Propan-2-ol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

500 mg/m³

DNEL related information

DNEL derivation method:

other: Based on occupational exposure limit

Overall assessment factor (AF):

1

Dose descriptor starting point:

other: worker OEL (8 hr TWA)

Value:

500 mg/m³

Explanation for the modification of the dose descriptor starting point:

No modification required as the DNEL is based on an occupational exposure limit.

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

1

AF for intraspecies differences:

1

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 000 mg/m³

DNEL related information

DNEL derivation method:

other: Based on occupational exposure level

Overall assessment factor (AF):

1

DNEL extrapolated from long term DNEL

Dose descriptor starting point:

other: worker OEL (8 hr TWA)

Value:

500 mg/m³

Modified dose descriptor starting point:

other: worker OEL (peak exposure limit)

Value:

1 000 mg/m³

Explanation for the modification of the dose descriptor starting point:

Substance-specific excursion factors (ratio of permitted short-term peak value to the MAK value) have been established by the DFG, depending on the mode of action. IPA is Category II, with a generic excursion factor of 2. Therefore a DNEL has been established based on the peak exposure limit which is 500*2 = 1000 mg/m³.

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:

888 mg/kg bw/day

DNEL related information

DNEL derivation method:

other: Based on occupational exposure limit

Overall assessment factor (AF):

1

Dose descriptor starting point:

other: worker OEL (8 hr TWA)

Value:

500 mg/m³

Modified dose descriptor starting point:

NOAEL

Value:

888 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Correction inhalation to dermal 500 mg/m³x 10 m³/d/70 kg = 71 mg/kg bw/day;

Correction for absorption: 71 mg/kg/d x 100%/8% = 888 mg/kg bw/day.

Dermal absorption of IPA is rapid but limited. Following a 4-hour occlusive application 84 to 86% of the applied dose was recovered from the skin and 8 to 9% was lost (presumably to volatilization); thus, approximately 5 to 8% of the applied dose was absorbed systemically (see toxicokinetic statement). For the purpose of the DNEL calculation, dermal absorption was conservatively assumed to be 8%.

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

Acute DNELs:

Worker: Production of IPA is in excess of 10 t/y. According to the REACh "Guidance on information requirements and chemical safety assessment, Part B: Hazard Assessment", above 10 t/y, the establishment of acute toxicity DNEL is unnecessary in most cases, as the DNEL based on repeated dose toxicity is normally sufficient to ensure that adverse effects do not occur. However, IPA is classified for STOT Single Exp. 3 (narcosis) after inhalation and oral exposure, so an acute inhalation systemic DNEL has been calculated based on the long-term DNEL and the generic excursion factor applicable to IPA.

Local DNELs:

Since there are only few and partially only conditionally convincing results concerning the irritant effect of 2-propanol in man and animal, any irritant effect is considered unlikely at this concentration.

Long-term DNELs:

IOEL/OEL

There is no IOEL value for IPA. A German MAK was available and deemed suitable for derivation of the DNEL.

Reference:  Deutsche Forschungsgemeinschaft MAK- und BAT-Werte-Liste 2021 Ständige Senatskommission zur Prüfung gesundheitsschädlicher Arbeitsstoffe Report No. 57.

"The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated the maximum concentration at the workplace (MAK value) and the Pregnancy Risk Group of isopropyl alcohol [67‐63‐0].

In carcinogenicity studies no tumours were observed in rats and mice up to 5000 ml/m³. From the LOAEC in rats and mice of 2500 ml/m³ where narcotic effects were observed, a MAK value of 200 ml/m3 is derived also considering the increased respiratory volume at the workplace because the blood:air partition coefficient of isopropyl alcohol is > 5 (see List of MAK and BAT Values, Sections I b and I c). Therefore, the MAK value of 200 ml/m³ is confirmed. At this concentration, no irritation is expected in humans based on the limited data in humans and animals.

Since a systemic effect is critical, Peak Limitation Category II is retained for isopropyl alcohol. Due to the half‐life of up to 2 hours in rats, the excursion factor of 2 is confirmed.

In developmental toxicity studies, isopropyl alcohol does not result in teratogenicity but in fetotoxicity at maternally toxic doses in rats and rabbits. According to a PBPK model and considering the increased respiratory volume at the workplace, the NOAEL of 600 mg/kg body weight in rats is scaled to a concentration of 1000 ml/m³. There is no PBPK model for rabbits but due to the similar NOAEL for developmental toxicity in rabbits the same concentration is supposed. Because fetotoxicity was only observed at maternally toxic doses, the difference of the NOAEC for fetotoxicity and the MAK value is sufficient so that isopropyl alcohol remains assigned to Pregnancy Risk Group C."

Reference

Hartwig, A., Arand, M., & MAK Commission. (2019). Isopropyl alcohol [MAK Value Documentation, 2018]. The MAK Collection for Occupational Health and Safety, 4(4), 2114-2121.

