Isobutyl acetate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

300 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Route of original study:

By inhalation

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

600 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

300 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: adoption of German OEL value

Overall assessment factor (AF):

6

Dose descriptor:

NOAEC

AF for dose response relationship:

1

Justification:

default 1

AF for differences in duration of exposure:

2

Justification:

default 2 (subchronic to chronic)

AF for interspecies differences (allometric scaling):

1

Justification:

default 1 (inhalation exposure)

AF for other interspecies differences:

1

Justification:

not necessary as rodents are 2-3 fold more sensitive for this substance

AF for intraspecies differences:

3

Justification:

reduced intraspecies factor due to unspecific cytotoxic effect

AF for the quality of the whole database:

1

Justification:

default 1 (no deficiencies)

AF for remaining uncertainties:

1

Justification:

default 1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

600 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: adoption of German OEL value

DNEL extrapolated from long term DNEL

Workers - 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:

neurotoxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEL

Value:

495 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Transient CNS effects were obvious after oral and inhalation uptake.

AF for dose response relationship:

1

Justification:

default 1

AF for differences in duration of exposure:

1

Justification:

not necessary as no worsening of effect was observed over time

AF for interspecies differences (allometric scaling):

4

Justification:

default 4

AF for other interspecies differences:

2.5

Justification:

default remaining toxicodynamic differences

AF for intraspecies differences:

5

Justification:

default 5

AF for the quality of the whole database:

1

Justification:

default 1 (no deficiencies)

AF for remaining uncertainties:

1

Justification:

default 1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/kg bw/day

Most sensitive endpoint:

neurotoxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

NOAEL

Value:

495 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Transient CNS effects were obvious after oral and inhalation uptake.

AF for dose response relationship:

1

Justification:

default 1

AF for interspecies differences (allometric scaling):

4

Justification:

default 4

AF for other interspecies differences:

2.5

Justification:

default remaining toxicodynamic differences

AF for intraspecies differences:

5

Justification:

default 5

AF for the quality of the whole database:

1

Justification:

default 1 (no deficiencies)

AF for remaining uncertainties:

1

Justification:

default 1

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:

no hazard identified

Additional information - workers

Workers - inhalation route - systemic effects long term exposure

In subchronic studies in rodents with the read across substance n-BuAc, systemic effects (body weight changes and transient sedation) and local respiratory effects occur simultaneous. From a mechanistic point of view it is most likely that systemic effects (i.e. body weight changes; but not sedation) are secondary to local respiratory effects (for further details see discussion). From occupational exposure to n-BuAc and volunteer studies it is known that irritating effects occur before CNS depressing effects, which mostly are evident only at very high exposure concentrations (AGS 2012, Greim 1999). Thus local irritating effects are considered the most sensitive endpoint observed and therefore used for DNEL derivation. Therefore, the DNEL for local effects long-term exposure inhalation was adopted as DNEL for systemic effects long-term exposure inhalation.

Workers - inhalation route - systemic effects short term exposure

As local effects are the most sensitive endpoint, application of the worker-DNEL acute for inhalation route local effects is considered to be protective for systemic effects too. Therefore, the DNEL for local effects short-term exposure inhalation was adopted as DNEL for systemic effects short-term exposure inhalation.

Workers - inhalation route - local effects long term exposure

No reliable long-term inhalation toxicity data for iso-BuAc are available. Therefore the German OEL for iso-BuAc was identified in analogy to the derivation performed for n-BuAc. This was considered adequate as both substances cause local irritating effects on the respiratory tract with iso-BuAc being slightly less irritating (cf. RD50 values for n-BuAc = 733 ppm and iso-BuAc = 818 ppm), the same mode of action applies (hydrolysis to acetic acid which is responsible for local irritation), and both substances have comparable hydolyis rates in vitro. The DNEL is based on a read-across to n-BuAc with a NOAEC of 500 ppm, identified in the subchronic inhalation toxicity studies of David et al. (2001;1998; section 7.5.1 and 7.9.1). Rats were exposed to 0, 500, 1500 or 3000 ppm of n-BuAc (6 hours per day, 5 days per week). The only significant systemic effect observed in the first study (David et al., 1998) was a dose dependent reduced body weight gain in the 1500 and 3000 ppm groups. Transient neurotoxic effects (sedation and hypoactivity) were also noted in animals of the mid and high dose group, but vanished 30 to 60 minutes after cessation of exposure.

