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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:
36.8 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
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Substance is not classified for actute inhalative hazard thus no hazard conclusion needs to be drawn.

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

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

The dermal DNEL can be derived based on an oral NOAEL as starting point. As only an inhalation NOAEC is available as dose descriptor, this inhalation NOAEC has to be converted to a corrected "oral" NOAEL. In a first step, the total dose is calculated received by the test animals within the 6 hour exposure period using the standard rat respiratory volume. In a second step, the differences in exposure time and respiratory volume of workers are accounted for. As result, an "oral" NOAEL for workers is derived (267 mg/kg bw/day).

 

Using this starting point NOAEL, the dermal systemic DNEL is deduced. Factor for the transfer from the oral to dermal route is 1. 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 2.676 mg/kg bw/day for butyric acid is calculated.

 

Dermal systemic DNEL butyric acid: 2.67 mg/kg bw/day

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

Acute / short-term exposure - systemic effects

 

In acute toxicity studies, butyric acid has been shown to be of moderate to low systemic toxicity.

 

LD50 oral: 1632 mg/kg bw in rats (BASF, 1978)

LC0 inhalation, 4-h exposure: 5.1 mg/L (Celanese / Biodynamics, 1989); 8-h exposure: 4.18 mg/L (BASF, 1978)

LD50 dermal: 6096 mg/kg bw

 

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

 

Butyric 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 1954). Weaker effects have not been examined. Dose descriptors for the deduction of a DNEL for acute local effects are not available.

 

Unlike these findings, inhalational exposure to saturated vapor concentrations was possible for 8 hours without mortality. But severe mucosal irritation and closed eyelids are reported as local effects. For inhalation exposure, severe effects are reported as are for dermal application, but this information is not suited as dose descriptors for the deduction of a DNEL.

 

Long term exposure systemic effects

 

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

 

After administration, n-butyl acetate will be rapidly metabolized in vivo in blood and various tissues by ubiquitous esterases. Half-life of this transformation is short resulting in complete cleavage of the ester. n-Butanol is formed which is rapidly metabolized in vivo to n-butyraldehyde by alcohol dehydrogenases and subsequently to n-butyric acid by aldehyde dehydrogenases. Thus, in the course of metabolic transformation of n-butyl acetate, butyric acid is generated rapidly and predominant as intermediary metabolite. Thus, it is justified to use n-butyl acetate as supporting substance in the evaluation of the systemic toxic effects of butyric acid.

 

Supporting substance: n-butyl acetate - Derivation of DNELs for butyric acid

 

There are several studies available where n-butyl acetate was administered using repeated doses.

In an inhalation subchronic repeated dose toxicity study (Bernard and Davis, 1996), test animals were exposed to n-butyl acetate for 6 h/d and 5 d/week over 91 days. The NOAEC determined was 500 ppm (2400 mg/m³).

In an inhalation 2-generation reproductive toxicity study (Nemec, 2007), F0 and F1 generation animals were exposed to n-butyl acetate for 6 h/d and 7 d/week over a period of 113 to 127 days and 134 to 154 days, respectively. The NOAEC for systemic toxicity was determined to be 750 ppm (3620 mg/m³).

In two inhalation developmental toxicity studies (Hackett et al, 1982 and Saillenfait et al, 2007), female test animals were exposed 7 h/d or 6 h/d for shorter time periods. The LOAEC for maternal and developmental toxicity in one study was 1500 ppm (7240 mg/m³) (Hackett et al). In the second study (Saillenfait et al), the NOAEC for maternal toxicity was 500 ppm (2400 mg/m³) and for developmental toxicity was 2000 ppm (9650 mg/m³).

In all studies available, exposure was by inhalation. Data/dose descriptors for other exposure routes are not available.

In the repeated dose toxicity study (Bernard and Davis, 1996), a NOAEC of 500 ppm was determined. The same concentration is the NOAEC maternal identified in the developmental toxicity study of Saillenfait. Being most conservative, this NOAEC will be used as dose descriptor in the derivation of DNELs.

