Propylene carbonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

70.53 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):

62.5

Dose descriptor starting point:

NOAEL

Value:

5 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

4 408 mg/m³

Explanation for the modification of the dose descriptor starting point:

As stated above, the oral 90 days repeated dose toxicity study of Huntsman (1989) was observed to be the most sensitive study and it is used to derive a DNEL long-term exposure, systemic effects, using a starting point of 5000 mg/kg bw/day.

For the route-to-route extrapolation from oral to inhalation, the dose descriptor starting point = 5000 mg/kg bw/day x 1/(0.38 m³/kg/day) x 6.7 m³/10 m³ x 0.5 = 4408 mg/m³. The oral dose for rats is converted to the corresponding air concentration using a standard breathing volume for the rat (0.38 m³/kg for 8 hours exposure of workers). For workers the resulting air concentration needs to be additionally corrected for the difference between basal caloric demand and caloric demand under light activity. This correction factor is derived from the inhaled volumes in 8 hours under the respective conditions (6.7 m³ for base level, 10 m³ for light activity). In addition, the NOAEL needs to be divided by 2 as the bioavailability via the inhalation route is considered as 100%, while for oral exposure this is only 50% (See toxicokinetic assessment in section 7.1 of the IUCLID file).

AF for dose response relationship:

2.5

Justification:

addressing the uncertainty related to the NOAEL used for DNEL derivation

AF for differences in duration of exposure:

2

Justification:

subchronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

Covered by calculation for route-to-route extrapolation

AF for other interspecies differences:

2.5

Justification:

rat to human

AF for intraspecies differences:

5

Justification:

worker population

AF for the quality of the whole database:

1

Justification:

default assessment factor

AF for remaining uncertainties:

1

Justification:

default assessment factor

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

20 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Dose descriptor:

NOAEC

Value:

100 mg/m³

AF for dose response relationship:

1

Justification:

default assessment factor

AF for differences in duration of exposure:

1

Justification:

default assessment factor for local effects

AF for interspecies differences (allometric scaling):

1

Justification:

default assessment factor (local effects)

AF for other interspecies differences:

1

Justification:

default assessment factor (local effects)

AF for intraspecies differences:

5

Justification:

worker population

AF for the quality of the whole database:

1

Justification:

default assessment factor

AF for remaining uncertainties:

1

Justification:

default assessment factor

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

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:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

250

Dose descriptor starting point:

NOAEL

Value:

5 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

5 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No long-term dermal toxicity studies are available for propylene carbonate. However, data from other repeated toxicity studies could be used after extrapolation to the dermal route. One key study is available for the inhalation route: a 90-day repeated inhalation study (Bushy Run Research Center, 1991). In addition, two reliable long-term toxicity tests are available for the oral route: a 90 days repeated dose toxicity test (Huntsman, 1989) and a prenatal developmental toxicity study (Huntsman, 1988).

In the 90-day repeated inhalation study (Bushy Run Research Center, 1991), rats were exposed at dose levels of 100, 500 and 1000 mg/m³ (nominal). Repeated exposure to propylene carbonate at concentrations up to 1000 mg/m³ produced only signs of minimal irritation to the eyes in rats. The NOAEC (systemic effects) was derived to be 1000 mg/m³ and the NOAEC (local effects) was derived to be 100 mg/m³. Although 100% absorption is expected after inhalation exposure to propylene carbonate, no systemic adverse effects were observed up to the highest dose.

Huntsman (1989) investigated the oral toxicity of propylene carbonate after repeated exposure (90 days) in male/female Sprague-Dawley rats. The oral administration of propylene carbonate (5 days a week) over a period of 90 days did not exert an apparent toxicological effect (NOAEL of > 5000 mg/kg bw/day).

Huntsman (1988) performed a prenatal developmental toxicity study in 27 Sprague-Dawley rats at dose levels of 1000, 3000 and 5000 mg/kg bw/day and reported that there were no gross fetal malformations observed in any dose group. Albeit maternal toxicity, development of fetuses was not affected in all surviving rats up to the highest concentration. The comparison of the data from both studies indicate that prolongation of treatment does not increase toxicity: if mortality was indeed treatment-related, gestation rather than time seems to sensitize to propylene carbonate-induced toxicity.

In conclusion and as maternal effects occurred at doses where no developmental effects were observed (i.e. 1000 mg/kg bw/day), the 90 days repeated dose study was considered as the most reliable and relevant study. The NOAEL of 5000 mg/kg bw/d was therefore selected as starting point for the DNEL derivation for long-term exposure, systemic effects for the dermal route. The uncertainty related to using a higher NOAEL as starting dose is covered by an additional assessment factor of 2.5 for dose response relationship.

For route-to-route extrapolation (oral to dermal), no default factor (i. e. factor 1) should be applied as part of the overall assessment factor, as it is assumed that dermal absorption will not be higher than oral absorption (See toxicokinetic assessment in section 7.1 of the IUCLID file).

