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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
184 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.75 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

There is no repeat dose data for isobutyric anhydride. As demonstrated in sections 5 and 7, isobutyric anhydride is hydrolyzed to isobutyric acid within minutes after exposure to water. Thus, DNEL values and test data from isobutyric acid are used for isobutyric anhydride.

Acute / short-term exposure - systemic effects

 

Acute oral and inhalation data is present for isobutyric anhydride, while isobutyric acid data is used for dermal toxicity.

 

LD50 oral: 7700 mg/kg bw (anhydride)

LC0 inhalation, 7-h exposure: 4210 mg/m³ (anhydride)

LD50 dermal: 474 mg/kg bw (acid)

 

From present studies, reliable short-term dose response relations cannot be deduced. Available data do not provide sufficient information on sublethal toxic effects to gather NOAELs as starting points. DNELs cannot be derived.

 

Acute /short-term exposure - local effects

 

Data is available for the anhydride for skin and eye irritation. While the test results are "irritating", a "corrosive" classification is used as the studies are assumed to understate the real-life toxicity. The classification used mirrors that of the hydrolysis product, isobutyric acid. Isobutyric acid is corrosive to skin and to the eye. Corrosive effects are observed after topical application of as little as 10 µL test substance (Smyth 1962). Weaker effects have not been examined. Dose descriptors for the deduction of a DNEL for acute local effects are not available.

 

 

Long term exposure systemic effects

 

Data for isobutyric acid on long term exposure could not be identified. To assess the risk of long-term exposure - systemic effects for isobutyric acid, data for isobutanol as supporting substance will be used as substitute on the following reasons.

 

After administration, isobutanol will rapidly be metabolized in vivo to isobutyraldehyde by alcohol dehydrogenases and subsequently to isobutyric acid by aldehyde dehydrogenases. In the course of metabolic transformation of isobutanol, isobutyric acid is generated rapidly and predominantly as intermediary metabolite. Thus, it is justified to use isobutanol as supporting substance in the evaluation of the systemic effects of isobutyric acid.

 

Supporting substance: isobutanol - Derivation of DNELs for isobutyric acid

 

There are several repeated dose toxicity studies available with isobutanol. As conservative approach, the study with the lowest NOAEL will be used in the deduction of DNELs.

 

Dermal systemic DNEL

 

The dermal DNEL will be obtained based on an oral NOAEL for isobutanol of 316 mg/kg bw/day (EPA/Res. Triangle Inst. 1987; Repeated dose toxicity, Sect. 7.5.1). Using the respective molecular weights (isobutyric acid 88.11, isobutanol 74.12), the NOAEL for isobutanol is converted to a NOAEL for isobutyric acid.

 

Oral systemic NOAEL for isobutyric acid: 375 mg/kg bw

 

For the oral-to-dermal extrapolation, a default factor of 1 is used. With an overall assessment factor of 100 (allometric scaling factor 4, factor for remaining interspecies differences 2.5, intraspecies factor 5 (worker), sub-chronic to chronic exposure factor 2 ), a DNEL of 3.75 mg/kg bw/day for isobutyric acid is derived.

 

Dermal systemic DNEL isobutyric acid: 3.75 mg/kg bw/day

 

Inhalation DNEL

 

Long term inhalation exposure data on systemic effects are available from a 90 day combined neurotoxicity/repeated dose toxicity study (Li/Monsanto 1999; Repeated dose toxicity, Sect. 7.5.3) and from a two generation reproduction study of isobutanol (OPP/AAC 2003; Toxicity to reproduction , Sect. 7.8.1). For both studies, aNOAEC (isobutanol) of 2500 ppm (7700 mg/m³, highest dose applied)has been determined. Using the respective molecular weight and the standard molar volume (24.06 L/mol at 20 °C), the NOAEC isobutanol can be converted to the NOAEC isobutyric acid.

 

Inhalation systemic NOAEC for isobutyric acid: 2500 ppm (9150 mg/m³).

 

Exposure was 6 h per day. This NOAEC has to be modified with respect to exposure conditions of workers (exposure time 8 h/d, increased respiratory rate = wRV of 10 m³/8h) resulting in acorrected starting point NOAEL of 4600 mg/m³. The overall assessment factor (25) consists of a factor for remaining interspecies differences of 2.5, an intraspecies factor of 5 (worker) and a sub-chronic-to-chronic exposure factor of 2. The allometric scaling factor is already accounted for in the derivation of the corrected starting point NOAEC. With this overall assessment factor, a DNEL of 184 mg/m³ for isobutyric acid is calculated.

 

Inhalation systemic DNEL isobutyric acid: 184 mg/m³.

 

Long-term exposure - local effects

 

For isobutyric acid, no data on local effects of long-term exposure are available. Long term exposure studies with isobutyric aid have not been conducted. Due to the severe corrosive reaction of isobutyric acid, effects similar to acute toxicity tests will occur. Dose descriptors for the derivation of DNELs are not available.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
92 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.88 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.88 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

There is no repeat dose data for isobutyric anhydride. As demonstrated in sections 5 and 7, isobutyric anhydride is hydrolyzed to isobutyric acid within minutes after exposure to water. Thus, DNEL values and test data from isobutyric acid are used for isobutyric anhydride.