In the second publication (David et al., 2001) the NOAEC of 500 ppm was confirmed, as well as reduced feed uptake in the mid and high dose group. More important, dose dependent necrosis of olfactory epithelium starting at 1500 ppm was noted. Therefore, the reduced feed uptake is assumed to be a secondary effect of the local irritating effect, as necrosis of olfactory epithelium is causing pain which might lead to reduced feed uptake of treated animals. Local irritating effects were attributed to the metabolite acetic acid which is generated from n-BuAc via hydrolysis by carboxyl esterase. A NOAEC of 500 ppm or 2410 mg/m3 can be derived from these studies. This NOAEC is converted into a starting dose of 1211 mg/m3 (*6 h/8 h * 6.7 m3 respiratory volume / 10 m3 respiratory volume during light activity) for DNEL derivation. According to the ECHA Guidance on Information Requirements and Chemical Safety Assessment Part R.8 the following factors should be applied:

Factor 1 for interspecies variability. This deviation from the default is based on the observation that rats have an about 2 to 3 fold higher carboxyl esterase activity than humans (Griem et al., 2002), i.e. they are about 2 to 3 fold more sensitive to the local irritating effects triggered through acetic acid than humans. No allometric scaling is necessary as an inhalation study is used. As the effect triggered through acetic acid is an unspecific cytotoxic effect which occurs when the buffer capacity of a cell is exhausted, the intraspecies factor can be reduced to 3 (deviation of default value 5 based on toxicokinetic consideration). For time extrapolation a default factor of 2 (sub-chronic to chronic) should be applied, as no distinct substance specific data are available to justify a deviation from the default. Also default assessment factors of 1 can be used for dose-response relation and quality of whole database (no deficiencies). This would result in an value of 42 ppm (202 mg/m3). This value would be lower than the legally binding German Occupational Exposure Limit of 62 ppm (300 mg/m3) derived in 2012 by the AGS.

The German OEL was also based on the studies from David et al. (1998 and 2001). The NOAEC of 500 ppm was corrected from the experimental exposure regimen to shift exposure (* 6 h / 8 h). A time extrapolation factor of 2 was applied for extrapolation from subchronic to chronic exposure. Additionally, an overall inter- and intraspecies variability factor of 3 was applied due to substance specific data (higher sensitivity of rats, unspecific cytotoxic effects responsible for irritating effects). The German OEL value is slightly higher than the calculated DNEL. But, due to the absence of substance specific data there remains some uncertainty if the calculated DNEL is not overly conservative due to the consequent consideration of time extrapolation, as local effects are often triggered by concentration rather than by time. Experience from the workplace indicates that an OEL of 62 ppm is sufficiently protective. Therefore, the legally binding German OEL is adopted as DNEL for local effects long term exposure inhalation.

Workers - inhalation route - local effects short term exposure

Local irritating effects are assumed to be mainly driven by the exposure concentration of the submission substance with respect to the corrosive properties of iso-BuAc's metabolite acetic acid but also by time. In accordance with the exceedance factor for short term values of the German AGW a multiplying factor of 2 is used to establish an acute DNEL inhalation for local effects from the worker DNEL long term for inhalation route, local effects. The resulting height of the DNEL Local effects acute exposure inhalation is supported by experience on occupationally exposed humans or available data from human volunteer studies and is considered to protect against effects caused by peak exposures.

Workers - dermal route - systemic effects long term exposure

No data on experiments with repeated dermal dosing of iso-BuAc are available. Read-across was performed from structurally closely related iso-butanol (for further details please see Read-across report attached in IUCLID section 13). Based on the data on physico-chemical properties on iso-BuAc a default assumption of 100% dermal absorption can be taken into account (i.e. water soluble liquid with molecular mass below 500 and log Pow in the range of -1 to 4).

Starting from acute inhalation data for iso-butanol a value of 8.1 mg/kg bw/ d would result (LOAEC 4545 mg iso-butanol/m3 corresponding to 7125 mg iso-BuAc/m3; correction for systemic bioavailability after inhalation exposure (80%); route to route extrapolation (7125 mg/m3 * 0.38 m3/kg bw * 6 h / 8 h); interspecies factor 10 (4 allometric scaling, 2.5 remaining differences); intraspecies factor 5 (default); time extrapolation factor 1 (transient effect which ceases upon end of exposure and not bioaccumulation potential of the substance); default factor 3 for dose-response (LOAEC to NOAEC) and default factor 1 for quality of whole database). Resulting in a DNEL of 8.1 mg/kg bw/d.