 

Dermal systemic DNEL

 

Due to the lack of other data, the dermal DNEL will be obtained based on the inhalation NOAEC for n-butyl acetate of 500 ppm (Bernard and Davis, 1996; Repeated dose toxicity, Sect. 7.5.3 ). Using the molecular weight (butyric acid: 88.11) and the molar volume, the NOAEC for n-butyl acetate is converted to a NOAEC for butyric acid.

 

Inhalation systemic NOAEC for butyric acid: 1830 mg/m³

 

The dermal DNEL can be derived based on an oral NOAEL as starting point. As only an inhalation NOAEC is available as dose descriptor, this inhalation NOAEC has to be converted to a corrected "oral" NOAEL. In a first step, the total dose is calculated received by the test animals within the 6 hour exposure period using the standard rat respiratory volume. In a second step, the differences in exposure time and respiratory volume of workers are accounted for. As result, an "oral" NOAEL for workers is derived (267 mg/kg bw/day).

 

Using this starting point NOAEL, the dermal systemic DNEL is deduced. Factor for the transfer from the oral to dermal route is 1. 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 2.676 mg/kg bw/day for butyric acid is calculated.

 

Dermal systemic DNEL butyric acid: 2.67 mg/kg bw/day

 

Inhalation DNEL

 

The long-term inhalation NOAEC for butyric acid will be used to derive a systemic inhalation DNEL.

 

Inhalation systemic NOAEC for butyric acid: 1830 mg/m³(see above)

 

Exposure period in the study 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 a corrected starting point NOAEC of 920 mg/m³. The overall assessment factor (25) consists of a factor for remaining interspecies differences of 2.5, an intraspecies factor of 5 (Workers) and a sub-chronic-to-chronic exposure factor of 2. The allometric scaling factor is already accounted for in the derivation of the corrected inhalation starting point NOAEC. With this overall assessment factor, a DNEL of 36.8 mg/m³ for butyric acid is calculated.

 

Inhalation systemic DNEL for butyric acid: 36.8 mg/m³

 

Long-term exposure - local effects

 

For butyric acid, no data on local effects resulting from long-term exposure are available. Long term exposure studies with butyric acid have not been conducted. Due to the severe corrosive reaction of butyric 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:
9.15 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.66 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
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.66 mg/kg bw/day
DNEL related information
Overall assessment factor (AF):
200
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

Acute / short-term exposure - systemic effects

 

In acute toxicity studies, butyric acid has been shown to be of moderate to low systemic toxicity.

 

LD50 oral: 1632 mg/kg bw in rats (BASF, 1978)

LC0 inhalation, 4-h exposure: 5.1 mg/L (Celanes / Bio/dynamics, 1989); 8-h exposure: 4.18 mg/L (BASF, 1978)

LD50 dermal: 6096 mg/kg bw

 

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

 

Butyric 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 1954). Weaker effects have not been examined. Dose descriptors for the deduction of a DNEL for acute local effects are not available.

 

Unlike these findings, inhalational exposure to saturated vapor concentrations was possible for 8 hours without mortality. But severe mucosal irritation and closed eyelids are reported as local effects. For inhalation exposure, severe effects are reported as for dermal application, but this information is not suited as dose descriptors for the deduction of a DNEL.

 

Long term exposure systemic effects

 

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

 

After administration, n-butyl acetate will be rapidly metabolized in vivo in blood and various tissues by ubiquitous esterases. Half-life of this transformation is short resulting in complete cleavage of the ester. n-Butanol is formed which is rapidly metabolized in vivo to n-butyraldehyde by alcohol dehydrogenases and subsequently to n-butyric acid by aldehyde dehydrogenases. Thus, in the course of metabolic transformation of n-butyl acetate, butyric acid is generated rapidly and predominant as intermediary metabolite. Thus, it is justified to use n-butyl acetate as supporting substance in the evaluation of the systemic toxic effects of butyric acid.

 

Supporting substance: n-butyl acetate - Derivation of DNELs for butyric acid

 

There are several studies available where n-butyl acetate was administered using repeated doses.

In an inhalation subchronic repeated dose toxicity study (Bernard and Davis, 1996), test animals were exposed to n-butyl acetate for 6 h/d and 5 d/week over 91 days. The NOAEC determined was 500 ppm (2400 mg/m³).

