##### ROBUST SUMMARIES and 

#### SIDS DOSSIER for:

##### n-PROPIONIC ACID

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##### CAS No. 79-09-4 

Sponsor Country: U.S.A.

April 2008

CONTENTS

[**1.0 GENERAL INFORMATION** 7](#general-information)

[**1.01 SUBSTANCE INFORMATION** 7](#substance-information)

[**1.02 OECD INFORMATION** 7](#oecd-information)

[**1.1 GENERAL SUBSTANCE INFORMATION**
8](#general-substance-information)

[**1.2 SYNONYMS** 8](#synonyms)

[**1.3 IMPURITIES** 8](#impurities)

[**1.4 ADDITIVES** 8](#additives)

[**1.5 QUANTITY** 8](#quantity)

[**1.6 LABELLING AND CLASSIFICATION** 9](#labelling-and-classification)

[**1.7 USE PATTERN** 9](#use-pattern)

[**1.8 OCCUPATIONAL EXPOSURE LIMIT VALUE**
10](#occupational-exposure-limit-value)

[**1.9 SOURCES OF EXPOSURE** 11](#sources-of-exposure)

[**1.10 ADDITIONAL REMARKS** 14](#additional-remarks)

[**2.0 PHYSICAL-CHEMICAL DATA** 17](#physical-chemical-data)

[**2.1 MELTING POINT** 17](#melting-point)

[**2.2 BOILING POINT** 18](#boiling-point)

[**2.3 DENSITY** 18](#density)

[**2.4 VAPOUR PRESSURE** 19](#vapour-pressure)

[**2.5 PARTITION COEFFICIENT** 20](#partition-coefficient-log10pow)

[**2.6 WATER SOLUBILITY** 20](#water-solubility)

[**2.7 FLASH POINT *(liquids)*** 21](#flash-point-liquids)

[**2.8 AUTO FLAMMABILITY *(solid/gases)***
22](#auto-flammability-solidgases)

[**2.9 FLAMMABILITY** 22](#flammability)

[**2.10 EXPLOSIVE PROPERTIES** 23](#explosive-properties)

[**2.11 OXIDIZING PROPERTIES** 23](#oxidizing-properties)

[**2.12 ADDITIONAL REMARKS** 23](#additional-remarks-1)

[**2.13 ADDITIONAL DATA** 23](#additional-data)

[**3.0 ENVIRONMENTAL FATE AND PATHWAYS**
24](#environmental-fate-and-pathways)

[**3.1 STABILITY** 24](#stability)

[**3.1.1 PHOTODEGRADATION** 24](#photodegradation)

[**3.1.2 STABILITY IN WATER** 25](#stability-in-water)

[**3.1.3 STABILITY IN SOIL** 26](#stability-in-soil)

[**3.2 MONITORING DATA (ENVIRONMENT)** 27](#monitoring-data-environment)

[**3.3 TRANSPORT AND DISTRIBUTION BETWEEN ENVIRONMENTAL COMPARTMENTS
INCLUDING ESTIMATED ENVIRONMENTAL CONCENTRATIONS AND DISTRIBUTION
PATHWAYS**
30](#transport-and-distribution-between-environmental-compartments-including-estimated-environmental-concentrations-and-distribution-pathways)

[**3.3.1 TRANSPORT BETWEEN ENVIRONMENTAL COMPARTMENTS**
30](#transport-between-environmental-compartments)

[**3.3.2 THEORETICAL DISTRIBUTION (FUGACITY CALCULATION)**
32](#theoretical-distribution-fugacity-calculation)

[**3.4 IDENTIFICATION OF MAIN MODE OF DEGRADABILITY IN ACTUAL USE**
33](#identification-of-main-mode-of-degradability-in-actual-use)

[**3.5 BIODEGRADATION** 33](#biodegradation)

[**3.6 BOD~5~,COD OR RATIO BOD~5~/COD** 35](#bod5cod-or-ratio-bod5cod)

[**3.7 BIOACCUMULATION** 35](#bioaccumulation)

[**3.8 ADDITIONAL REMARKS** 36](#additional-remarks-2)

[**4.0 ECOTOXICOLOGICAL DATA** 36](#ecotoxicological-data)

[**4.1 ACUTE/PROLONGED TOXICITY TO FISH**
36](#acuteprolonged-toxicity-to-fish)

[**4.2 ACUTE TOXICITY TO AQUATIC INVERTEBRATES**
42](#acute-toxicity-to-aquatic-invertebrates)

[**A. Daphnia** 42](#a.-daphnia)

[**B. Other** 44](#b.-other)

[**4.3 TOXICITY TO AQUATIC PLANTS e.g. Algae**
45](#toxicity-to-aquatic-plants-e.g.-algae)

[**4.4 TOXICITY TO BACTERIA** 49](#toxicity-to-bacteria)

[**4.5 CHRONIC TOXICITY TO AQUATIC ORGANISMS**
49](#chronic-toxicity-to-aquatic-organisms)

[**4.5.1 CHRONIC TOXICITY TO FISH** 49](#chronic-toxicity-to-fish)

[**4.5.2 CHRONIC TOXICITY TO AQUATIC INVERTEBRATES**
49](#chronic-toxicity-to-aquatic-invertebrates)

[**4.6 TOXICITY TO TERRESTRIAL ORGANISMS**
49](#toxicity-to-terrestrial-organisms)

[**4.6.1 TOXICITY TO SOIL DWELLING ORGANISMS**
49](#toxicity-to-soil-dwelling-organisms)

[**4.6.2 TOXICITY TO TERRESTRIAL PLANTS**
50](#toxicity-to-terrestrial-plants)

[**4.6.3 TOXICITY TO OTHER NON MAMMALIAN TERRESTRIAL SPECIES (INCLUDING
AVIAN)**
51](#toxicity-to-other-non-mammalian-terrestrial-species-including-avian)

[**4.7 BIOLOGICAL EFFECTS MONITORING (INCLUDING BIOMAGNIFICATION)**
51](#biological-effects-monitoring-including-biomagnification)

[**4.8 BIOTRANSFORMATION AND KINETICS**
51](#biotransformation-and-kinetics)

[**4.9 ADDITIONAL REMARKS** 51](#additional-remarks-3)

[**5.0 TOXICITY** 52](#toxicity)

[**5.1 ACUTE TOXICITY** 52](#acute-toxicity)

[**5.1.1 ACUTE ORAL TOXICITY** 52](#acute-oral-toxicity)

[**5.1.2 ACUTE INHALATION TOXICITY** 54](#acute-inhalation-toxicity)

[**5.1.3 ACUTE DERMAL TOXICITY** 56](#acute-dermal-toxicity)

[**5.1.4 ACUTE TOXICITY, OTHER ROUTES OF ADMINISTRATION**
57](#acute-toxicity-other-routes-of-administration)

[**5.2 CORROSIVENESS/IRRITATION** 58](#corrosivenessirritation)

[**5.2.1 SKIN IRRITATION/CORROSION** 58](#skin-irritationcorrosion)

[**5.2.2 EYE IRRITATION/CORROSION** 59](#eye-irritationcorrosion)

[**5.3 SKIN SENSITISATION** 60](#skin-sensitisation)

[**5.4 REPEATED DOSE TOXICITY** 60](#repeated-dose-toxicity)

[**5.5 GENETIC TOXICITY IN VITRO** 77](#genetic-toxicity-in-vitro)

[**A. BACTERIAL IN VITRO TEST** 77](#a.-bacterial-in-vitro-test)

[**B. NON‑BACTERIAL IN VITRO TEST** 82](#b.-nonbacterial-in-vitro-test)

[**5.6 GENETIC TOXICITY IN VIVO** 85](#genetic-toxicity-in-vivo)

[**5.7 CARCINOGENICITY** 86](#carcinogenicity)

[**5.8 TOXICITY TO REPRODUCTION** 88](#toxicity-to-reproduction)

[**5.9 DEVELOPMENTAL TOXICITY/TERATOGENICITY**
92](#developmental-toxicityteratogenicity)

[**5.10 OTHER RELEVANT INFORMATION** 100](#other-relevant-information)

[**A. Specific toxicities** 100](#a.-specific-toxicities)

[**B. Toxicodynamics, toxicokinetics**
101](#toxicodynamics-toxicokinetics)

[**C. Other** 105](#c.-other)

[**5.11 EXPERIENCE WITH HUMAN EXPOSURE**
107](#experience-with-human-exposure)

[**6.0 REFERENCES** 110](#references)

# **1.0 GENERAL INFORMATION**

# **1.01 SUBSTANCE INFORMATION**

**A. CAS-Number** 79-09-4

**B. Name** *(IUPAC name)* n-Propionic Acid

**C. Name** *(OECD name)* n-Propionic Acid

**D. CAS Descriptor** Not applicable in this case

**E. EINECS-Number** 201-176-3

**F. Molecular Formula** C3 H6 O2

**G. Structural Formula** CH3-CH2-COOH

######## H. Substance Group Not applicable

######## I. Substance Remark None

**J. Molecular Weight** 74.08

# **1.02 OECD INFORMATION**

**A. Sponsor Country:** U.S.A.

**B. Lead Organisation:**

Name of Lead Organisation: American Chemistry Council

Contact person: Barbara Francis

Address: 1300 Wilson Blvd.

Arlington, VA 22209

U.S.A.

