Propionic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

73 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

35

Modified dose descriptor starting point:

NOAEC

Value:

2 566 mg/m³

Explanation for the modification of the dose descriptor starting point:

No experimental data on repeated exposure by inhalation available. Recommended approach using oral data for route to route extrapolation.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1.4

Justification:

The default factor for allometric scaling (dog to human) is used.

AF for other interspecies differences:

2.5

Justification:

Default assessment factor for remaining differences.

AF for intraspecies differences:

5

Justification:

Default assessment factor "worker".

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

31 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

62 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

20.9 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

35

Modified dose descriptor starting point:

NOAEL

Value:

733 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Recommended approach using oral data and assuming the same absorption for dermal and oral route.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1.4

Justification:

The default factor for allometric scaling (dog to human) is used.

AF for other interspecies differences:

2.5

Justification:

Default assessment factor for remaining differences.

AF for intraspecies differences:

5

Justification:

Default assessment factor "worker".

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Propionic acid is a short chain carboxylic acid exhibiting corrosive properties. It has a sour, disagreeable odor and a low odor threshold. The most prominent toxic effect after short or long term exposure is local irritation. Propionic acid is found naturally in humans as a normal intermediary metabolite that represents up to 4% of the normal total plasma fatty acids. It is formed as a result of catabolism of amino acids, as a terminal 3-carbon fragment in the oxidation of longer-chained fatty acids, and from the oxidation of the side chain of cholesterol. Propionic acid occurs naturally in foods, and together with other short-chain fatty acids, is ubiquitous in the gastrointestinal tract of humans and other mammals as end-products of microbial digestion. [OECD SIDS, 2007]

In an evaluation by the Joint FAO/WHO Expert Committee on Food Additives which was reaffirmed in 1997, the acceptable daily intake (ADI) of propionic acid and its sodium and calcium salts was designated as “not limited.” A similar conclusion was reached by the USEPA (2003) when it proposed to establish an exemption from the requirement of a tolerance limit for residues of propionic acid and its sodium salts. In the United States, propionic acid is a material generally regarded as safe (GRAS) by the Food and Drug Administration (FDA) for direct addition to human food when used as an anti-microbial agent or as a flavoring agent [21 CFR 184.1081].

Long-term exposure – systemic effects

 

Inhalation exposure – calculation of the NOAECcorr:

In order to derive the worker DNEL long-term for inhalation route systemic, the NOAEL of 733 mg/kg bw/day from the subchronic oral toxicity study (BASF, 1988) is considered to represent the appropriate dose descriptor for systemic effects related to long-term inhalation exposure.

In order to derive a worker DNEL and under the assumption of a daily exposure period of 8 hours, the oral NOAEL is converted into an inhalation NOAECcorr according to the following formula:

inhalation NOAECcorr

= oral NOAEL × ABSoral(dog)/ABSinhalation(human) × bw(human) / wRV(human)

= 733 mg/kg bw/d × 0.5 × 70 kg / 10 m³ = 2566 mg/m³

with:

oral NOAEL: 733 mg/kg bw/day

ABSoral(dog)/ABSinhalation(human): 0.5 [ratio of oral absorption in the dog to inhalative absorption in the human]

bw(human): standard human body weight (70 kg)

wRV(human): 10 m³ (8 hours) [worker respiratory volume]

Accordingly, the oral NOAEL of 733 mg/kg bw/day is transformed in an inhalation NOAECcorr of 2566 mg/m³.

This NOAECcorr serves as dose descriptor starting point to derive the corresponding DNEL value.

 

Dermal exposure - calculation of the NOAELcorr:

In order to derive a worker DNEL, the oral NOAEL of 733 mg/kg bw/day (BASF, 1988) is converted into a dermal NOAEL according to the following formula:

dermal NOAEL

= oral NOAEL × ABSoral(rat) / ABSdermal(human)

= 733 mg/kg bw/d × 1

= 733 mg/kg bw/d

with:

oral NOAEL: 733 mg/kg bw/day

ABSoral(rat)/ABSdermal(human): 1 [ratio of oral absorption in the dog to dermal absorption in the human]

Accordingly, the oral NOAEL of 733 mg/kg bw/day is transformed in a dermal NOAEL of 733 mg/kg bw/day. This NOAELcorr serves as dose descriptor starting point to derive the corresponding DNEL value.

