/kg bw/day (equivalent to 10 ppm assuming 100% oral absorption in rats) which is the lowest NOEL 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 rats, whereas absorption in humans via inhalation is assumed to be only 63% based on results from human volunteer studies with Styrene. 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:

No additional assessment factor is applicable to account for the lower sensitivity of a screening study in this case. In the study 4 dose levels were used with severe effects occurring at the highest dose level, some effects in the two mid dose levels and no effects in the lowest dose level. At the highest dose level clear toxicity was observed, which likely exceeded the maximum tolerated dose. It should also be taken into account that the test substance administration to the rats was done by oral gavage which can lead to bolus dose effects. Furthermore, the only effect observed at the next higher dose level (100 mg/kg bw/day) was a tendency to reduced average body weights. Therefore, the rat NOEL of 30 mg/kg bw/day is considered to be very conservative and it is unlikely that any additional relevant effects would be observed at lower dose levels in a full reproductive toxicity study according to OECD guideline 414 or 416.

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 the rat. 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:

6 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:

other: NOEL

Value:

30 mg/kg bw/day

Modified dose descriptor starting point:

other: NOEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOEL for reproductive and developmental effects was 30 mg/kg bw/day in an OECD 422 oral gavage study in rats Based on available PBPK data for the structural analogue styrene it is assumed that DVB is well absorbed (100%) when administered orally in rats, 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 NOEL 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:

No additional assessment factor is applicable to account for the lower sensitivity of a screening study in this case. In the study 4 dose levels were used with severe effects occurring at the highest dose level, some effects in the two mid dose levels and no effects in the lowest dose level. At the highest dose level clear toxicity was observed, which likely exceeded the maximum tolerated dose. It should also be taken into account that the test substance administration to the rats was done by oral gavage which can lead to bolus dose effects. Furthermore, the only effect observed at the next higher dose level (100 mg/kg bw/day) was a tendency to reduced average body weights. Therefore, the rat NOEL of 30 mg/kg bw/day is considered to be very conservative and it is unlikely that any additional relevant effects would be observed at lower dose levels in a full reproductive toxicity study according to OECD guideline 414 or 416.

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 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 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 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 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 classifcation 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 422 study was selected as most relevant study for determining the long-term DNELs because of the reproductive toxicity effects (reduced parturition and birth rate, increased pup mortality and reduced pup body weight) seen in this study. The NOEL for reproductive and developmental effects was 30 mg/kg bw/day (equivalent to 10 ppm assuming 100% oral absorption in rats) which is the lowest NOEL 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 NOEL for reproductive and developmental effects was 30 mg/kg bw/day in an OECD 422 oral gavage study in rats Based on available PBPK data for the structural analogue styrene it is assumed that DVB is well absorbed (100%) when administered orally in rats, 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 NOEL 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.