4-methylpentan-2-ol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

83 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

208 mg/m³

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

83 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

104 mg/m³

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Overall assessment factor (AF):

2

Dose descriptor starting point:

LOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.8 mg/kg bw/day

DNEL related information

Overall assessment factor (AF):

1

Acute/short term exposure

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

Additional information - workers

Occupational exposure limits (OEL) for MIBC are in force in different EU countries. Short-term (15-min) limit values are 20 ppm (85 mg/m³) in Germany, 40 ppm (170 mg/m³) in Austria, Belgium, Spain, Sweden and UK and 50 ppm (200 mg/m³) in Denmark and 8-hour limit values are 20 ppm (85 mg/m³) in Germany, and 25 ppm (100 mg/m³) in Austria, Belgium, Denmark, France, Spain, Sweden and UK. However, the scientific backgrounds for setting these national OELs are not available.

MIBC is efficiently metabolized to methylisobutyl ketone (MIBK), which is subsequently metabolized to diacetone alcohol (DAA) by hydroxylation by the hepatic microsomal mixed function oxidase system. Thus, MIBK may be used as an appropriate surrogate for MIBC and vice versa considering that both compounds are quantitatively (80%) metabolized to DAA.

Acute / short-term exposure - systemic effects

Dermal DN(M)EL

A DNEL for short term duration (short term event, peak exposure) will not need to be derived in the case where an acute toxicity hazard (leading to C&L) has not been identified. The acute dermal LD50 of MIBC is 3.56 ml/kg (Smyth et al., 1951).

Inhalation DN(M)EL

Indicative occupational exposure limit (IOEL) values have been published for MIBK in Commission Directive 2000/39/EC of 8 June 2000. Thelimit value above which exposure to MIBK should not occur and related to a 15-minute period (STEL) is 50 ppm (208 mg/m³).

Supporting this IOEL is a DNEL calculated from an acute 4-h inhalation toxicity study with MIBC (Blair, 1981). In this study, all exposed animals were anaesthetised within the first hour of exposure to 10000 mg/m3 and regained consciousness within half an hour of completion of exposure.For DNEL derivation, the concentration of 10000 mg/m³is used as PoD. The application of assessment factors of 3 for extrapolation of a NAEC and 2.5 for intraspecies differences and 5 for interspecies differences leads to aDNEL of 266.6 mg/m³.

The DNEL for acute / short-term inhalation exposure - systemic effects is 208 mg/m³ based on the MIBK IOEL.

Acute / short-term exposure - local effects

Dermal DN(M)EL

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

Inhalation DN(M)EL

Silverman et al.(1946) reported that the results of human trials for sensory response to various concentrations of MIBC in air showed that eye irritation occurred at an exposure of 50 ppm (208 mg/m3) for15 minutes. Odor was not objectionable at this concentration. Exposure at more than 50 ppm was required to cause nasal and throat irritation and 25 ppm (104 mg/m3) was estimated to be the highest concentration acceptable for 8 hours.

In view of the eye irritation occurring in persons exposed at 50 ppm, the application of assessment factors of 2 for extrapolation of a NAEC and 1 for intraspecies differences leads to a DNEL of 104 mg/m³(25 ppm).

The DNEL for acute / short-term inhalation exposure - local effects is 104 mg/m³ based on eye irritation in humans.

Long-term exposure - systemic effects

Dermal DN(M)EL

The DNEL is derived using the 8-hour MIBK IOEL of 83 mg/m3 as point of departure (PoD). As the MW was not greater than 500 g/mol nor the log P less than -1 or greater than 4, dermal absorption was assumed to be the same as for the inhalation route. Considering absorption of 100% by inhalation and by dermal route, the equivalent dermal (internal) dose is 11.8 mg/kg (83 mg/m3 x 10 m3 / 70 kg) for workers.

Supporting this calculation, is the DNEL derived from the inhalation 2-year studies with MIBK. The Pod is theNOAEC 450 ppm (1840 mg/m³).As the MW was not greater than 500 g/mol nor the log P less than -1 or greater than 4, dermal absorption was assumed to be the same as for the inhalation route. Considering a ventilation rate of 0.29 m3/kg in rats for a 6-hour exposure, the equivalent dermal (internal) dose is 533.3 mg/kg bw. The application of assessment factors of 2.5 for remaining interspecies differences, 4 for allometric scaling and 5 for intraspecies leads to a DNEL of 10.7 mg/kg bw.

TheDNEL for long-term dermal exposure - systemic effects is 11.8 mg/kg bw based on the MIBK IOEL.

Inhalation DN(M)EL

Indicative occupational exposure limit (IOEL) values have been published for MIBK in Commission Directive 2000/39/EC of 8 June 2000. Thelimit value above which exposure to MIBK should not occur and related to a reference period of eight-hours time-weighted average (TWA) is 20 ppm (83 mg/m³).