Absorption Data

Oral: Oral absorption is nearly 100% as evidenced by the nearly complete lack of radiolabel in feces for up to 168 hours following gavage administration of radiolabeled IPA (see toxicokinetic statement)

Inhalation: IPA has a molecular weight of <500 g/mol and a log Kow between 0 and 4; therefore, it is assumed to be well absorbed equivalently by the oral and inhalation route; therefore, inhalation absorption assumed to be 100%.

Dermal: Dermal absorption of IPA is rapid but limited. Following a 4-hour occlusive application 84 to 86% of the applied dose was recovered from the skin and 8 to 9% was lost (presumably to volatilization); thus, approximately 5 to 8% of the applied dose was absorbed systemically (see toxicokinetic statement). For the purpose of the DNEL calculation, dermal absorption was conservatively assumed to be 8%.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

89 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other: Based on occupational exposure limit

Overall assessment factor (AF):

2

Dose descriptor starting point:

other: worker OEL (8 hr TWA)

Value:

500 mg/m³

Modified dose descriptor starting point:

other: worker OEL (8 hr TWA) adjusted for continual exposure

Value:

178 mg/m³

Explanation for the modification of the dose descriptor starting point:

The long-term DNEL for the general population was derived from the worker OEL.

Starting Dose for DNEL calculation: 500 mg/m³ (based on occupational exposure of 8 hours/day, 5 days/week) (adjusted below for continuous exposure)

Modified dose for DNEL Calculation General Population – Inhalation =500 mg/m³ x10/6.7x 8/24 x 5/7 (adjusted for continuous exposure) = 178 mg/m³.

AF for intraspecies differences:

2

Justification:

when extrapolating from animal to human, the recommended AF is 10 for general population and 5 for worker – since the starting dose is adjusted for continuous exposure an additional 2 -fold AF for differences was considered sufficient.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

178 mg/m³

DNEL related information

DNEL derivation method:

other: Based on occupational exposure level

Overall assessment factor (AF):

2

DNEL extrapolated from long term DNEL

Explanation for the modification of the dose descriptor starting point:

The acute inhalation systemic DNEL for the general population was derived from the long-term inhalation DNEL.

Substance-specific excursion factors (ratio of permitted short-term peak value to the MAK value) have been established by the DFG, depending on the mode of action. IPA is Category II, with a generic excursion factor of 2. Therefore a DNEL has been established based on the long-term DNEL which is 89*2 = 178 mg/m³.

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:

319 mg/kg bw/day

DNEL related information

DNEL derivation method:

other: Based on occupational exposure limit

Overall assessment factor (AF):

2

Dose descriptor starting point:

other: worker OEL (8 hr TWA) adjusted for continual exposure

Value:

178 mg/m³

Modified dose descriptor starting point:

other: worker OEL (8 hr TWA) corrected for dermal exposure

Value:

638 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Correction inhalation to dermal: 178 mg/m³x 20m³ /day/70 kg = 51 mg/kg bw/day

Correction for absorption (see below): 51 mg/kg bw/day x 100%/8% = 638 mg/kg bw/day

Dermal absorption of IPA is rapid but limited. Following a 4-hour occlusive application 84 to 86% of the applied dose was recovered from the skin and 8 to 9% was lost (presumably to volatilization); thus, approximately 5 to 8% of the applied dose was absorbed systemically (see toxicokinetic statement). For the purpose of the DNEL calculation, dermal absorption was conservatively assumed to be 8%.

AF for intraspecies differences:

2

Justification:

when extrapolating from animal to human, the recommended AF is 10 for general population and 5 for worker – since the starting dose is adjusted for continuous exposure an additional 2-fold AF for differences was considered sufficient

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:

26 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other: Based on occupational exposure limits

Overall assessment factor (AF):

2

Modified dose descriptor starting point:

other: worker OEL (8 hr TWA) adjusted for continual oral exposure

Value:

51 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Correction inhalation to oral: 178 mg/m3x 20 m3/d/70 kg = 51 mg/kg/d (no adjustment for absorption)

AF for intraspecies differences:

2

Justification:

when extrapolating from animal to human, the recommended AF is 10 for general population and 5 for worker – since the starting dose is adjusted for continuous exposure an additional 2 -fold AF for differences was considered sufficient.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

51 mg/kg bw/day

DNEL related information

Explanation for the modification of the dose descriptor starting point:

The acute oral systemic DNEL for the general population was derived from the long-term oral DNEL.

Substance-specific excursion factors (ratio of permitted short-term peak value to the MAK value) have been established by the DFG, depending on the mode of action. IPA is Category II, with a generic excursion factor of 2. Therefore a DNEL has been established based on the long-term DNEL which is 26*2 = 51 mg/kg bw/day.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)