In an inhalation 2-generation reproductive toxicity study (Nemec, 2007), F0 and F1 generation animals were exposed to n-butyl acetate for 6 h/d and 7 d/week over a period of 113 to 127 days and 134 to 154 days, respectively. The NOAEC for systemic toxicity was determined to be 750 ppm (3620 mg/m³).

In two inhalation developmental toxicity studies (Hackett et al, 1982 and Saillenfait et al, 2007), female test animals were exposed 7 h/d or 6 h/d for shorter time periods. The LOAEC for maternal and developmental toxicity in one study was 1500 ppm (7240 mg/m³) (Hackett et al). In the second study (Saillenfait et al), the NOAEC for maternal toxicity was 500 ppm (2400 mg/m³) and for developmental toxicity was 2000 ppm (9650 mg/m³).

 

In all studies, exposure was by inhalation. Data/dose descriptors for other exposure routes are not available.

 

In the repeated dose toxicity study (Bernard and Davis, 1996), a NOAEC of 500 ppm was determined. The same concentration is the NOAEC maternal identified in the developmental toxicity study of Saillenfait. Being most conservative, this NOAEC will be used as dose descriptor in the derivation of DNELs.

 

Dermal systemic DNEL

 

Due to the lack of other data, the dermal DNEL will be obtained based on the inhalation NOAEC for n-butyl acetate of 500 ppm (OPP/CMA, 1996; Repeated dose toxicity, Sect. 7.5.3 ). Using the molecular weight (butyric acid: 88.11) and the molar volume, the NOAEC for n-butyl acetate is converted to a NOAEC for butyric acid.

 

Inhalation systemic NOAEC for butyric acid: 1830 mg/m³

 

The dermal DNEL can be derived based on an oral NOAEL as starting point. As only an inhalation NOAEC is available as dose descriptor, this inhalation NOAEC has to be converted to an corrected "oral" NOAEL. In a first step, the total dose is calculated received by the test animals within the 6 hour exposure period using the standard rat respiratory volume. In a second step the difference in exposure time between test animals and general population are accounted for. As result, an "oral" NOAEL for the general population is derived (132.7 mg/kg bw/day).

 

Using this starting point NOAEL the dermal systemic DNEL is deduced. Factor for the transfer from the oral to dermal route is 1. With an overall assessment factor of 200 (allometric scaling factor 4, factor for remaining interspecies differences 2.5, intraspecies factor 10 (general population), sub-chronic to chronic exposure factor 2 ), a DNEL of 0.66 mg/kg bw/day for butyric acid is calculated.

 

Dermal systemic DNEL for butyric acid: 0.66 mg/kg bw/day

 

Inhalation DNEL

 

The long-term inhalation NOAEC for butyric acid will be used to derive a systemic inhalation DNEL.

 

Inhalation systemic NOAEC for butyric acid: 1830 mg/m³(see above)

 

Exposure period in the study was 6 h per day. This NOAEC has to be modified with respect to exposure conditions of the general population resulting in a corrected starting point NOAEC of 457,5 mg/m³. The overall assessment factor (50) consists of a factor for remaining interspecies differences of 2.5, an intraspecies factor of 10 (general publication) and a sub-chronic-to-chronic exposure factor of 2. The allometric scaling factor is already accounted for in the derivation of the corrected inhalation starting point NOAEC. With this overall assessment factor, a DNEL of 9.15 mg/m³ for butyric acid is calculated.

 

Inhalation systemic DNEL for butyric acid: 9.15 mg/m³

 

Oral systemic DNEL

 

An "oral" starting point was already calculated as basis for the deduction of the dermal systemic DNEL. To derive an oral systemic DNEL the same procedure is used. Dose descriptor is the inhalation systemic NOAEC.

 

Inhalation systemic NOAEC for butyric acid: 1830 mg/m³ (see above)

 

The corrected starting point is an "oral" NOAEL of 132.7 mg/m³ as above under Dermal systemic DNEL. With an overall assessment factor of 200 (allometric scaling factor 4, factor for remaining interspecies differences 2.5, intraspecies factor 10 (general population), sub-chronic to chronic exposure factor 2 ), a DNEL of 0.66 mg/kg bw/day for butyric acid is calculated.

 

Oral systemic DNEL for butyric acid: 0.66 mg/kg bw/day

 

Long-term exposure - local effects

 

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