Supporting this IOEL are the results of toxicity and carcinogenicity studies of MIBK in F344N rats and B6C3F1 mice following 2-year inhalation exposure (Stout et al., 2008). From these long-term studies, a NOAEC of 450 ppm (1845 mg/m³) could be derived for repeated toxicity and carcinogenicity. For the purpose of DNEL derivation, the NAEC (8h) for workers will be 927 mg/m3 (1845 mg/m3 x 6h/8h x 6.7 m3/10 m³) after correction for difference in exposure conditions and between respiratory rates under standard conditions and under conditions of light activity.The application of assessment factors of 2.5 for remaining interspecies differences and 5 for intraspecies differences leads to a DNEL of 74.2 mg/m³.

The DNEL for long-term inhalation exposure - systemic effects is 83 mg/m³ based on the MIBK IOEL.

Long-term exposure - local effects

Dermal DN(M)EL

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

Inhalation DN(M)EL

MIBC is classified as an irritant for the respiratory tract. Eye irritation have been observed in persons exposed at 50 ppm (208 mg/m³) MIBC for 15 minutes (Silverman et al., 1946) and 25 ppm (104 mg/m³) was suggested to be a reliable safe limit for exposure. However, no clinical and histological signs of respiratory tract irritation were observed during a 6-week inhalation toxicity study in rats up to a concentration of 890 ppm (3698 mg/m³) (Blair, 1982).

Considering this discrepancy, the DNEL of 83 mg/m³for long-term inhalation exposure - systemic effects is assumed to be protective for the local effects.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14.7 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

155.2 mg/m³

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14.7 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

52.1 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Overall assessment factor (AF):

4

Dose descriptor starting point:

LOAEC

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.2 mg/kg bw/day

DNEL related information

Overall assessment factor (AF):

2

Acute/short term exposure

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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.2 mg/kg bw/day

DNEL related information

Overall assessment factor (AF):

2

Acute/short term exposure

DNEL related information

Additional information - General Population

MIBC is efficiently metabolized to MIBK, which is subsequently metabolized to DAA by hydroxylation by the hepatic microsomal mixed function oxidase system. Thus, methyl i-butyl ketone may be used as an appropriate surrogate for MIBC and vice versa considering that both compounds are quantitatively (80%) metabolized to DAA.

Acute / short-term exposure - systemic effects

Dermal DN(M)EL

A DNEL for short term duration (short term event, peak exposure) will not need to be derived in the case where an acute toxicity hazard (leading to C&L) has not been identified. The acute dermal LD50 of MIBC is 3.56 ml/kg (Smyth et al., 1951).

Inhalation DN(M)EL

The DNEL is derived using the 15-min MIBK IOEL of 208 mg/m3 as point of departure (PoD). The PoD adjusted to the ventilation rate of the general population (10 m3/6.7 m3) is 310.4 mg/m3. The application of assessment factors of 2 (10/5) for the additional intraspecies differences leads to a DNEL of 155.2 mg/m³.

Supporting this IOEL is a DNEL calculated from an acute 4-h inhalation toxicity study with MIBC (Blair, 1981). In this study, all exposed animals were anaesthetised within the first hour of exposure to 10000 mg/m3 and regained consciousness within half an hour of completion of exposure.For DNEL derivation, the concentration of 10000 mg/m³is used as PoD. The application of assessment factors of 3 for extrapolation of a NAEC and 2.5 for intraspecies differences and 10 for interspecies differences leads to aDNEL of 133.3 mg/m³.

The DNEL for acute / short-term inhalation exposure - systemic effects is 155.2 mg/m³based on the MIBK IOEL.

Oral DN(M)EL

A DNEL for short term duration (short term event, peak exposure) will not need to be derived in the case where an acute toxicity hazard (leading to C&L) has not been identified. The acute oral LD50 of MIBC is 2.59 g/kg (Smyth et al., 1951).

Acute / short-term exposure - local effects

Dermal DN(M)EL

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

Inhalation DN(M)EL

Silverman et al.(1946) reported that the results of human trials for sensory response to various concentrations of MIBC in air showed that eye irritation occurred at an exposure of 50 ppm (208 mg/m3) for15 minutes. Odor was not objectionable at this concentration. Exposure at more than 50 ppm was required to cause nasal and throat irritation and 25 ppm (104 mg/m3) was estimated to be the highest concentration acceptable for 8 hours.

In view of the eye irritation occurring in persons exposed at 50 ppm, the application of assessment factors of 2 for extrapolation of a NAEC and 2 for additional intraspecies differences leads to a DNEL of 52.1 mg/m³

The DNEL for acute / short-term inhalation exposure - local effects is 52.1 mg/m3 based on eye irritation in humans.