 

Long- and short-term exposure – local effects

Propionic acid is a local irritant. The irritative effects of the substance are thus the most important end point. Identical occupational exposure levels based on local irritation have been published by SCOEL (1993) and MAK (2010) which covers also systemic effects. The 8 -hour TWA of 10 ppm (31 mg/m³) and STEL of 20 ppm (62 mg/m³) were justified by MAK commission as follows (for further details see corresponding MAK document, chapter 13 of IUCLID):

The lateralization threshold (van Thriel et al. 2006) and the results of the study of Walker et al. (2001) show that at concentrations around 40 ml/m³ trigeminally- mediated effects in the respiratory tract are to be expected. The physiological indicators of trigeminally-mediated irritation (nasal airway resistance, blinking frequency, neurogenic inflammation markers) used in the study with test persons (HVBG 2007) did not reveal any significant changes up to the highest exposure concentration of 10 ml/m³. Unlike in the workplace-relevant studies with acetic acid, slight eye irritation was reported after exposure to propionic acid concentrations of 10 ml/m³. As these effects, like the olfactory impressions, decreased over the 4-hour exposure period, it seems unlikely that they were trigeminally mediated, as a summation of the effects over time should be apparent. As the blinking frequency was unchanged, it can be assumed that the NOAEL for objective local effects is above 10 ml/m³. The reported odour nuisance was quantitatively slight, typical adaptation effects were observed and the annoyance did not lead to interference with cognitive performance. Even at concentrations of 10 ml/ m³, unreasonable annoyance as defined by the MAK value is not, therefore, evident. A MAK value of 10 ml/m³ has therefore been established for propionic acid.

As the physiological indicators did not provide any evidence of irritative effects at 10 ml/m³ and the eye irritation was subjectively felt to be very slight, an excursion factor of 2 has been set for short term peak exposures (20 ml/m³).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

18.3 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

70

Modified dose descriptor starting point:

NOAEC

Value:

1 283 mg/m³

Explanation for the modification of the dose descriptor starting point:

No experimental data on repeated exposure by inhalation available. Recommended approach using oral data for route to route extrapolation.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1.4

Justification:

The default factor for allometric scaling (dog to human) is used.

AF for other interspecies differences:

2.5

Justification:

Default assessment factor for remaining differences.

AF for intraspecies differences:

10

Justification:

Default assessment factor "general population".

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.7 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

30.8 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:

10.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

70

Modified dose descriptor starting point:

NOAEL

Value:

733 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Recommended approach using oral data and assuming the same absorption for dermal and oral route.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1.4

Justification:

The default factor for allometric scaling (dog to human) is used.

AF for other interspecies differences:

2.5

Justification:

Default assessment factor for remaining differences.

AF for intraspecies differences:

10

Justification:

Default assessment factor "general population".

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

70

Modified dose descriptor starting point:

NOAEL

Value:

733 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Oral repeated dose toxicity study available.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1.4

Justification:

The default factor for allometric scaling (dog to human) is used.

AF for other interspecies differences:

2.5

Justification:

Default assessment factor for remaining differences.

AF for intraspecies differences:

10

Justification:

Default assessment factor "general population".

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Propionic acid is a short chain carboxylic acid exhibiting corrosive properties. It has a sour, disagreeable odor and a low odor threshold. The most prominent toxic effect after short or long term exposure is local irritation. Propionic acid is found naturally in humans as a normal intermediary metabolite that represents up to 4% of the normal total plasma fatty acids. It is formed as a result of catabolism of amino acids, as a terminal 3-carbon fragment in the oxidation of longer-chained fatty acids, and from the oxidation of the side chain of cholesterol. Propionic acid occurs naturally in foods, and together with other short-chain fatty acids, is ubiquitous in the gastrointestinal tract of humans and other mammals as end-products of microbial digestion. [OECD SIDS, 2007]

In an evaluation by the Joint FAO/WHO Expert Committee on Food Additives which was reaffirmed in 1997, the acceptable daily intake (ADI) of propionic acid and its sodium and calcium salts was designated as “not limited.” A similar conclusion was reached by the USEPA (2003) when it proposed to establish an exemption from the requirement of a tolerance limit for residues of propionic acid and its sodium salts. In the United States, propionic acid is a material generally regarded as safe (GRAS) by the Food and Drug Administration (FDA) for direct addition to human food when used as an anti-microbial agent or as a flavoring agent [21 CFR 184.1081].

Long-term exposure – systemic effects

 

Inhalation exposure – calculation of the NOAECcorr:

In order to derive the general population inhalative long-term DNEL for systemic effects, the NOAEL of 733 mg/kg bw/day from the subchronic oral toxicity study (BASF, 1988) is considered to represent the appropriate dose descriptor.