Tel: 703-741-5609

Fax: 703-741-6091

# **1.1 GENERAL SUBSTANCE INFORMATION** 

**A. Type of Substance** element \[ \]; inorganic \[ \]; natural
substance \[ \]; organic \[ X \];

organometalic \[  \]; petroleum product \[ \]

**B. Physical State** *(at 20°C and 1.013 hPa)*

gaseous \[ \]; liquid \[ X \]; solid \[ \]

**C. Purity** *(indicate the percentage by weight/weight)*

\>99% weight/weight

# **1.2 SYNONYMS** 

> 1-propionic acid
>
> propionic acid
>
> methyl acetic acid
>
> ethyl formic acid
>
> ethane carboxylic acid
>
> methacetonic acid

pseudoacetic acid

carboxyethane

# **1.3 IMPURITIES** 

> CAS No: None
>
> EINECS No:
>
> Name:
>
> Value:
>
> Remarks:

# **1.4 ADDITIVES** 

> CAS No: None
>
> EINECS No:
>
> Name:
>
> Value:
>
> Remarks:
>
> Reference:

# **1.5 QUANTITY** 

> 115,000 tonnes
>
> Remarks: U.S. production in 2003. Annual consumption of propionic acid
> in the U.S. was about 91 thousand metric tonnes in 2003.
>
> Reference: Chemical Economics Handbook, 2003.
>
> Remarks: In 2003, approximately 124 thousand metric tons were produced
> in Western Europe; annual production in Japan is reported to be 3
> thousand metric tones.
>
> Reference: Chemical Economics Handbook, 2003.

# **1.6 LABELLING AND CLASSIFICATION**

[Labelling]{.underline}

Type: Hazardous

Specific limits:

Symbols: C (corrosive)

Note: B (do not transport with food and feedstuffs)

R-phrases: 34 (causes burns)

S-phrases: 1/2-23-36-45

Text of S-phrases:

> S1: keep locked up

S2: keep out of reach of children

S23: do not breathe vapor

S36: wear suitable protective clothing

> S45: in case of accident or if you feel unwell, seek medical advice
> immediately
>
> Remark: Flammable and corrosive material; no open flames no sparks, no
> smoking. Avoid all contact, use ventilation, local exhaust or
> breathing protection; use face shield, protective gloves and
> protective clothing.
>
> Reference: International Chemical Safety Cards. 2006. Available at
> [www.cdc.gov/niosh/ipcsneng](http://www.cdc.gov/niosh/ipcsneng)

[Classification]{.underline} Corrosive

Type:

Category of danger:

R-phrases:

Remarks: UN Hazard Class 8, UN Packing Group III

> Reference: International Chemical Safety Cards. 2006. Available at
> [www.cdc.gov/niosh/ipcsneng](http://www.cdc.gov/niosh/ipcsneng)

# **1.7 USE PATTERN** 

**A. General**

**Type of Use: Category: Non dispersive**

Use resulting in inclusion into or onto matrix

**Type of Use: Category: Wide dispersive**

industrial Basic industry: basic chemicals

industrial Chemical industry: used in synthesis

industrial Chemical industry: intermediate for plastics, polymers,
herbicides, fragrance chemicals

industrial Chemical industry: intermediate for pharmaceuticals

use Manufacture of food and feed preservatives

use Synthetic flavor ingredient

> References: Bizzari, S.N., Fenelon, S. and Ishikawa-Yamaki. 1999. CEH
> Marketing
>
> Research Report, dated May 1999.
>
> Budavari, S. (Ed.). 1996. The Merck Index. An Encyclopedia of
> Chemicals, Drugs, and Biologicals, 12^th^ Edition. Whitehouse Station,
> NJ: Merck and Co., Inc.
>
> Katz, G.V. and Guest, D. Aliphatic Carboxylic Acids. *In:* Clayton,
> G.D. and Clayton, F.E. (Eds.). 1994. Patty's Industrial Hygiene and
> Toxicology, 4^th^ Edition. Volume II, Part E: New York: John Wiley &
> Sons, Inc.
>
> n-Propionic acid (CAS 79-09-4). Hazardous Substance Databank
>
> (HSDB), Number 1192, updated on 06/24/2005.

B.  **Uses in Consumer Products**

> Feed and corn preservative, used to control fungi and bacteria in
> drinking water for livestock and poultry.
>
> Approved as a direct additive to food for human consumption.

# **1.8 OCCUPATIONAL EXPOSURE LIMIT VALUE**

\(a\) Type of Limit: TLV/TWA (US)

Value: 10 ppm (30 mg/m^3^)

Short Term Exposure

Limit Value:

Time Schedule:

Remark: 8 hour TWA (time weighted average) ACGIH

TLV: 10 ppm

STEL: none

> Reference: American Conference of Governmental Industrial Hygienists,
> Inc. (ACGIH). 2005. Guide of Occupational Exposure Values-2005.
> Cincinnati, OH: American Conference of Governmental Industrial
> Hygienists, Inc.

\(b\) Type of Limit: NIOSH REL (US)

Value: 10 ppm (30 mg/m^3^)

Short Term Exposure

Limit Value: 15 ppm (45 mg/m^3^)

Time Schedule:

Remark: 10-hour TWA

> Reference: American Conference of Governmental Industrial Hygienists,
> Inc. (ACGIH). 2005. Guide of Occupational Exposure Values-2005.
> Cincinnati, OH: American Conference of Governmental Industrial
> Hygienists, Inc.

\(c\) Type of Limit: MAK (DE)

Value: 10 ppm (31 mg/^3^)

Short Term Exposure

Limit Value:

Time Schedule: 5 minute, momentary value Frequency 8

Remark: Category I: local irritant

> Reference: American Conference of Governmental Industrial Hygienists,
> Inc. (ACGIH). 2005. Guide of Occupational Exposure Values-2005.
> Cincinnati, OH: American Conference of Governmental Industrial
> Hygienists, Inc.

# **1.9 SOURCES OF EXPOSURE** 

> \(a\) Remark: In humans, propionic acid is one of the metabolic
> products from the breakdown of several amino acids. Propanoic acid is
> formed as the body oxidizes longer chain odd-numbered fatty acids or
> the side chain of cholesterol. It is a normal intermediary metabolite
> in the body that is utilized by most organs and tissues, and can be
> metabolized to glucose, carbohydrates, amino acids, and lipids. If
> directly ingested, propionic acid is rapidly absorbed from the
> mammalian gastrointestinal tract, and thus enters a known metabolic
> pathway.
>
> Reference: U.S. Environmental Protection Agency. 2003. Proposed Rule:
> Propanoic Acid, and its Calcium and Sodium Salts; Exemption from the
> Requirement of a Tolerance.  U.S. Federal Register: January 13, 2003
> (Volume 68, Number 8), Page 1575-1580.

\(b\) Remark: Propionic acid is formed in intermediary metabolism in the
body as the terminal

> 3-carbon fragment during oxidation of odd-numbered caron fatty acids.
> Oxidation of the side chain of cholesterol by mitochondria from
> propionic acid. Propionic acid is metabolized and utilized in the same
> way as other fatty acids and even after large doses, no significant
> amounts of propionic acid is excreted in the urine.
>
> Reference: WHO (World Health Organization). 1974. Propionic Acid and
> its Calcium, Potassium and Sodium Salts. 17^th^ Report of the Joint
> FAO/WHO Expert Committee on Food Additives. WHO Technical Report
> Series 539.

\(c\) Remark: In human plasma, propionic acid represents up to 4% of the
total fatty acid and

> is a by-product of normal intermediate metabolism. Absorbed propionate
> is removed by the liver, kidneys, heart, muscle and adipose tissue.
> Propionic acid is a normal
>
> intermediary metabolite and a normal constituent of foods.
>
> Reference: WHO (World Health Organization). 1974. Propionic Acid and
> its Calcium, Potassium and Sodium Salts. 17^th^ Report of the Joint
> FAO/WHO Expert Committee on Food Additives. WHO Technical Report
> Series 539.

\(d\) Remark: Propionic acid is formed during the catabolism of amino
acids (isoleucine,

> valine, methionine, and threnine) and β oxidation of odd-numbered
> fatty acids; it is also derived from anerobic bacterial fermentation
> of carbohydrages in the colon.
>
> Reference: Mellon, A.F., Deshpande, S.A., Mathers, J.C., and Bartlett,
> K. 2000. Effect of oral antibiotics on intestinal production of
> propionic acid. Arch. Dis. Child. 82: 169-172.

\(e\) Remark: Propionic acid is used as an anti-mold and anti-rope
agent, as a preservative and

> as a flavoring agent in foods. No safety concerns were noted at
> current levels of ingestion and a "not limited" acceptable daily
> intake (ADI) was approved for propionic acid in 1973 and again in
> 1997.
>
> Reference: WHO (World Health Organization). 1974. Propionic Acid and
> its Calcium, Potassium and Sodium Salts. 17^th^ Report of the Joint
> FAO/WHO Expert Committee on Food Additives. WHO Technical Report
> Series 539.
>
> WHO (World Health Organization). 1997. Propionic Acid and its Calcium,
> Potassium and Sodium Salts. 49^th^ Report of the Joint FAO/WHO Expert
> Committee on Food Additives. WHO Technical Report Series 884.

\(f\) Remark: NIOSH has statistically estimated that 23,167 workers
(5,489 of these are

> females) are potentially exposed to propionic acid in the United
> States; this
>
> estimate does not include farm workers. Occupational exposure may
> occur
>
> through inhalation and dermal contact with propionic acid where it is
> produced or
>
> used.
>
> Reference: NIOSH. National Occupational Exposure Survey (NOES). 1983.

\(g\) Remark: The general population may be exposed to propionic acid
via inhalation of ambient

> air, ingestion of food and drinking water, and dermal contact with
> consumer products containing propionic acid.
>
> Reference: n-Propionic Acid. CASRN 79-09-4. Hazardous Substance Data
> Bank (HSDB)
>
> Number 1192, updated on 06/24/2005.

\(h\) Remark: Propionic acid is formed as the free acid in various
enzymatic and fermentation

> processes and is produced during anaerobic carbohydrate metabolism in
> the
>
> stomachs of ruminants.
>
> Reference: Propionic Acid. CASRN 79-09-4. Hazardous Substance Data
> Bank (HSDB) Number 1192, updated on 06/24/2005.

\(i\) Remark: Propionic acid occurs in dairy products in small amounts.

> Reference: Budavari, S. (Ed). 1996. The Merck Index. An Encyclopedia
> of Chemicals,
>
> Drugs, Biologicals, 12^th^ Edition. Whitehouse Station, NJ: Merck and
> Company,
>
> Inc.