Long-term exposure - systemic effects

Dermal DN(M)EL

The DNEL is derived using the 8-hour MIBK IOEL of 83 mg/m3 as point of departure (PoD). The PoD adjusted for ventilation rate (10m3/6.7m3) and exposure duration (8h/24h, 5d/7d) is 29.5 mg/m3.

As the MW was not greater than 500 g/mol nor the log P less than -1 or greater than 4, dermal absorption was assumed to be the same as for the inhalation route. Considering absorption of 100% by inhalation and by dermal route, the equivalent dermal (internal) dose for the general population is 8.4 mg/kg bw (29.5 mg/m3 x 20 m3 / 70 kg). The application of an assessment factors of 2 (10/5) for the additional intraspecies differences leads to a DNEL of 4.2 mg/kg bw.

Supporting this calculation, is the DNEL derived from the inhalation 2-year studies. The PoD is theNOAEC 450 ppm (1840 mg/m³) for MIBK.As the MW was not greater than 500 g/mol nor the log P less than -1 or greater than 4, dermal absorption was assumed to be the same as for the inhalation route. Considering a ventilation rate of 0.29 m3/kg in rats for a 6-hour exposure, the equivalent dermal (internal) dose is 533.6 mg/kg for the rat. Corrected for exposure duration in study (5 days/week) to default general population exposure (7 days/ week), the dose is 381.1 mg/kg bw. The application of assessment factors of 2.5 for remaining interspecies differences, 4 for allometric scaling and 10 for intraspecies leads to a DNEL of 3.8 mg/kg bw.

TheDNEL for long-term dermal exposure - systemic effects is4.2 mg/kg bw based on the MIBK IOEL.

Inhalation DN(M)EL

The DNEL is derived using the 8-hour MIBK IOEL of 83 mg/m3 as point of departure (PoD). The PoD adjusted to the ventilation rate (10 m3/6.7 m3) and exposure duration (8h/24h, 5d/7d) of the general population is 29.5 mg/m3. The application of assessment factors of 2 (10/5) for the additional intraspecies differences leads to a DNEL of 14.7 mg/m³.

Supporting this calculation is the DNEL derived from the inhalation 2-year studies.The PoD is theNOAEC 450 ppm (1840 mg/m³) for MIBK.For the purpose of DNEL derivation, the NAEC (24h) for general population will be 328 mg/m³(1840 mg/m³x 6h/24h x 5/7) after correction for difference in exposure conditions.The application of assessment factors of 2.5 for remaining interspecies differences and 10 for intraspecies differences leads to a DNEL of 13.1 mg/m³.

The DNEL for long-term inhalation exposure - systemic effects is 14.7 mg/m³based on the MIBK IOEL.

Oral DN(M)EL

The DNEL is derived using the 8-hour MIBK IOEL of 83 mg/m3 as point of departure (PoD). The PoD adjusted for ventilation rate (10m3/6.7m3) and exposure duration (8h/24h, 5d/7d) is 29.5 mg/m3.

As the MW was not greater than 500 g/mol nor the log P less than -1 or greater than 4, oral absorption was assumed to be the same as for the inhalation route. Considering absorption of 100% by inhalation and by oral route, the equivalent oral (internal) dose for the general population is 8.4 mg/kg bw (29.5 mg/m3 x 20 m3 / 70 kg). The application of an assessment factors of 2 (10/5) for the additional intraspecies differences leads to a DNEL of 4.2 mg/kg bw.

Supporting this calculation is the DNEL derived from the inhalation 2-year studies. The PoD is theNOAEC 450 ppm (1840 mg/m³) for MIBK.As the MW was not greater than 500 g/mol nor the log P less than -1 or greater than 4, oral absorption was assumed to be the same as for the inhalation route. Considering a ventilation rate of 0.29 m3/kg in rats for a 6-hour exposure, the equivalent oral (internal) dose is 533.6 mg/kg for the rat. Corrected for exposure duration in study (5 days/week) to default general population exposure (7 days/ week), the dose is 381.1 mg/kg bw. The application of assessment factors of 2.5 for remaining interspecies differences, 4 for allometric scaling and 10 for intraspecies leads to a DNEL of 3.8 mg/kg bw.

TheDNEL for long-term oral exposure - systemic effects is4.2 mg/kg bw based on the MIBK IOEL.

Long-term exposure - local effects

Dermal DN(M)EL

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

Inhalation DN(M)EL

Eye irritation have been observed in persons exposed at 50 ppm (208 mg/m³) for 15 minutes (Silverman et al., 1946) and 25 ppm (104 mg/m3) was suggested to be a reliable safe limit for exposure and MIBC is classified as an irritant for the respiratory tract. However, no clinical and histological signs of respiratory tract irritation were observed during a 6-week inhalation toxicity study in rats up to a concentration of 890 ppm (3698 mg/m3) (Blair, 1982).

Considering this discrepancy,the DNEL of 14.7 mg/m³for long-term inhalation exposure - systemic effects is assumed to be protective for the local effects.