A NOAEL of 316 mg iso-butanol/kg bw/d was identified in a 90 day oral gavage study with rats, based on observed clinical signs of CNS depression (hypoactivity) at 1000 mg/kg bw/d. No adaption for differences in bioavailability has to be performed as oral uptake is supposed to be 100%. Based on molecular weight the NOAEL for iso-butanol corresponds to 495 mg iso-BuAc/kg bw/d. According to ECHA Guidance R.8 an overall assessment factor of 50 results (interspecies factor 10 (4 allometric scaling, 2.5 remaining differences); intraspecies factor 5 (default); time extrapolation factor 1 (transient effect which ceases upon end of exposure and no bioaccumulation potential of the substance); default factor 1 for dose-response and quality of whole data base). This results in a DNEL of 10 mg/kg bw/d. Derivations based on the acute inhalation study or the sub-chronic oral study with isobutanol yield comparable DNELs (8.1 versus 10 mg/kg bw/d), differences are probably due to e.g. spacing. Both values are associated with uncertainties. E.g. gavage application is probably associated with peak exposure not occurring after dermal exposure. There is uncertainty about the distance between the LOAEC and the NOAEC and the bioavailability in the inhalation study. Further, the inhalation study is only an acute study. Therefore, the DNEL Systemic effects long-term exposure dermal was derived on basis of the oral toxicity study. This approach is considered to be conservative, due to the peak exposure (bolus effect that results from gavage) and due to the fact that the active metabolite was applied.

Workers - dermal route - systemic effects short term exposure

 

Observed CNS effects are acute, transient effects (cf. classification for specific target organ toxicity single exposure category 3 (STOT SE3, H336 –narcosis)). The systemic long-term DNEL dermal is based on these transient CNS effects observed in a sub-chronic study. As there was no worsening of narcotic effects in the 90-day study, the long-term DNEL should also be applied for acute exposure, because the data indicate that acute exposure to similar concentrations already causes effects. This is supported by two studies on n-BuAc (structurally closely related read-across substance): In a 90 day inhalation toxicity study slight CNS effects (indicated as reduced activity levels: less movement, decreased alertness and slower response to tapping on the chamber) were observed only during exposure period and at exposure levels higher than 500 ppm (2410 mg/m³, i.e. NOAEC), where already severe local irritation (necrosis) was observed (see section1.1.1). Furthermore, in an acute inhalation toxicity study, only transient sedative effects were observed (cf IUCLID section 7.9.1 study record: OPP/CMA (+1994; rat; acute; inhalation/vapour; RL1).

Workers - dermal route - local effects long term exposure

This DNEL was not derived as no respective hazard was observed.

Workers - dermal route - local effects short term exposure

This DNEL was not derived as no respective hazard was observed.

Workers - hazard for the eyes - local effects

The substance is not irritant or corrosive to eyes. Therefore, no hazard for the eyes was identified.

AGS, Ausschuss für Gefahrstoffe (2012)

Begründung zu Butylacetate in TRGS 900 online:http://www.baua.de/de/Themen-von-A-Z/Gefahrstoffe/TRGS/Arbeitsplatzgrenzwerte.html__nnn=true

Greim, H. (1999) Gesundheitsschädliche Arbeitsstoffe, Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werten, Loseblattsammlung, 28. Lfg DFG Deutsche Forschungsgemeinschaft, WILEY-VCH Verlag Weinheim

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

35.7 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Route of original study:

By inhalation

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

300 mg/m³

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

35.7 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: based on German OEL value

Overall assessment factor (AF):

12

Dose descriptor:

NOAEC

AF for dose response relationship:

1

Justification:

default 1

AF for differences in duration of exposure:

2

Justification:

default 2 (subchronic to chronic)

AF for interspecies differences (allometric scaling):

1

Justification:

default 1 (inhalation exposure)

AF for other interspecies differences:

1

Justification:

not necessary as rodents are 2-3 fold more sensitive for this substance

AF for intraspecies differences:

6

Justification:

reduced intraspecies factor 3 for workers due to unspecific cytotoxic effect and additional factor 2 for general population

AF for the quality of the whole database:

1

Justification:

default 1 (no deficiencies)

AF for remaining uncertainties:

1

Justification:

default 1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

300 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/kg bw/day

Most sensitive endpoint:

neurotoxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

495 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Transient CNS effects were obvious after oral and inhalation uptake

AF for dose response relationship:

1

Justification:

default 1

AF for differences in duration of exposure:

1

Justification:

not necessary as no worsening of effect was observed over time

AF for interspecies differences (allometric scaling):

4

Justification:

default 1

AF for other interspecies differences:

2.5

Justification:

default remaining toxicodynamic differences

AF for intraspecies differences:

10

Justification:

default 10

AF for the quality of the whole database:

1

Justification:

default 1 (no deficiencies)

AF for remaining uncertainties:

1

Justification:

default 1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/kg bw/day

Most sensitive endpoint:

neurotoxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

NOAEL

Value:

495 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Transient CNS effects were obvious after oral and inhalation uptake