\(j\) Remark: Propionic acid has been isolated from beef and dry cured
ham.

> Reference: Furia, T.E. and Bellanca, N. (Eds.). 1975. Fenaroli,
> Handbook of Flavor
>
> Ingredients, Volume 2. *Cited in:* Propionic Acid. CASRN 79-09-4.
> Hazardous
>
> Substance Data Bank (HSDB) Number 1192, updated on 06/24/2005.

\(k\) Remark: Propionic acid occurs naturally in Swiss cheese at levels
which may be as high as

> 1%.
>
> Reference: Furia, T.E. and Bellanca, N. (Eds.). 1975. Fenaroli,
> Handbook of Flavor Ingredients, Volume 2. *Cited in:* Propionic Acid.
> CASRN 79-09-4. Hazardous Substance Data Bank (HSDB) Number 1192,
> updated on 06/24/2005.

\(l\) Remark: Propionic acid has been qualitatively detected as a
volatile component of baked

> potatoes and cooked meats. Propionic acid was detected in German fruit
> brandies and desert wines at an average concentration of 0.2 and 1.1
> mg/kg, respectively.
>
> It has also been identified in popcorn at a concentration of 300
> ug/kg.
>
> Reference: Coleman, E.C. et al. J. 1981. J. Agric. Food Chem. 29:
> 42-48; *and* Shibamoto, T. et al. 1981. J. Agric. Food Chem. 29:
> 57-63; and Buttery, R.G. et al. 1997. J. Agric. Food Chem. 45: 837-43.
> *All references cited in:* Propionic Acid. CASRN 79-09-4. Hazardous
> Substance Data Bank (HSDB) Number 1192, updated on 06/24/2005.

\(m\) Remark: Two samples of mussels (Mytilus edulis) from the Oarai
Coast, Japan contained

> propionic acid at a concentration of 2.73 and 0.50 ug/l.
>
> Reference: Yashura, A. and Morita, M. 1987. Chemosphere 16: 2559-2565.
> *Cited in:* Propionic Acid. CASRN 79-09-4. Hazardous Substance Data
> Bank (HSDB) Number 1192, updated on 06/24/2005.

\(n\) Remark: Human exposure can occur during the use of propionic acid
as a feed and grain

> preservative, or from the use of salts of propionic acid used as
> preservatives (e.g., ammonium propionate) or calcium and sodium
> propionate used as preservatives in baked goods. The salts of
> propionic acid can release propionate anion, especially in an aqueous
> environment, and the concentration of the anion or propionic acid
> itself is then dependent on pH. Use of propionic acid as a feed or
> grain preservative may result in its release to the environment
> through various waste streams. Its use to control fungi and bacteria
> in drinking water for live stock and poultry is expected to result in
> its direct release to the environment.
>
> Reference: Propionic Acid. CASRN 79-09-4. Hazardous Substance Data
> Bank (HSDB)
>
> Number 1192, updated on 06/24/2005.

\(o\) Remark: The general population may be exposed to propionic acid
via inhalation of

> ambient air, ingestion of food and drinking water, and dermal contact
> with this compound in consumer products containing propionic acid.
> Environmental data suggests that environmental concentrations of
> propionic acid occur as a result of natural and artifical sources, but
> at low levels.
>
> Propionic acid's production and use as a feed and corn preservative
> and chemical intermediate may result in its release to the environment
> through various waste streams. Its use to control fungi and bacteria
> in drinking water for livestock and poultry is expected to result in
> its release to the environment. It is also released to the environment
> with the manufacture and use of coal-derived and shale oil liquid
> fuels, and during the disposal of coal liquefication and gasification
> and wood preserving chemical waste byproducts. Textile mills, sewage
> treatment facilities and municipal and industrial landfills, hazardous
> waste sites and gasoline and diesel fueled engines can release
> propionic acid to the environment.
>
> Reference**:** Propionic Acid. CASRN 79-09-4. Hazardous Substance Data
> Bank (HSDB)
>
> Number 1192, updated on 06/24/2005.

# **ADDITIONAL REMARKS**

> \(a\) Remark: In 2003, the U.S.EPA proposed to establish an exemption
> from the requirement
>
> of a tolerance limit for residues of propanoic acid, and its calcium
> and sodium salts when used as either an inert or active ingredient in
> pesticide formulations that are applied to growing crops or raw
> agricultural commodites (RAC) before or after harvest, and for
> pesticide formulations that are applied to animals, under the Federal
> Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality
> Protection Act of 1996 (FQPA). The Agency completed the Tolerance
> Reassessment process for propanoic acid. Based on the results of that
> reassessment, EPA on its own initiative, under section 408(e) of the
> FFDCA, 21 U.S.C. 346a, is proposing to establish an unlimited
> exemption from the requirement of a tolerance for residues of
> propanoic acid (CAS Reg. No. 79-09-4); propanoic acid, calcium salt
> (CAS Reg. No. 4075-81-4); and propanoic
>
> acid, sodium salt (CAS Reg. No. 187-40-6), when used as either an
> active or inert ingredient in pesticide formulations that are applied
> to growing crops or raw agricultural commodities and in pesticide
> formulations that are applied to animals.
>
> Based on the available data, the lower toxicity of propanoic acid and
> its calcium and sodium salts, and considering the FDA affirmed GRAS
> uses, the USEPA concluded in 2003 that propanoic acid and its calcium
> and sodium salts do not pose a dietary risk under reasonably
> foreseeable circumstances. Accordingly, the EPA determined that there
> is a reasonable certainty that no harm will result to the general
> population, and to infants and children from aggregate exposure to
> propanoic acid and its calcium and sodium salts. For propanoic acid
> and its calcium and sodium salts, due to the expected low oral
> toxicity, a safety factor analysis was not used to assess the risk.
> For the same reasons and especially considering the available
> developmental toxicity information, the additional tenfold safety
> factor for the protection of infants and children was determined to be
> unnecessary.
>
> Reference: U.S. Environmental Protection Agency. 2003. Proposed Rule:
> Propanoic Acid, and its Calcium and Sodium Salts; Exemption from the
> Requirement of a Tolerance.  U.S. Federal Register: January 13, 2003
> (Volume 68, Number 8), Page 1575-1580.

\(b\) Remark: In 2003, the USEPA stated "Propanoic acid demonstrates an
acute toxicity

> profile that is consistent with that of an acid: it is highly acutely
> toxic for eye and dermal irritation, i.e., it is corrosive to the eyes
> and skin. These effects are most appropriately addressed through the
> use of protective equipment and labeling, not through establishment of
> tolerance exemptions."
>
> "When considering the oral exposure pathway, the most relevant in
> establishing a tolerance exemption, propanoic acid and its calcium and
> sodium salts have low toxic potential. There are no concerns for
> mutagencity, carcinogenicity, or developmental or reproductive
> concerns. Propanoic acid is a normal component of metabolism in the
> human body. The human body has a known pathway to metabolize propanoic
> acid. No additional data are necessary to assess the toxicity of these
> chemicals.
>
> Reference: U.S. Environmental Protection Agency. 2003. Proposed Rule:
> Propanoic Acid, and its Calcium and Sodium Salts; Exemption from the
> Requirement of a Tolerance.  U.S. Federal Register: January 13, 2003
> (Volume 68, Number 8), Page 1575-1580.

\(c\) Remark: Propionic acid is a substance generally regarded as safe
(GRAS) for direct

> addition to human food.
>
> Reference: Code of Federal Regulations. Volume 21, Section 184.1881,
> 4/1/98. U.S.
>
> Government Printing Office, Washington, DC.

\(d\) Remark: Propionic acid is exempt from tolerance requirements for
residues in or on meat

> and meat by-products of cattle, sheep, hogs, poultry, milk and eggs
> when applied as a bactericide or fungicide to livestock drinking
> water, poultry litter, or storage areas for silage and grain.
>
> Reference: Code of Federal Regulations. Volume 40, Part 180, Section
> 1023(b), 7/1/98. U.S.
>
> Government Printing Office, Washington, DC.

\(e\) Remark: Propionic acid is exempt from tolerance requirements for
residues in or one

> barley, wheat, corn, rye, hay, grasses, timothy, vetch, from
> post-harvest application when used as a preservative.
>
> Reference: Code of Federal Regulations. Volume 40, Part 180, Section
> 1023(a), 7/1/98. U.S.
>
> Government Printing Office, Washington, DC.

\(f\) Remark: Propionic acid is exempt from tolerance requirements for
residues when used on

> cottonseed, peanuts, rice grain and soybeans when used as a
> preservative.
>
> Reference: Code of Federal Regulations. Volume 40, Part 180, Section
> 1023(c), 7/1/98. U.S.
>
> Government Printing Office, Washington, DC.

\(g\) Remark: Propionic acid is a normal intermediary metabolite that
occurs naturally in foods,

> especially dairy products. In an evaluation by the Joint FAO/WHO
> Expert Committee on Food Additives (JECFA), the acceptable daily
> intake of propionic acid and its sodium and calcium salts was "not
> limited". In this context, "not limited" means that the material is
> considered to be of very low toxicity, and, because of its occurance
> naturally in foods and as a normal metabolite in man, its use as a
> food additive should simply conform to "good manufacturing practices".
>
> Reference: WHO (World Health Organization). 1974. Propionic Acid and
> its Calcium, Potassium and Sodium Salts. 17^th^ Report of the Joint
> FAO/WHO Expert Committee on Food Additives. WHO Technical Report
> Series 539.
>
> WHO (World Health Organization). 1997. Propionic Acid and its Calcium,
> Potassium and Sodium Salts. 49^th^ Report of the Joint FAO/WHO Expert
> Committee on Food Additives. WHO Technical Report Series 884.