In order to derive a consumer DNEL and under the assumption of a daily exposure period of 24 hours, the oral NOAEL is converted into an inhalation NOAECcorr according to the following formula:

inhalation NOAECcorr

= oral NOAEL × ABSoral(dog)/ABSinhalation(human) × bw(human) / sRV(human)

= 733 mg/kg bw/d × 0.5 × 70 kg / 20 m³ = 1283 mg/m³

with:

oral NOAEL: 733 mg/kg bw/day

ABSoral(dog)/ABSinhalation(human): 0.5 [ratio of oral absorption in the dog to inhalative absorption in the human]

bw(human): standard human body weight (70 kg)

sRV(human): 20 m³ (24 hours) [consumer respiratory volume]

Accordingly, the oral NOAEL of 733 mg/kg bw/day is transformed in an inhalation NOAECcorr of 1283 mg/m³.

This NOAECcorr serves as dose descriptor starting point to derive the corresponding DNEL value.

 

Dermal exposure - calculation of the NOAELcorr:

In order to derive a consumer DNEL, the oral NOAEL of 733 mg/kg bw/day (BASF, 1988) is converted into a dermal NOAEL according to the following formula:

dermal NOAEL

= oral NOAEL × ABSoral(rat) / ABSdermal(human)

= 733 mg/kg bw/d × 1

= 733 mg/kg bw/d

with:

oral NOAEL: 733 mg/kg bw/day

ABSoral(rat)/ABSdermal(human): 1 [ratio of oral absorption in the dog to dermal absorption in the human]

Accordingly, the oral NOAEL of 733 mg/kg bw/day is transformed in a dermal NOAEL of 733 mg/kg bw/day. This NOAELcorr serves as dose descriptor starting point to derive the corresponding DNEL value.

Oral exposure:

In an evaluation by the Joint FAO/WHO Expert Committee on Food Additives which was reaffirmed in 1997, the acceptable daily intake (ADI) of propionic acid and its sodium and calcium salts was designated as “not limited.” A similar conclusion was reached by the USEPA (2003) when it proposed to establish an exemption from the requirement of a tolerance limit for residues of propionic acid and its sodium salts. In the United States, propionic acid is a material generally regarded as safe (GRAS) by the Food and Drug Administration (FDA) for direct addition to human food when used as an anti-microbial agent or as a flavoring agent [21 CFR 184.1081].

An oral consumer DNEL for systemic effects was derived from the oral NOAEL of 733 mg/kg bw/day (BASF, 1988).

 

Long- and short-term exposure – local effects

Propionic acid is a local irritant. The irritative effects of the substance are thus the most important end point. Identical occupational exposure levels based on local irritation have been published by SCOEL (1993) and MAK (2010) which covers also systemic effects. The 8 -hour TWA of 10 ppm (31 mg/m³) and STEL of 20 ppm (62 mg/m³) were justified by MAK commission as follows (for further details see corresponding MAK document, chapter 13 of IUCLID):

The lateralization threshold (van Thriel et al. 2006) and the results of the study of Walker et al. (2001) show that at concentrations around 40 ml/m³trigeminally- mediated effects in the respiratory tract are to be expected. The physiological indicators of trigeminally-mediated irritation (nasal airway resistance, blinking frequency, neurogenic inflammation markers) used in the study with test persons (HVBG 2007) did not reveal any significant changes up to the highest exposure concentration of 10 ml/m³. Unlike in the workplace-relevant studies with acetic acid, slight eye irritation was reported after exposure to propionic acid concentrations of 10 ml/m³. As these effects, like the olfactory impressions, decreased over the 4-hour exposure period, it seems unlikely that they were trigeminally mediated, as a summation of the effects over time should be apparent. As the blinking frequency was unchanged, it can be assumed that the NOAEL for objective local effects is above 10 ml/m³. The reported odour nuisance was quantitatively slight, typical adaptation effects were observed and the annoyance did not lead to interference with cognitive performance. Even at concentrations of 10 ml/ m³, unreasonable annoyance as defined by the MAK value is not, therefore, evident. A MAK value of 10 ml/m³has therefore been established for propionic acid.

As the physiological indicators did not provide any evidence of irritative effects at 10 ml/m³and the eye irritation was subjectively felt to be very slight, an excursion factor of 2 has been set for short-term peak exposures (20 ml/m³).

The values are regarded to be safe for workers; according to the ECHA Guidance document the intraspecies factor is by a factor of 2 higher for general population than for worker. Also the possible exposure time may be by a factor 3 (8 hrs. vs. 24 hrs) and by a factor 1.4 (5 days/week vs. 7 days/week) longer. Therefore, an additional AF of 8.4 is added to the OEL value, resulting in a long-term DNEL for general population of 1.2 ppm ( 3.7 mg/m³). For short-term peak exposure, an additional AF of 2 is considered, resulting in a DNEL of 10 ppm (30.8 mg/m³).