Registration Dossier

Administrative data

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:
11 mg/kg bw/day
Most sensitive endpoint:
neurotoxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Value:
550 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 2.5 for 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:
11 mg/kg bw/day
Most sensitive endpoint:
neurotoxicity
Route of original study:
By inhalation
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:
550 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, 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, as necrosis of olfactory epithelium is causing pain which might lead to reduced feed uptake. 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 (no details on exposure concentrations available) (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 the inhalation route (derived from local effects) is considered to be protective also for systemic effects. 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

The DNEL is based on a NOAEC of 500 ppm, identified in the subchronic inhalation toxicity studies of David et al. (2001;1998; cf. study records in registration dossier IUCLID: section 7.5.2 OPP/CMA (+1996, EPA OTS 798.2450, KS, RL1); section 7.9.1 OPP/CMA (+1996; rat; 13 weeks neurotoxicity; inhalation/vapor, KS, RL1)). 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 (2410 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 for DNEL derivation:

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 (2410 mg/m3 * 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 n-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 n-BuAc are available.

Thus for dermal DNEL derivation a route-to-route extrapolation has to be performed either from inhalation data available for n-butyl acetate or the results from an oral toxicity study with repeated exposures to the metabolite of the submission substance, i.e. n-butanol. Based on the data on physico-chemical properties on n-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 the inhalation data for n-BuAc a value of 11 mg/kg bw/ d would result (NOAEC 2410 mg/m3; correction for systemic bioavailability after inhalation exposure (80%); route to route extrapolation (* 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 no bioaccumulation potential of the substance); default factor 1 for dose-response and quality of whole database).

A NOAEL of 125 mg n-butanol/kg bw/d was identified in a 90 day oral gavage study with rats, based on observed clinical signs of CNS depression (hypoactivity and ataxia) at 500 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 n-butanol corresponds to 196 mg nBuAc/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 not bioaccumulation potential of the substance); default factor 1 for dose-response and quality of whole data base). This results in a DNEL of 3.9 mg/kg bw/d. The DNEL derived on basis of the oral study with n-butanol is only slightly lower (about 3-fold) than the DNEL derived on basis of the inhalation study with n-butyl acetate. This difference might be due to differences in spacing of the dose groups or reflect the difference between original substance and metabolite. Additionally, gavage application might cause a bolus effect and unrealistic peak blood-levels, which would not occur after dermal application. Overall, the calculation on basis of the oral study with n-butanol is regarded to be unrealistically conservative and therefore the DNEL Systemic effects long-term exposure dermal is derived by route-to-route extrapolation from the inhalation study with n-butyl acetate. This approach is already considered to be a conservative one, as a dermal absorption of 100% is assumed. 

 

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 acute, transient CNS effects (indicated as reduced activity levels: less movement, decreased alertness and slower response to tapping on the chamber), observed in a sub-chronic study. As there was no worsening of narcotic effects in the 90-day study, nor an alteration of time until sedation after treatment free weekends, 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 the fact that observations of CNS effects in a 90 day inhalation toxicity study were made only during exposure phases and at exposure levels higher than 500 ppm (2410 mg/m3, i.e. NOAEC; cf. IUCLID study record OPP/CMA (+1996; rat; 13 weeks neurotoxicity; inhalation/vapor; RL1)), which is the approximate no effect level observed in an acute inhalation toxicity study as well (LOAEC = 7230 mg/m³, with default assessment factor for NOAEC à LOAEC = 3, thus NOAEC = 2410 mg/m³; cf. IUCLID 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
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:
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:
6 mg/kg bw/day
Most sensitive endpoint:
neurotoxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
554 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:
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:
6 mg/kg bw/day
Most sensitive endpoint:
neurotoxicity
Route of original study:
By inhalation
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:
554 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:
2 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:
196 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 deficienciese)
AF for remaining uncertainties:
1
Justification:
default 1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 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:
196 mg/kg bw/day
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 deficienciese)
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 6 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 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

No data on experiments with repeated oral dosing of n-BuAc are available.

Thus for oral DNEL derivation data from an oral subchronic toxicity with the read-across substance n-butanol was used. The identified NOAEL is 125 mg n-butanol/kg bw/d (90 day oral gavage study with rats, CNS depression).

Uptake in gastrointestinal tract upon oral exposure = 100 % for n-butanol and n-BuAc, therefore no adaption for bioavailability is performed. Conversion of the n-butanol NOAEL based on molecular weight leads to a NOAEL of 196 mg n-BuAc/kg bw/d.

According to ECHA Guidance R.8 an overall assessment factor of 100 results (interspecies factor 10 (4 allometric scaling, 2.5 remaining differences); intraspecies factor 10 (default); time extrapolation factor 1 (transient effect which ceases upon end of exposure and not bioaccumulation potential of the substance); default factor 1 for dose-response and quality of whole data base). This results in a DNEL of 2 mg/kg bw/d.

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.

GP - hazard for the eyes - local effects

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