\(h\) Remark: Propionic acid is designated as a hazardous substance
under Section 311 of the

> Federal Water Pollution Control Act and further regulated by the Clean
> Water Act Amendments of 1977 and 1978.
>
> Reference: Code of Federal Regulations. Volume 40, Part 116.4, 7/1/98.
> U.S.
>
> Government Printing Office, Washington, DC.

\(i\) Remark: Manufacture of propionic acid is conducted in closed
equipment, using process

> scrubbers and conservation vents. The manufacturing process is
> controlled and monitored inside in control rooms. These conditions
> limit worker exposure.
>
> Reference: Eastman Chemical Company unpublished information (2001).

\(j\) Remark: Propionic acid is used as an industrial intermediate to
produce cellulose acetate

> propionate, diethyl ketone, herbicides pharmaceuticals and propionic
> anhydride. Workplace exposures during conversion to these other
> products are limited by the use of closed systems and engineering
> controls.
>
> Reference: Bizzari, S.N., Fenelon, S. and Ishikawa-Yamaki. 1999. CEH
> Marketing
>
> Research Report, dated May 1999; and information from U.S
> manufacturers.

\(k\) Remark: In the United States consumption of propionic acid was
estimated in 1997 to be

> as follows:

+---------------------------------+-----------------------+------------+
| Use                             | Amount                | \% of      |
|                                 |                       | Total      |
|                                 | (thousand metric      |            |
|                                 | tons)                 |            |
+---------------------------------+-----------------------+------------+
| Feed and corn preservation      | 84                    | 39.8       |
+---------------------------------+-----------------------+------------+
| Herbicides                      | 61                    | 28.9       |
+---------------------------------+-----------------------+------------+
| Calcium and Sodium salts        | 41                    | 19.4       |
+---------------------------------+-----------------------+------------+
| Cellulose Acetate Propionate    | 20                    | 9.5        |
+---------------------------------+-----------------------+------------+
| Other                           | 5                     | 2.3        |
+---------------------------------+-----------------------+------------+
| Total                           | 211                   | 100        |
+---------------------------------+-----------------------+------------+

> The feed and corn preservation usage is for both ammonium propionate
> and propionic acid for preservation of animal feed, wet corn and
> silage. For 75% of this application, propionic acid is converted to
> ammonium propionate, since this salt form is less corrosive to
> machinery and easier to handle. In feed and corn preservation
> applications, either ammonium propionate or propionic acid (both
> liquids) are added either directly or on an absorbent (such as
> vermiculite), to the feed to prevent mold.
>
> Reference: Bizzari, S.N., Fenelon, S. and Ishikawa-Yamaki. 1999. CEH
> Marketing
>
> Research Report, dated May 1999; and information from U.S
> manufacturers

\(l\) Remark: NFPA Hazard Classifications for n-propionic acid:

> Flammability: 2 (material must be moderately heated before ignition
> will occur)
>
> Reactivity: 0 (normally stable even under fire exposure conditions)
>
> Health: 3 (materials that, on short exposure, could cause serious
> temporary or residual injury)
>
> Reference: NFPA. 2002. National Fire Protection Association. Fire
> Protection Guide to Hazardous Materials. 13th edition. NFPA. Quincy,
> MA.

\(m\) Remark: U.S.DOT proper shipping name: Propionic Acid, Propionic
Acid, Solution

> ID Number: UN1848
>
> Hazard class: 8
>
> Packing Group: PG III
>
> Reference: Propionic Acid. CASRN 79-09-4. Hazardous Substance Data
> Bank (HSDB)
>
> Number 1192, updated on 06/24/2005.

# **2.0 PHYSICAL-CHEMICAL DATA**

# **2.1 MELTING POINT**

> \(a\) Preferred result reliability score = 2, valid with restrictions;
> data from
>
> handbook or collection of data

Value: -21.5 degree C

Remark : -6.7 degree F

> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: Budavari, S. (Ed.) 1996. The Merck Index. An Encyclopedia
> of Chemicals, Drugs, and Biologicals, 12^th^ Edition. Whitehouse
> Station, NJ: Merck and Co., Inc.

\(b\) Value: -22 degree C

> Remark: -7.6 degree F
>
> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: Verschueren K. 1996, Handbook of Environmental Data on
> Organic Chemicals. Third edition. Van Nostrand Reinhold. New York.

\(c\) Value: -20.7 degree C

> Remark: -5.26 degree F
>
> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: Lide, D.R. (Ed.). 1998. CRC Handbook of Chemistry and
> Physics. Boca Raton, FL: CRC Press, Inc.

# **2.2 BOILING POINT** 

(a) Preferred result reliability score = 2, valid with restrictions;
    data from handbook

> or collection of data

Value: 141.1 degree C at 1013.25 hPa (760 mm Hg)

Remark: 286 degree F

> Reference: Lide, D.R. (Ed.). 1998. CRC Handbook of Chemistry and
> Physics. Boca Raton, FL: CRC Press, Inc.

\(b\) Value: 141.1 degree C at 760 mm Hg

Remark: 122 degree C at 400 mm Hg

85.5 degree C at 100 mm Hg

> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: Budavari, S. (Ed.) 1996. The Merck Index -- Encyclopedia of
> Chemicals, Drugs, and Biologicals, 12^th^ Edition. Whitehouse Station,
> NJ: Merck and Co., Inc.

\(c\) Value: 141 degree C

> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: Verschueren K. 1996. Handbook of Environmental Data on
> Organic Chemicals, 3^rd^ Edition. New York: Van Nostrand Reinhold.

# 

# **2.3 DENSITY**

(a) Preferred result reliability score = 2, valid with restrictions;
    data from handbook or collection of data.

> Type: relative density

Value: 0.99336

> Temperature: 20 degree C

Method other: specific gravity

> Reference: Budavari, S. (Ed.) 1996. The Merck Index -- Encyclopedia of
> Chemicals, Drugs, and Biologicals, 12^th^ Edition. Whitehouse Station,
> NJ: Merck and Co., Inc.

\(b\) Type: relative density

> Value: 0.9930
>
> Temperature: 20 degree C

Method other: specific gravity

> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: Lide, D.R. (Ed.). 1998. CRC Handbook of Chemistry and
> Physics. Boca Raton, FL: CRC Press, Inc.

\(c\) Type: relative density

> Value: 0.9942
>
> Temperature: 20 degree C

Method other: specific gravity

> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: Sax, N.I. and Lewis, R.J., Sr. 1987. Hawley's Condensed
> Chemical Dictionary. New York: Van Nostrand Reinhold Company.

# **2.4 VAPOUR PRESSURE** 

(a) Preferred result reliability score = 2, valid with restrictions;
    data from handbook

> or collection of data
>
> Value: 4.7 hPa
>
> Temperature: 25 degree C
>
> Remark: Reported as 3.53 mm Hg at 25 degree C.
>
> Reference: Daubert, T.E. and Danner, R.P. 1989. Physical and
> Thermodynamic Properties of Pure Chemicals. Data Compilation.
> Washington, DC: Taylor and Francis.

\(b\) Value: 4.5 hPa

Temperature: 25 degree C

Reliability: score = 2, valid with restrictions; data from handbook or
collection of data

> Reference: Ambrose, D. et al. 1981. Thermodynamic properties of
> organic oxygen compounds. LI. The vapor pressures of some esters and
> fatty acids. J. Chem. Therm. 13: 795-802.

\(c\) Value: 3.87 hPa

> Temperature: 20 degree C
>
> Remark: Reported as 2.9 mm Hg at 20 degree C.
>
> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: Verschueren K. 2001. Handbook of Environmental Data on
> Organic Chemicals, 4^th^ Edition. New York: John Wiley& Sons.

\(d\) Value: 3.99 hPa

Temperature: 20 degree C

Remark: Reported as 3 mm Hg at 20 degree C.

> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: NIOSH. 1994. NIOSH Pocket Guide to Chemical Hazards. DHHS
> (NIOSH) Publication No. 94-116.

# **2.5 PARTITION COEFFICIENT log~10~P~ow~**

(a) Preferred result reliability score = 2, valid with restrictions;
    data from handbook

> or collection of data; accepted calculation method

log P~ow~: 0.33 at 25 degree C

Method: other; calculated using structural features

> Year: 1995
>
> Remark: calculated value

Reference: Hansch, C., Leo, A.J. and Hoekman, D. 1995. Exploring
QSAR-Hydrophobic, Electronic, and Steric Constants. Washington, DC:
American Chemical Society.

\(b\) log P~ow~: 0.25-0.33

> Method: no data
>
> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: Verschueren K. 2001. Handbook of Environmental Data on
> Organic Chemicals, 4^th^ Edition. New York: John Wiley& Sons

\(c\) log P~ow~: 0.58 at 25 degree C

Method: other: (calculated, KOWWIN)

> Remark: calculated using structural features
>
> Reliability: score = 2, valid with restrictions; accepted calculation
> method
>
> Reference: KOWWIN. Version 1.66. Log Octanol-Water Partition
> Coefficient. EPIWIN (Estimation Program Interface for Windows),
> Version 3.05. Syracuse Research Corporation, Syracuse, NY.

# **2.6 WATER SOLUBILITY**

(a) Preferred result reliability score = 2, valid with restrictions;
    data from handbook

> or collection of data

Value: miscible

Description: miscible

> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: Budavari, S. (Ed.) 1996. The Merck Index. An Encyclopedia
> of Chemicals, Drugs, and Biologicals, 12^th^ Edition. Whitehouse
> Station, NJ: Merck and Co., Inc.

\(b\) Value: miscible with water

> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: Yalkowsky, S.H. and Dannenfelser, R.M. 1992. The Aquasol
> Database of Aqueous Solubility, 5^th^ Edition. Tucson, AZ: University
> of Arizona, College of Pharmacy.
>
> \(c\) Value: miscible with water

Description: miscible

> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: Verschueren K. 2001, Handbook of Environmental Data on
> Organic Chemicals. 4^th^ Edition. New York: John Wiley & Sons.