AF for dose response relationship:

2.5

Justification:

addressing the uncertainty related to the NOAEL used for DNEL derivation

AF for differences in duration of exposure:

2

Justification:

subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

rat to human

AF for other interspecies differences:

2.5

Justification:

rat to human

AF for intraspecies differences:

5

Justification:

worker population

AF for the quality of the whole database:

1

Justification:

default assessment factor

AF for remaining uncertainties:

1

Justification:

default assessment factor

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/cm²

DNEL related information

DNEL derivation method:

other: long-term, inhalation DNEL for local effects: interspecies (1: local effects) x intraspecies (10) x exposure duration (1: local effects)

Dose descriptor:

NOAEC

Value:

100 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.4 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):

125

Dose descriptor starting point:

NOAEL

Value:

5 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

2 174 mg/m³

Explanation for the modification of the dose descriptor starting point:

As stated above, the oral 90 days repeated dose toxicity study of Huntsman (1989) was observed to be the most sensitive study and it is used to derive a DNEL long-term exposure, systemic effects, using a starting point of 5000 mg/kg bw/day.

For the route-to-route extrapolation from oral to inhalation, the dose descriptor starting point = 5000 mg/kg bw/day x 0.5 / 1.15 m³/kg = 2174 mg/m³. The oral dose for rats is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m³/kg for 24 hours exposure). In addition, the NOAEL needs to be divided by 2 as the bioavailability via the inhalation route is considered as 100%, while for oral exposure this is only 50% (See toxicokinetic assessment in section 7.1 of the IUCLID file).

AF for dose response relationship:

2.5

Justification:

addressing the uncertainty related to the NOAEL used for DNEL derivation

AF for differences in duration of exposure:

2

Justification:

subchronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

Covered by calculation for route-to-route extrapolation

AF for other interspecies differences:

2.5

Justification:

rat to human

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

default assessment factor

AF for remaining uncertainties:

1

Justification:

default assessment factor

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor:

NOAEC

Value:

100 mg/m³

AF for dose response relationship:

1

Justification:

default assessment factor

AF for differences in duration of exposure:

1

Justification:

default assessment factor for local effects

AF for interspecies differences (allometric scaling):

1

Justification:

default assessment factor for local effects

AF for other interspecies differences:

1

Justification:

default assessment factor for local effects

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

default assessment factor

AF for remaining uncertainties:

1

Justification:

default assessment factor

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:

10 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):

500

Dose descriptor starting point:

NOAEL

Value:

5 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

5 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No long term dermal toxicity studies are available for propylene carbonate. However, data from other repeated dose toxicity studies could be used after extrapolation to the dermal route.

As discussed above in the Workers discussion section, the oral 90 days repeated dose toxicity study of Huntsman (1989) was observed to be the most sensitive study. The NOAEL of 5000 mg/kg bw/d was selected as starting point for the DNEL derivation for long-term exposure, systemic effects for the dermal route. The uncertainty related to using a higher NOAEL as starting dose is covered by an additional assessment factor of 2.5 for dose response relationship.

For route-to-route extrapolation (oral to dermal), no default factor (i. e. factor 1) should be applied as part of the overall assessment factor, as it is assumed that dermal absorption will not be higher than oral absorption (See toxicokinetic assessment in section 7.1 of the IUCLID file).

AF for dose response relationship:

2.5

Justification:

addressing the uncertainty related to the NOAEL used for DNEL derivation

AF for differences in duration of exposure:

2

Justification:

subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

rat to human

AF for other interspecies differences:

2.5

Justification:

rat to human

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

default assessment factor

AF for remaining uncertainties:

1

Justification:

default assessment factor

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:

DNEL (Derived No Effect Level)

Value:

10 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):

500

Dose descriptor starting point:

NOAEL

Value:

5 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

5 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

As stated above, the oral 90 days repeated dose toxicity study of Huntsman (1989) was observed to be the most sensitive study and it is used to derive a DNEL long-term exposure, systemic effects, using a starting point of 5000 mg/kg bw/day.

AF for dose response relationship:

2.5

Justification:

addressing the uncertainty related to the NOAEL used for DNEL derivation

AF for differences in duration of exposure:

2

Justification:

subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

human to rat

AF for other interspecies differences:

2.5

Justification:

human to rat

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

1

Justification:

default assessment factor

AF for remaining uncertainties:

1

Justification:

default assessment factor

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

Long-term exposure, local effects, oral exposure:

- No local effects were observed in the Pharmakon Research International Inc. study (1989) after repeated oral exposure but this study is not relevant as route-to-route extrapolation is not applied for local effects according to ECHA Practical guide no 14 (2012). Therefore, it is not possible to derive a long-term exposure for local effects after oral exposure.