Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
83 mg/m³
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
208 mg/m³
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
83 mg/m³
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
208 mg/m³
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:
11.8 mg/kg bw/day
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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

According to Guidance on information requirements and chemical safety assessment,Chapter R.8: Characterisation of dose [concentration]-response for human health, a registrant is allowed to use an IOEL as a DNEL for the same exposure route and duration, unless new scientific information that he has obtained in fulfilling his obligations under REACH does not support the use of the IOEL for this purpose. However, when the registrant is using a substance in a way that leads to other exposure routes or exposure durations than the exposure route and duration on which the IOEL is based (typically derived for inhalation exposure over 8 hours per working day (TWA) and/or short term exposures, typically of 15 minutes duration (STEL)) or if other human populations are exposed, the relevant DNELs should be derived. For example, in the case when the use may lead to dermal or oral exposure of the population at large or vulnerable sub-populations, DNELs to cover these situations will be required.

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

The SCOEL recommendation (1991) is based on investigation of occupational exposure to MIBK at 80-500 ppm (333-2080 mg/m3), for 20 to 30 mins/day, for 3 to 12 months) as reported by Linari et al. (1964) with a follow up by Armeli et al. (1968) 5 years later when exposure had diminished to 50-105 ppm (208-437 mg/m3). With the higher exposure, a majority of the 19 workers exposed complained of nausea (17), vomiting (10), diarrhea (6), irritation of eyes (17), and airways (13). 16 workers experienced neurasthenic symptoms. The follow up of 14 workers 5 years later with lower exposure showed a lowered, but still existing prevalence of neurasthenia (4/14) and irritative symptoms (2/14).The SCOEL has considered that the human data of Armeli, which showed effects just below 100 ppm (410 mg/m3), were an adequate basis for setting the limits.

Acute / short-term exposure - systemic effects

Dermal DNEL

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 LD0 of MIBK is higher than 2000 mg/kg (Gardner, 1996).

Inhalation DNEL

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

According to the available data set, no new scientific information available since the publication of the SCOEL recommendation is susceptible to change the IOEL value.

The DNEL for acute / short-term inhalation exposure - systemic effects is the 15-min IOEL of 208 mg/m3.

Acute / short-term exposure - local effects

Dermal DNEL

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. MIBK is not classified as a skin irritant.

Inhalation DNEL

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

According to the available data set, no new scientific information available since the publication of the SCOEL recommendation is susceptible to change the IOEL value.

The DNEL for acute / short-term inhalation exposure - local effects is the 15-min IOEL of 208 mg/m3.

Long-term exposure - systemic effects

Dermal DNEL

The DNEL is derived using the 8-hour 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 a default 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 (NTP, 2007; Stout et al, 2008). The PoD is the NOAEC 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 533.3 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.

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

Inhalation DNEL

Indicative occupational exposure limit (IOEL) values have been published for MIBK in Commission Directive 2000/39/EC of 8 June 2000. The limit 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 (NTP, 2007; 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 IOEL.

Long-term exposure - local effects

Dermal DNEL

MIBK is classified R66 /EUH066 (Repeated exposure may cause skin dryness or cracking) but no-threshold effect and/or no dose-response information is available to derive a DNEL.

Inhalation DNEL

Indicative occupational exposure limit (IOEL) values have been published for MIBK in Commission Directive 2000/39/EC of 8 June 2000. The limit 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).

According to the available data set, no new scientific information available since the publication of the SCOEL recommendation is susceptible to change the IOEL value.

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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.7 mg/m³
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
155.2 mg/m³
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.7 mg/m³
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
155.2 mg/m³
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

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
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
4.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
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

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 LD0of MIBK is higher than 2000 mg/kg (Gardner, 1996).

Inhalation DN(M)EL

The DNEL is derived using the 15-min 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.

The DNEL for acute / short-term inhalation exposure - systemic effects is 155.2 mg/m3 based on the 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 LD50of MIBK is 2080 mg/kg (Smyth et al., 1951).

Acute / short-term exposure - local 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. MIBK is not classified as a skin irritant.

Inhalation DN(M)EL

The DNEL is derived using the 15-min 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.

The DNEL for acute / short-term inhalation exposure - systemic effects is 155.2 mg/m3 based on the IOEL.

Long-term exposure - systemic effects

Dermal DN(M)EL

The DNEL is derived using the 8-hour 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 a default 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 (NTP, 2007; Stout et al, 2008). The PoD is the NOAEC 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.

The DNEL for long-term dermal exposure - systemic effects is 4.2 mg/kg bw based on the IOEL.

Inhalation DN(M)EL

The DNEL is derived using the 8-hour 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/m3 based on the IOEL.

Oral DN(M)EL

The DNEL is derived using the 8-hour 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 a default 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 -NTP, 2007; Stout et al., 2008). The PoD is the NOAEC 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.

The DNEL for long-term oral exposure - systemic effects is 4.2 mg/kg bw based on the IOEL.

Long-term exposure - local effects

Dermal DN(M)EL

MIBK is classified R66 /EUH066 (Repeated exposure may cause skin dryness or cracking) but no-threshold effect and/or no dose-response information is available to derive a DNEL.

Inhalation DN(M)EL

The DNEL is derived using the 8-hour 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.

The DNEL for long-term inhalation exposure - local effects is 14.7 mg/m3 based on the IOEL.