# **2.7 FLASH POINT *(liquids)***

(a) Preferred result reliability score = 2, national standard method
    (ASTM), however

> full study details not available
>
> Value: 52 degree C
>
> Method: closed cup
>
> Remark: reported as 126 degree F
>
> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: NFPA. 2002. Fire Protection Guide on Hazardous Materials,
> 13^th^ Edition. Quincy, MA: National Fire Protection Association.

\(b\) Value: 58 degree C

Method: Open cup

Remark: reported as 136 degree F

> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: Budavari, S. (Ed.) 1996. The Merck Index -- Encyclopedia of
> Chemicals, Drugs, and Biologicals, 12^th^ Edition. Whitehouse Station,
> NJ: Merck and Co., Inc.

\(c\) Value: 54.4 degree C

> Method: no data
>
> Remark: reported as 130 degree F
>
> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: Sax, N.I. and Lewis, R.J., Sr. 1987. Hawley's Condensed
> Chemical Dictionary. New York: Van Nostrand Reinhold Company.

\(d\) Value: 50 degree C

Method: other: DIN 51755

Remark: 122 degree F

> Test material: propionic acid, purity 99.5%
>
> Reliability: score = 4,
>
> Reference: BASF Corporation. Propionic Acid. CAS#79-09-4. Material
> Safety Data Sheet. Mount Olive, NJ. Revised 01.29.2000.

# **2.8 AUTO FLAMMABILITY *(solid/gases)***

> \(a\) Preferred result reliability score = 2, valid with restrictions;
> data from handbook
>
> or collection of data
>
> Value: 465 degree C
>
> Method: no data
>
> Remark: reported as 870 degree F
>
> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference: NFPA. 2002. Fire Protection Guide on Hazardous Materials,
> 13^th^ Edition. Quincy, MA: National Fire Protection Association.
>
> \(b\) Value: 512 degree C
>
> Method: no data
>
> Remark: reported as 955 degree F
>
> Reliability: score = 2, valid with restrictions; data from handbook or
> collection of data
>
> Reference Sax, N.I. and Lewis, R.J., Sr. 1987. Hawley's Condensed
> Chemical Dictionary. New York: Van Nostrand Reinhold Company.

# **2.9 FLAMMABILITY** 

(a) Value: Flammable range 2.9 - 12.1 volume %

> Remark: 29,000 -- 121,000 ppm

Remark: moderate fire risk

> Reliability: score = 2, valid with restrictions, data from handbook or
> collection of data
>
> Reference: NFPA. 2002. National Fire Protection Association. Fire
> Protection Guide to Hazardous Materials. 13th edition. NFPA. Quincy,
> MA.

# **2.10 EXPLOSIVE PROPERTIES** 

> Remark: May be ignited by heat, sparks or flame. Vapors may form
> explosive mixtures with air. Vapors may travel to source of ignition
> and flash back. Vapor heavier than air. Vapors may spread along ground
> and collect in low or confined areas (sewers, basements, tanks). Vapor
> explosion hazard indoors, outdoor, or in sewers. Containers may
> explode when heated or involved in fire. Runoff to sewer may create
> fire or explosion hazard.
>
> Reference: U.S. Department of Transportation (USDOT). 2000. Emergency
> Response Guidebook. Research and Special Programs Administration,
> Edition 5800.8. Government Printing Office G-1321, Washington, DC.

# **2.11 OXIDIZING PROPERTIES** 

No data available

# **2.12 ADDITIONAL REMARKS**

> Remark: Hazardous polymerisation will not occur. Incompatible with
> strong oxidizers and strong bases.
>
> Reference: Propinoic Acid. CAS No. 79-09-4. Material Safety Data Sheet
> (MSDS). MSDS No. P6643. Effective date February 18, 2005. Mallinckrodt
> Baker Inc., Philadelphia, PA.

# **2.13 ADDITIONAL DATA**

\(a\) Remark: Dissociation constant in water; pKa = 4.87 at 25 degree C.

> pKa value indicates that propionic acid is expected to exist in the
> ionized form at
>
> ambient pH values (pH 5 to 9).
>
> Reliability: score = 2, valid with restrictions, data from handbook or
> collection of data
>
> Reference: Riddick, J.A. , Bunger, W.B., and Sakano, T.K. 1985.
> Organic Solvents: Physical
>
> Properties and Methods of Purification. Techniques of Chemistry, 4^th^
> Edition,
>
> Volume II. New York: John Wiley and Sons.

\(b\) Remark: pKa acid dissociation constant = 4.875 at 25 degree C.

> Reliability: score = 2, valid with restrictions, data from handbook or
> collection of data
>
> Reference: Serjeant, E.P. and Dempsey, B. 1979. Ionization of Organic
> Acids in Aqueous
>
> Solution. IUPAC Chemical Date Series No. 23. New York: Pergamon Press.

\(c\) Remark: Log H = - 4.74 at 25 degree C.

> Reliability: score = 2, valid with restrictions, data from handbook or
> collection of data
>
> Reference: Verschueren K. 2001, Handbook of Environmental Data on
> Organic Chemicals.
>
> 4^th^ Edition. New York: John Wiley & Sons.

\(d\) Remark: Vapor density = 2.56 (air =1)

> Reliability: score = 2, valid with restrictions, data from handbook or
> collection of data
>
> Reference: Sax, N.I. 1989. Dangerous Properties of Industrial
> Materials, 7^th^ Edition. Volume
>
> 1-3. New York: Van Nostrand Reinhold. *Cited in*: Propionic Acid.
> CASRN 79
>
> 09-4. Hazardous Substance Data Bank (HSDB) Number 1192, updated on
>
> 06/24/2005.

\(e\) Remark: Conversion factors: 1 mg/m^3^ = 0.325 ppm, 1 ppm = 3.80
mg/m^3^

> Reliability: score = 2, valid with restrictions, data from handbook or
> collection of data
>
> Reference: Verschuren, K. 2001. Handbook of Environmental Data on
> Organic Chemicals, Fourth Edition. New York: John Wiley & Sons.

\(f\) Remark: Propionic acid has a slightly pungent, disagreeable, sour
or rancid odor

> (Budavari) and an odor threshold of 0.61 mg/m^3^ or 0.16 ppm (Amoore
> and Hautala).
>
> Reliability: score = 2, valid with restrictions, data from handbook or
> collection of data
>
> Reference Amoore, J.E. and Hautala, E. 1983. Odor as an aid to
> chemical safety: odor thresholds compared with threshold limit values
> and volatilities for 214 chemicals in air and water dilution. J. Appl.
> Toxicol. 3: 272-290. *and*
>
> Budavari, S. (Ed.) 1996. The Merck Index -- Encyclopedia of Chemicals,
> Drugs,
>
> and Biologicals, 12^th^ Edition. Whitehouse Station, NJ: Merck and
> Co., Inc.

\(g\) Remark: Henry's Law constant = 4.15 E-7 atm-m3/mol at 25 degree C
(measured).

> Reliability: score = 2, valid with restrictions, data from handbook or
> collection of data
>
> Reference: Hine, J. and Mookerjee, P.K. 1975. The intrinsic
> hydrophobic character of organic
>
> compounds. Correlations in terms of structural contributions. J. Org.
> Chem. 40:
>
> 292-298.

\(h\) Remark: Henry's Law constant = 3.441x 10^-7^ atm-m3/mol at 25
degree C (calculated).

Calculated from water solubility of 1,000,000 mg/L (miscible), vapour
pressure of 3.53 mm Hg, and molecular weight of 74.08 g/mol.

Reliability: score =2, valid with restrictions, accepted calculation
method

Reference: EPISuite v3.12. 2000. U.S. Environmental Protection Agency.

\(i\) Remark: Koc = 1.201 (calculated from molecular structure)

Reliability: score =2, valid with restrictions, accepted calculation
method

Reference: PCKOCWIN, Version 1.66. Soil Adsorption Coefficient. EPISuite
v3.12, U.S. Environmental Protection Agency (2000).

# **3.0 ENVIRONMENTAL FATE AND PATHWAYS**

# **3.1 STABILITY**

# **3.1.1 PHOTODEGRADATION** 

> \(a\) preferred value reliability score = 2, valid with restriction;
> accepted calculation
>
> method
>
> Type: Atmospheric photooxidation
>
> Light Source:
>
> Light spectrum:
>
> Rel. intensity: based on intensity of sunlight
>
> Degradation: T1/2 \~ 7.7 - 9.2 days
>
> Method: calculation
>
> GLP: no
>
> Test substance: n-propionic acid
>
> Remark: If released to the atmosphere, vapor phase propionic acid is
> expected to undergo a gas-phase reaction with photochemically-produced
> hydroxyl (OH) radicals. The 2^nd^-order rate constants for the
> gas-phase reaction with hydroxyl (OH) radicals were calculated as 1.16
> E-12, 1.22 E-12, and 1.3878 E-12 cm^3^/(molecule\*sec) at 25 degrees
> C. Based on 1.5 E+6 OH molecules/cm3 and assuming 12 hours of sunlight
> per day, and employing each of the calculated rate constants, the
> estimated half-lives are 7.707, 8.767, and 9.219 days.
>
> Reference: Atkinson, R. 1989. Kinetics and Mechanism of the Gas-Phase
> Reactions of the Hydroxyl Radical with Organic Compounds. J. Phys.
> Chem. Ref. Data. Monograph No. 1.
>
> AOPWIN. Version 1.91. 2000. Atmospheric Oxidation. EPISuite v3.12,
> U.S. Environmental Protection Agency.