Acute / short-term exposure - systemic effects

 

Acute oral and inhalation data is present for isobutyric anhydride, while isobutyric acid data is used for dermal toxicity.

 

LD50 oral: 7700 mg/kg bw (anhydride)

LC0 inhalation, 7-h exposure: 4210 mg/m³ (anhydride)

LD50 dermal: 474 mg/kg bw (acid)

 

From present studies, reliable short-term dose response relations cannot be deduced. Available data do not provide sufficient information on sublethal toxic effects to gather NOAELs as starting points. DNELs cannot be derived.

 

Acute /short-term exposure - local effects

 

Data is available for the anhydride for skin and eye irritation. While the test results are "irritating", a "corrosive" classification is used as the studies are assumed to understate the real-life toxicity. The classification used mirrors that of the hydrolysis product, isobutyric acid. Isobutyric acid is corrosive to skin and to the eye. Corrosive effects are observed after topical application of as little as 10 µL test substance (Smyth 1962). Weaker effects have not been examined. Dose descriptors for the deduction of a DNEL for acute local effects are not available.

 

Long term exposure systemic effects

 

Data for isobutyric acid on long term exposure could not be identified. To assess the risk of long-term exposure - systemic effects for isobutyric acid, data for isobutanol as supporting substance will be used as substitute on the following reasons.

 

After administration, isobutanol will rapidly be metabolized in vivo to isobutyraldehyde by alcohol dehydrogenases and subsequently to isobutyric acid by aldehyde dehydrogenases. In the course of metabolic transformation of isobutanol, isobutyric acid is generated rapidly and predominantly as intermediary metabolite. Thus, it is justified to use isobutanol as supporting substance in the evaluation of the systemic effects of isobutyric acid.

 

Supporting substance: isobutanol - Derivation of DNELs for isobutyric acid

 

There are several repeated dose toxicity studies available with isobutanol. As conservative approach, the study with the lowest NOAEL will be used in the deduction of DNELs.

 

Dermal systemic DNEL

 

The dermal DNEL will be obtained based on anoral NOAEL for isobutanol of 316 mg/kg bw/day(EPA/Res. Triangle Inst. 1987; Repeated dose toxicity, Sect. 7.5.1). Using the respective molecular weights (isobutyric acid 88.11, isobutanol 74.12), the NOAEL for isobutanol is converted to a NOAEL for isobutyric acid.

 

Oral systemic NOAEL for isobutyric acid: 375 mg/kg bw

 

For the oral-to-dermal extrapolation, a default factor of 1 is used. With an overall assessment factor of 100 (allometric scaling factor 4, factor for remaining interspecies differences 2.5, intraspecies factor 5 (worker), sub-chronic to chronic exposure factor 2 ), a DNEL of 3.75 mg/kg bw/day for isobutyric acid is derived.

 

Dermal systemic DNEL isobutyric acid: 3.75 mg/kg bw/day

 

Inhalation DNEL

 

Long term inhalation exposure data on systemic effects are available from a 90 day combined neurotoxicity/repeated dose toxicity study (Li/Monsanto 1999; Repeated dose toxicity, Sect. 7.5.3) and from a two generation reproduction study of isobutanol (OPP/AAC 2003; Toxicity to reproduction , Sect. 7.8.1). For both studies, aNOAEC (isobutanol) of 2500 ppm (7700 mg/m³, highest dose applied)has been determined. Using the respective molecular weight and the standard molar volume (24.06 L/mol at 20 °C), the NOAEC isobutanol can be converted to the NOAEC isobutyric acid.

 

Inhalation systemic NOAEC for isobutyric acid: 2500 ppm (9150 mg/m³).

 

Exposure was 6 h per day. This NOAEC has to be modified with respect to exposure conditions of workers (exposure time 8 h/d, increased respiratory rate = wRV of 10 m³/8h) resulting in acorrected starting point NOAEL of 4600 mg/m³. The overall assessment factor (25) consists of a factor for remaining interspecies differences of 2.5, an intraspecies factor of 5 (worker) and a sub-chronic-to-chronic exposure factor of 2. The allometric scaling factor is already accounted for in the derivation of the corrected starting point NOAEC. With this overall assessment factor, a DNEL of 184 mg/m³ for isobutyric acid is calculated.

 

Inhalation systemic DNEL isobutyric acid: 184 mg/m³.

 

Long-term exposure - local effects

 

For isobutyric acid, no data on local effects of long-term exposure are available. Long term exposure studies with isobutyric aid have not been conducted. Due to the severe corrosive reaction of isobutyric acid, effects similar to acute toxicity tests will occur. Dose descriptors for the derivation of DNELs are not available.

 

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