AF for dose response relationship:

1

Justification:

default 1

AF for interspecies differences (allometric scaling):

4

Justification:

default 4

AF for other interspecies differences:

2.5

Justification:

default remaining toxicodynamic differences

AF for intraspecies differences:

10

Justification:

default 10

AF for the quality of the whole database:

1

Justification:

default 1 (no deficiencies)

AF for remaining uncertainties:

1

Justification:

default 1

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:

5 mg/kg bw/day

Most sensitive endpoint:

neurotoxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

495 mg/kg bw/day

AF for dose response relationship:

1

Justification:

default 1

AF for differences in duration of exposure:

1

Justification:

not necessary as no worsening of effect was observed over time

AF for interspecies differences (allometric scaling):

4

Justification:

default 4

AF for other interspecies differences:

2.5

Justification:

default remaining toxicodynamic differences

AF for intraspecies differences:

10

Justification:

default 10

AF for the quality of the whole database:

1

Justification:

default 1 (no deficiencies)

AF for remaining uncertainties:

1

Justification:

default 1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/kg bw/day

Most sensitive endpoint:

neurotoxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

NOAEL

Value:

495 mg/kg bw/day

AF for dose response relationship:

1

Justification:

default 1

AF for interspecies differences (allometric scaling):

4.5

Justification:

default 4

AF for other interspecies differences:

2.5

Justification:

default remaining toxicodynamic differences

AF for intraspecies differences:

10

Justification:

default 10

AF for the quality of the whole database:

1

Justification:

default 1 (no deficiencies)

AF for remaining uncertainties:

1

Justification:

default 1

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

GP - inhalation route - systemic effects long term exposure

Application of the GP-DNEL long-term for inhalation route local effects is considered to be protective for systemic effects too (for justification see discussion on worker DNELs).

GP - inhalation route - systemic effects short term exposure

As local effects are the most sensitive endpoint application of the GP-DNEL acute for inhalation route local effects is considered to be protective for systemic effects too.

GP - inhalation route - local effects long term exposure

The DNEL local effects long-term exposure inhalation for the general population is derived from the DNEL for workers, which was adapted from the legally binding eight hour limit value in Germany.

This value has to be corrected for the continuous exposure over 24 hours for the general population instead of 8 hours for workers and 7 days instead of 5 days. An additional assessment factor of 2 is to be considered (intraspecies differences: quotient of default value for general population (10) versus workers (5)):300 mg/m³ x (8 h/24 h) x (5 d/7 d) x (5/10) = 35.7 mg/m³ (7 ppm)

GP - inhalation route - local effects short term exposure

The DNEL local effects acute exposure inhalation for the general population is derived from the DNEL local effects acute exposure inhalation for workers. An additional assessment factor of 2 is to be considered (intraspecies differences: quotient of default value for general population (10) versus workers (5)): 600 mg/m³ x (5/10) = 300 mg/m³ (62 ppm).

GP - dermal route - systemic effects long term exposure

The DNEL of 5 mg/kg bw/d was derived similar to the dermal DNEL for systemic effects long term exposure for workers applying an additional assessment factor of 2 (intraspecies differences: quotient of default value for general population (10) versus workers (5))

GP - dermal route - systemic effects short term exposure

The DNEL of 5 mg/kg bw/d for systemic effects acute dermal exposure was based on the DNEL for systemic effects long term dermal, applying a factor of 1. I.e. the same DNEL should be applied for acute and long term exposure, because the DNEL for systemic effects long term dermal exposure is based on transient CNS effects (hypoactivity and ataxia) observed in a sub chronic study which cease with the end of exposure.

GP - dermal route - local effects long term exposure

This DNEL was not derived as no respective hazard was observed.

GP - dermal route - local effects short term exposure

This DNEL was not derived as no respective hazard was observed.

GP - oral route - systemic effects long term exposure

This DNEL value is identical to the DNEL for systemic effects long term dermal exposure, as the latter one was derived on basis of an oral study by route-to-route extrapolation.

GP - oral route - systemic effects short term exposure

The DNEL for systemic effects acute oral exposure was based on the DNEL for systemic effects long term oral, applying a factor of 1. I.e. the same DNEL should be applied for acute and long term exposure, because the DNEL for systemic effects long term dermal exposure is based on transient CNS effects (hypoactivity and ataxia) observed in a sub chronic study which cease with the end of exposure. Additionally, route-to-route extrapolation from the inhalation study is not regarded as appropriate due to first-pass metabolism after oral application.

GP - hazard for the eyes - local effects

The substance is not irritant or corrosive to eyes. Therefore, no hazard for the eyes was identified.