\(b\) Type: Atmospheric Photooxidation

> Rel. intensity: based on intensity of sunlight
>
> Degradation: T1/2 \~ 11 days
>
> Test substance: n-propionic acid
>
> Remark: According to a model of gas/particle partitioning of
> semivolatile organic compounds in the atmosphere, propionic acid,
> which has a vapor pressure of 3.53 mmHg at 25 degree C, is expected to
> exist solely as a vapor in ambient atmosphere. Vapor-phase n-propionic
> acid is degraded in the atmosphere by reaction with photo-chemically
> produced hydroxyl radicals; the half-life for this reaction is
> estimated at 11 days, calculated from its rate constant of 1.16 x
> 10^-12^ cm^3^/molecule-sec independent of temperature of the range
> 247-445 K, and an atmospheric concentration of 5 x 10^5^ hydroxy
> molecules/cm^3^.
>
> Reliability: score = 2, valid with restriction; accepted calculation
>
> method
>
> Reference: Bidleman, T.F. 1988. Environ. Sci. Technol. 22: 361-367.
>
> Atkinson, R. 1994. J.Phys. Chem. Ref. Monograph 2*. Cited in:*
> Propionic Acid. CASRN 79-09-4. Hazardous Substance Data Bank (HSDB)
> Number 1192, updated on 06/24/2001.

# **3.1.2 STABILITY IN WATER**

> \(a\) Remark: Propionic acid is miscible in water. Propionic acid is
> not expected to undergo hydrolysis in the environment, due to the lack
> of hydrolyzable functional groups. With a pKa of 4.87, propionic acid
> and propionate ion will exist in environmental waters in varying
> proportions that are pH dependent.
>
> Reference: Yalkowsky, S.H. and Dannenfelser, R.M. 1992. The Aquasol
> Database of Aqueous Solubility, 5^th^ Edition. Tucson, AZ: University
> of Arizona, College of Pharmacy.
>
> Lyman, W.J., Riehl, W.F., and Rosenblatt, D.H. 1990. Handbook of
> Chemical Property Estimation Methods. Washington, DC: American
> Chemical Society.
>
> Swann, R.L., Lasowski, D.A., McCall, P.J., Vander Kuy, K., and
> Disburger, H.J. 1983. A rapid method for the estimation of the
> environmental parameters octanol/water partition coefficient, soil
> sorption constant, water to air ratio, and water solubility. Residue
> Reviews: 85: 17-28.

# **3.1.3 STABILITY IN SOIL**

\(a\) Test substance: n-propionic acid

Type:

> Dissipation time:
>
> Method:
>
> Remarks: The sorption characteristics of propionic acid is likely to
> depend on organic content of the soil as well as pH and electrolyte
> concentration.
>
> A Koc value of approximately 1.21 has been calculated, based on log
> Kow value of 0.33. This value suggests that propionic acid has very
> high mobility in soil.

Reliability: score = 2, valid with restrictions; acceptable calculation
method

> Reference: Hansch, C., Leo, A. and Hoekman, D. 1995. Exploring QSAR --
> Hydrophobic, Electronic, and Steric Constants. Washington, DC:
> American Chemical Society.
>
> Swann, R.L., Lasowski, D.A., McCall, P.J., Vander Kuy, K., and
> Disburger, H.J. 1983. A rapid method for the estimation of the
> environmental parameters octanol/water partition coefficient, soil
> sorption constant, water to air ratio, and water solubility. Residue
> Reviews: 85: 17-28.

\(b\) Test substance: n-propionic acid

> Type:
>
> Dissipation time:
>
> Method:
>
> Remarks: Based on the preferred vapor pressure of 4.7 hPa at 25ºC,
> propionic acid is not expected to volatilize readily from dry soil
> surfaces. Volatilization may be important from moist soil surfaces,
> given estimated Henry's Law constant of 4.15 x 10^-6^ atm-cu m/mol at
> 25ºC, propionic acid is not expected to volatilize from moist soil
> surfaces.
>
> Reliability: score = 2, valid with restrictions; acceptable
> calculation methods
>
> Reference: Hine, J. and Mookerjee, P.K. 1975. The intrinsic
> hydrophobic character of organic compounds. Correlations in terms of
> structural contributions. J. Org. Chem. 40: 292-298.
>
> Swann, R.L. et al. 1983. A rapid method for the estimation of the
> environmental parameters octanol/water partition coefficient, soil
> sorption constant, water to air ratio, and water solubility. Residue
> Reviews: 85: 17-28.
>
> Lyman, W.J., Riehl, W.F., and Rosenblatt, D.H. 1990. Handbook of
> Chemical Property Estimation Methods. Washington, DC: American
> Chemical Society.

# **3.2 MONITORING DATA (ENVIRONMENT)** 

\(a\) Type of Measurement

Media: air

> Remark: Trace amounts of propionic acid, 0.09 nmol/m^3^ and 0.19
> nmol/m^3^, were detected in late winter Arctic aerosols at Barrow,
> Alaska (Li SM, Winchester JW). Propionic acid has also been detected
> in the atmosphere at \<1 ppb (summer 1993 and 1.1 ppb (winter 1994),
> and \< 1 ppb (winter 1995) at Socorro, NM. In Langmuir NM, propionic
> acid was detected at \<1 ppb (winter 1995) (Gaffney JS et. al.).
>
> The average and maximum propionic acid concentrations for the ambient
> air over the Netherlands in 1980 was reported to be 0.15 and 2.0 ppb
> (Guichert R, Schulting FL) Propionic acid was detected in the ambient
> air of Los Angeles, CA from July to Sept, 1984 at concentrations
> ranging from 0.019 to 0.305 ppb (Kawamura K et. al.) In a study
> monitoring long range transport of photochemical air pollution from
> the industrial coastal area of Tokyo Bay to central Japan, propionic
> acid concentrations were found to fluctuate, increasing during daytime
> and falling off during night (Satsumamabayashi H et al). This suggests
> that propionic acid is produced by photooxidation of anthropogenic
> compounds during long-range transport.
>
> References: Li SM, Winchester JW. 1989 Atmos Environ 23: 2401-15.
>
> Gaffney J.Sl et al. Environ Sci Technol 31: 3053-61.
>
> Guichert R, Schulting F.L. 1985. Sci Total Environ 43: 193-219.
>
> Kawamura K et al. 1985. Environ Sci Tech 19: 1082-6.
>
> Satsumamabayashi H. et al. 1989. Tellus 41B: 219-29.
>
> Satsumamabayashi H. et al. 1995. Atmos Environ 29: 255-6.
>
> \(b\) Type of Measurement

Media: water

> Remark: Propionic acid has been detected in rain and snow
> precipitation at low concentrations (e.g., 0.3 umol/75 cm parts per
> trillion to 0.8 umol/94 cm ppt)
>
> Reference: Chapman et al. 1986. Atmos Environ 20: 1717-27.
>
> \(c\) Type of Measurement

Media: water

> Remark: Propionic acid was detected in groundwater samples near a coal
> gasification site near Hoe Creek in northeastern Wyoming (Stuermer DH
> et al). It has been detected in groundwaters contaminated with
> leachates from municipal and industrial landfills, and hazardous waste
> sites (Albaiges et al; Burrows et al; Lema et al). Leachates at sites
> from the Netherlands, United Kingdom, Canada, France and Spain
> contained propionic acid at concentrations of 3.4, 1.36, 1.01, 5.25
> and 0.91 g/l (Lema et al). Wood preserving chemicals at Pensacola, FL
> are responsible for propionic acid concentrations of 23.60 and 0.02
> mg/l at ground water depths of 6 and 18 m, respectively (Goerlitz et
> al).
>
> References: Stuermer DH et al. 1982. Environ Toxicol Chem 16: 582-7.
>
> Albaiges J et al. 1986. Water Res 20: 1153-9.
>
> Burrows W.D., Rowe R.S. 1975. J Water Pollut Control Fed 47: 92-93.
>
> Lema J.M. et al. 1988. Water Air Soil Pollut 40: 223-50.
>
> Goerlitz D.F. et al. 1985. Environ Sci Technol 19: 995-61

(d) Type of Measurement

> Media: water
>
> Remark: The Ohio and Little Miami Rivers and Tanners Creek, Ohio water
> contained propionic acid at concentrations ranging from 0.1 to 0.8
> ug/l (Murtaugh et al). Water samples from Lake Kizaki, Japan on Oct
> 28, 1977 contained propionic acid at concentrations ranging from
> undetected levels to 90 ugC/l (Hama et al).
>
> References: Murtaugh J.J., Bunch R.L. 1965. J Water Pollut Control Fed
> 37: 410-5.
>
> Hama T., Handa N. 1981. Rikusiugaka Zasshi 42: 8-19.
>
> \(e\) Type of Measurement

Media: waste water

Remark: Propionic acid was detected in landfill leachates at a
concentration of 985 ug/ml in samples from the Taichung sanitary
landfill in Taiwan (Yan and Jen, 1992). Propionic acid is found in
wastewater ponds in Spain from oil oil production at concentrations
ranging from 32588 to 2017173 ug/ml. Propionic acid is produced as a
result of breakdown and oxidation of fatty acids present in the oil and
waste (Sanchez-Cresp, 1990). Propionic acid is also found in the liquid
exudates from kitchen and garden wastes (Wilkins and Larsen, 1995, 1996)

> Reference: Yan, C.T. and Jen, J.F. 1992. Analyt. Chim. Acta 259:
> 259-264.
>
> Sanchez-Crespo, R. and Parada Alvarez-Buylla, J. 1990. Org.
> Micropollut. Aquat. Environ. Proc. Eur. Supp.6: 115-117.
>
> Wilkin, K. and Larsen, K. 1995. J. High Resol. Chromatogr. 18:
> 373-377.
>
> Wilkin, K. and Larsen, K. 1996. Chemosphere 32: 2049-2055..

\(f\) Media: animal feed products

> Remark: Propionic acid is incorporated in manufactured animal feeds to
> help control fungal growth. Propionic acid is also used to as a
> topical antifungal agent to treat dermatomycoses. At a concentration
> of 3 ug/ml it is an effective fungicidal against *Aspergillus
> parasiticus*.
>
> Reference: Booth, N.H. and McDonald, L.E. (eds). 1982. Veterinary
> Pharmacology and Therapeutics, 5^th^ Edition. Iowas State University
> Press, Ames, IA.

\(g\) Media: animal feed/water

> Remark: Propionic acid is used as a feed and corn preservative and is
> used to control fungi and bacteria in drinking water for livestock and
> poultry.
>
> Reference: Chemical Marketing Reporter. 1997. Chemical Profile:
> Propionic Acid. February 24, 1997.
>
> U.S. Environmental Protection Agency (USEPA). RED Facts: Propionic
> Acid (79-09-4). Available at: <http://www.epa.gov/REDs/>

\(h\) Media: human food products

> Remark: n-Propionic acid has been identified as a volatile component
> of); baked potato (Coleman, E.C., et al., 1981) and cooked beef and
> ham (Furia and Bellanca, 1975). Dalieb fruit contained propionic acid
> at an average concentration of 84 mg/kg (Harper et al., 1986). German
> fruit brandies and dessert wines had concentrations of 0.2 and 1.1
> mg/L propionic acid, respectively (Sponholtz, W.R. et al., 1989).
> Propionic acid was detected but not quantified as a fruit volatile in
> strawberry (Dirinck, P. et al). Propionic acid also occurs in small
> amounts in dairy products; it occurs naturally in Swiss cheese at
> levels as high as 1% (Furia and Bellanca, 1975).
>
> References: Coleman, E.C. et al. 1981. J. Agric. Food Chem. 29: 42-48.
>
> Harper, D.B. et al. 1986. J. Agric. Food Chem. 37: 685-688.
>
> Budavari, S. (Ed.) 1996. The Merck Index -- Encyclopedia of Chemicals,
> Drugs, and Biologicals, 12^th^ Edition. Whitehouse Station, NJ: Merck
> and Co., Inc.
>
> Furia, T.E. and Bellanca, N. (eds) 1975. Fenaroli's Handbook of Flavor
> Ingredients, Volume 2. Cleveland: The Chemical Rubber Company.
>
> Sponholtz, W.R. et al., 1989. Deutsche-Lebensmittel-Rundschau 85:
> 247-251.
>
> Dirinck, P. et al. 1984. *in*: Analysis of Volatiles, Walter Degruyter
> & Co., Berlin, Germany. pp. 381-400.

\(i\) Media: Blood and runimal contents of cattle

> Remark: Propionic acid was among the volatile fatty acids detected in
> the blood and rumen fluid of steers fed alfalfa grass, orchard grass
> or fescue at different temperatures.
>
> Reference: Martz, F.A., Payne, C.P., Matches, A.G., Belyea, R.L., and
> Warren, W.P. 1990. J. Dairy Sci. 73: 1280-1287.

\(j\) Media: other

> Remark: Propionic acid was identified in raw sewage in Haifa, Israel
> (Narkis, N. and Henfeld-Furie, S., 1978); it has also been reported as
> a component of diesel exhaust (Hampton, C.V., et al., 1982).
>
> References: Narkis, N. and Henfeld-Furie, S. 1978. Water Res. 12: 437-
>
> Hampton, C.V. et al. 1982. Environ. Sci. Technol. 16: 287-298.

# **3.3 TRANSPORT AND DISTRIBUTION BETWEEN ENVIRONMENTAL COMPARTMENTS INCLUDING ESTIMATED ENVIRONMENTAL CONCENTRATIONS AND DISTRIBUTION PATHWAYS**

# **3.3.1 TRANSPORT BETWEEN ENVIRONMENTAL COMPARTMENTS**

> \(a\) Remark: Based on a Henry's Law constant of 4.45 x 10^-7^ atm-
>
> m/mole, volatilization from water surfaces is not expected. With a pKa
> of 4.87, propionic acid and propionate ion will exist in environmental
> waters in varying proportions that are pH dependent. Under alkaline
> conditions (pH\>6.87), propionic acid is expected to exist as its
> conjugate base, the propionate ion. Ions are not expected to
> volatilize from water or adsorb to particulate matter as strongly as
> their neutral counterparts.
>
> Reference: Swann, R.L., Lasowski, D.A., McCall, P.J., Vander Kuy, K.,
> and Disburger, H.J. 1983. A rapid method for the estimation of the
> environmental parameters octanol/water partition coefficient, soil
> sorption constant, water to air ratio, and water solubility. Residue.
> Reviews: 85: 17-28.
>
> Meylan, W.M. et al. 1992. Environ. Sci. Technol. 26: 1560-1567.
>
> Lyman, W.J. et al. 1990. Handbook of Chemical Property Estimation
> Methods. Washington DC: American Chemical Society.
>
> \(b\) Remark: Based on a classification scheme, and an estimated Koc
>
> value of 1.21, determined from a structure-estimation method,
> propionic acid is expected to have very high mobility in soil.

Reference: Swann, R.L. et al. 1983. Res. Rev. 85: 17-28.

> Meylan, W.M. et al. 1992. Environ. Sci. Technol. 26: 1560-1567.

\(c\) Remark: Volatilization of propionic acid from moist soil surfaces
is

> not expected to be an important process, given a Henry's Law constant
> of 4.45 x 10^-7^ atm-m3/mole. Propionic acid is expected to volatilize
> from dry soil surfaces. With a pKa of 4.87, propionic acid and its
> conjugate base will exist in soils in varying proportions that are pH
> dependent.
>
> Reference: Daubert, T.E. and Danner, R.P. 1989. Physical and
> Thermodynamic Properties of Pure Chemicals. Data Compilation.
> Washington, DC: Taylor and Francis.
>
> Hine, J. and Mookerjee, P.K. 1975. The intrinsic hydrophobic character
> of organic compounds. Correlations in terms of structural
> contributions. J. Org. Chem. 40: 292-298.
>
> Riddick, J.A. , Bunger, W.B., and Sakano, T.K. 1985. Organic Solvents:
> Physical Properties and Methods of Purification. Techniques of
> Chemistry, 4^th^ Edition, Volume II. New York: John Wiley and Sons.
> *Cited in:* Propionic Acid. CASRN 79-09-4. Hazardous Substance Data
> Bank (HSDB) Number 1192, updated on 06/24/2005.

\(d\) Remark: Volatilization from moist soil surfaces is not expected to

> be an important fate process for propionic acid, however, based on its
> vapor pressure, it may volatilize from dry soil surfaces.
>
> Reference: Hine, J. and Mookerjee, P.K. 1975. The intrinsic
> hydrophobic character of organic compounds. Correlations in terms of
> structural contributions. J. Org. Chem. 40: 292-298.

\(e\) Type: volatility

Media: water - air

Method other: estimate

> Year:
>
> Method: calculated using EPIWIN
>
> Remark: Based on the Henry's Law constant of 3.441E-7 atm m^3^/mol,
> vapor pressure of 3.53 mm Hg, and water solubility of 1,000,000 mg/L
> (assumed for the miscible n-propionic acid), the estimated
> volatilization half-life from a model river (1 meter deep, flowing 1
> m/sec, wind velocity of 5 m/sec) is estimated as 61.07 days. The
> estimated half life from a model lake (1 m deep, flowing 0.05 m/sec,
> wind velocity 0.5 m/sec) is estimated at 1.832 years
>
> Reliability: score = 2, valid with restrictions; acceptable
> calculation method
>
> Reference: EPIWIN (Estimation Program Interface for Windows), Version
> 3.11. 2000. U.S. Environmental Protection Agency.
>
> Lyman, W.J., Riehl, W.F., and Rosenblatt, D.H. 1990. Handbook of
> Chemical Property Estimation Methods. Washington, DC: American
> Chemical Society. *and*
>
> EPISuite v3.12, U.S. Environmental Protection Agency (2000).

# **3.3.2 THEORETICAL DISTRIBUTION (FUGACITY CALCULATION)**

\(a\) Preferred value (score = 2 )

> Type: fugacity model level III
>
> Media: other: air, water, soil, and sediment

Method Calculation: Level III Fugacity Model

> Year: 2000
>
> Result:
>
> Air (level II1): 5.495%
>
> Soil (level 1):
>
> Water (level II1): 37.4%
>
> Soil (level III): 56.5%
>
> Test condition:
>
> Data used:
>
> Molar mass:
>
> Log P~ow~:
>
> Vapor pressure:
>
> Water solubility:
>
> Equation used for additional data:
>
> Volumes used:
>
> Remark: Air half-life calculated using the measured value from
> Atkinson (1989) as reported in Section 3.1.1 (a).
>
> Air: half life = 210 hr, emissions = 1000 kg/hr
>
> Water: half life = 208 hr, emissions = 1000 kg/hr
>
> Soil: half life = 416 hr, emissions = 1000 kg/hr
>
> Sediment: half life = 1870 hr, emissions = 0 kg/hr
>
> Persistence time: 304 hr
>
> Remark: Physical properties used for distribution modelling were
> aqueous solubility 1,000,000 mg/L, vapor pressure 3.53 mm Hg, Henry's
> Law Constant 4.15 E-7, log Kow 0.33, melting point -21.5 deg. C. Model
> run at 25 deg. C
>
> Result: Sediment = 0.0655%
>
> Remark: The Fugacity modelling for the acid used the log Kow predicted
> for the acid in its unionized form. However, propionic acid will exist
> primarily as the propionate anion in aqueous solution at pHs above 5.
> Therefore, the amount of substance partitioning to water may be
> underestimated in these calculations.
>
> Reliability: score = 2, valid with restrictions; acceptable
> calculation method
>
> Reference: Level III Fugacity Model. 2000. EPISuite v3.12, U.S.
> Environmental Protection Agency.

# **3.4 IDENTIFICATION OF MAIN MODE OF DEGRADABILITY IN ACTUAL USE**

# **3.5 BIODEGRADATION** 

(a) Critical Study for SIDS Endpoint (score = 2)

Type: aerobic

> Inoculum: domestic sewage

Concentration: 2 mg/l

Contact time: 30 days

Degradation: 74% after 30 days

> Results: readily biodegradable
>
> 2 days = 60%
>
> Kinetic: 5 days = 71%
>
> 10 days = 73%
>
> 30 days = 74%
>
> Control: other: glucose, 2 mg/l
>
> Method other: Warburg Respirometer (standard manometric technique)
>
> GLP: no
>
> Test substance: propionic acid, purity not specified
>
> Remark: Warburg flasks contained 1.0 ml of sewage cell suspension, 100
> umoles of phosphate buffer (pH 7.1), and 3.0 umoles of substrate.
> Flasks were sealed and oxygen uptake was monitored as the measure of
> oxidation of the compound. Additional tests were performed with
> glucose to assess toxicity of the test substance on the inoculum. The
> results indicate that propionic acid should biodegrade under aerobic
> conditions. Theoretical BOD values were corrected for endogenous
> respiration. Oxygen consumption was 3.6, 4.3, 4.5, and 4.6 mg/l on
> days 2, 5, 10, and 30, respectively. The pH of the test medium ranged
> from 6.5 to 7.5 SU and were adjusted as needed with KOH.
>
> Comment: The authors did not address or correct for potential
> endogenous propionic acid production by microorganisms in the
> inoculum, which could have increased the overall amount of propionate
> present in the inoculum. .
>
> Reliability: score = 2, valid with restrictions; see comment above.
>
> Reference: Dias, F.F. and Alexander, M. 1971. Effect of chemical
> structure on the biodegradability of aliphatic acids and alcohols.
> Applied Microbiology 22: 1114-1118.
>
> \(b\) Test substance: n-propionic acid
>
> Type: aerobic
>
> Inoculum: activated sludge solids

Concentration: 500 mg/l

Contact time: 24 hours

Degradation: 40.4% in 24 hrs

Results: readily biodegradable

> Kinetic: 6 hr: 18.6%
>
> 12 hr: 30.8%
>
> 24 hr: 40.4%
>
> Method other: Warburg respirometer
>
> Propionic acid was added at a concentration of 500 mg/l to activated
> sludge solids at 2500 mg/l in a Warburg respirometer with oxygen
> uptake as the measure of oxidation of the compound.
>
> Test substance: n-propionic acid, purity not specified
>
> GLP: no data
>
> Remark: Warburg test with domestic sludge as inoculum, oxygen
> consumption at 24 hours was 40.4% of theoretical value.
>
> Reliability: score = 2, reliable with restriction; purity of test
> material not specified.
>
> Reference: Malaney, G.W. and Gerhold, R.M. 1969. Structural
> determinants in the oxidation of aliphatic compounds by activated
> sludge. J. Water Pollution Control Fed. 41(No.2, Part 2): R18-R33.

\(c\) Test material: n-propionic acid

> Type: anaerobic
>
> Inoculum: acetate-enriched culture originated from domestic sewage
> sludge

Concentration: 500 to 1000 mg/l

Contact time: 20 days

Degradation: 100% after 20 days

Results: readily biodegradable

> Kinetic: lag time, 2 days
>
> Removal rate: 100 mg/l/day

Control: no data

> Method other: Hungate serum bottle technique (methane fermentation-see
>
> Miller, T.C. and Wolin, M.J. 1974. J. Appl. Microbiol. 27: 985)
>
> GLP: no data
>
> Test substance: n-propionic acid, purity not specified
>
> Method: Hungate serum bottles were filled with water and the air was
> displaced with an inert gas mixture of carbon dioxide and methane. A
> 50 ml inoculum was injected into the serum bottle along with 100 mg of
> acetate and 25 mg of the test compound. Gas production was monitored
> and subsequent injections of the pure test compound were made with a
> microliter syringe as needed. Propionic acid was injected into the
> serum bottle to yield initial concentrations of 500 mg/l for the first
> six injections. Injections were increased to doses of 1000 mg/l in the
> 7^th^ injection and thereafter. Daily additions of inorganic salt
> solution, plus acetate and the test material was made in a long term
> feeding acclimation study.
>
> Remark: When digesters were acclimated to 10,000 mg/L propionic acid
> for 20 days under anaerobic conditions, the utilization efficiency
> during the acclimation interval in completely mixed reactors was 47%.
>
> Reliability: score = 2, acceptable with restriction; purity of test
> material not specified.
>
> Reference: Chou, W.Lin, Speece, R.E., and Siddiqui, R.H. 1978.
> Acclimation and degradation of petrochemical wastewater components by
> methane fermentation. Biotechnology and Bioengineering Symposium No.
> 8: 391-414.

# **BOD~5~,COD OR RATIO BOD~5~/COD**

**BOD~5~**

> \(a\) Method other: Warburg test
>
> BOD~5~ 71%
>
> GLP: no data
>
> Remark: Warburg test with domestic sewage as inoculum, oxygen
> consumption at 2 days was approximately 60% of theoretical value.
>
> Test substance: n-propionic acid, purity not specified (Fisher
> Scientific Co.)
>
> Reliability: score = 2, valid with restriction, purity of test
> material not specified.
>
> Reference: Dias, F.F. and Alexander, M. 1971. Effect of chemical
> structure on the biodegradability of aliphatic acids and alcohols.
> Applied Microbiology 22: 1114-1118.

**COD**

> \(a\) Method other: Dichromate test

COD: 1.513 g/g

> GLP: no
>
> Test Substance: n-propionic acid
>
> Reference: Jones, H.R. 1971. Environmental control in the organic and
> petrochemical industries. Noyes Data Corporation.

# 

# **3.7 BIOACCUMULATION**

\(a\) BCF: 3.16

Method other: calculated as per Lyman, et al. 1982, using BCFWIN

> Year: 1982
>
> Remark: Estimated by Equation 5-2 (Kow) of Lyman et al, 1982. Log Kow
> used = 0.33. Based upon a BCF of 3.16, propionic acid is not expected
> to bioaccumulate in the tissue of aquatic organisms.
>
> Reference: Lyman WJ et al. 1982. Handbook of chemical property
> estimation methods. Environmental behavior of organic compounds.
> McGraw-Hill. New York.*.*
>
> BCFWIN. Version 2.15. 2000. BCF Estimate from Log Kow. EPISuite v3.12,
> U.S. Environmental Protection Agency.

# **3.8 ADDITIONAL REMARKS**

None

# **4.0 ECOTOXICOLOGICAL DATA** 

# **4.1 ACUTE/PROLONGED TOXICITY TO FISH**

\(a\) preferred result Critical Study for SIDS Enpoint (reliability = 2)

Type: static

> Species: *Pimephales promelas* (fathead minnow, fish, fresh water)
>
> Unit: mg/l
>
> Exposure Period: 96 hours

LC0:

> LC50: 51.8
>
> Analyt. Monitoring: no
>
> Method: other, American Public Health Association. 1971. Standard
> Methods for the Examination of Water and Wastewater.
>
> Year: 1974
>
> GLP: no data
>
> Method: Two independent acute toxicity tests were conducted with the
> test material . In each test, ten fish (2.5 to 5.0 cm in length) were
> exposed to five concentrations of propionic acid at nominal
> concentrations of 0, 25, 50, 65, 85, and 120 mg/L in a test volume of
> 18.5 liter. No buffers were used and the test soluions were not
> neutralized after addition of the acid test material. Water
> temperature was maintained between 71 and 76 degrees F. The pH of the
> dilution water was between 7.2 and 7.6; the pH of dilution water was
> adjusted with dilute hydrochoric acid or sodium hydroxide, as
> required. Total alkalinity was 30-40 mg/L and hardness was 30 to 60
> mg/L. Initial dissolved oxygen concentrations ranged between 7.5 and
> 9.0 mg/L; dissolved oxygen in vessels was maintained above 5 mg/L
> throughout the test interval by controlled aeration. Minimal aeration
> did not begin until at least 4 hours after test initiation. Initial pH
> values for test solutions ranged between 4.5 and 5.0.
>
> There was no control mortality. The LC50 values were recalibrated
> using Trimmed Spearman-Karber Method (Version 1.0, 1986) based on
> reported response data.
>
> Test substance: propionic acid, purity [\<]{.underline} 100%
>
> Result: 24 hr LC50 (95%conf limits): 76.6 (72.3-81.2) mg/l
>
> 48 hr LC50 (95%conf limits): 57.3 (51.2-64.2) mg/l
>
> 96 hr LC50 (95%conf limits): 51.8 (45.9-58.5) mg/l
>
> Remark: The test was conducted without preconditioning, i.e., pH
> buffering of the exposure concentrations. This is supported by the
> reported pH of 4.5 to 5.0 in the initial test solution. Adverse
> effects observed may have been due, in part, to the increase in
> hydrogen ion concentration. The optimal pH range for this species of
> freshwater fish is generally \>6.0 to \<8.0 (OPPTS 850.1075, 1996).
>
> Reliability: score = 2, reliable with restriction; no analytical
> monitoring
>
> Reference: Waggy, G.T. and Payne, J.R. 1974. Environmental Impact
> Project Analysis Acute Aquatic Toxicity Testing. Union Carbide
> Corporation, Project No. 910F44, File No. 19133, dated January 25,
> 1974.

\(b\) Type: static

> Species: *Lepomis macrochirus* (bluegill sunfish)
>
> Unit: mg/l
>
> Exposure Period: 96 hours
>
> LC0: 56.0
>
> LC50: 85.3
>
> LC100: 180.0
>
> Analyt. Monitoring: none
>
> Method: USEPA. 1975. Methods for acute toxicity tests with fish,
> macroinvertebrates and amphibians. EPA-660/3-75-009.
>
> Six exposure levels (18, 32, 56, 100, 180, and 320 mg/ml) and a
> control were used to determine the toxicity of n-propionic acid to
> bluegill sunfish. Fresh stock solutions for the test were prepared by
> weighing the test material and dissolving it in a volumetric flask
> with distilled water. Solutions were not buffered after addition of
> the test material. Test was started by introducing the test material
> into the test vessels, mixing with dilution water, and then
> introducing fish. Dilution water was reconstituted to pH 7.1, hardness
> 44 mg/l (as CaCO3), alkalinity 30 mg/l (as CaCO3), and specific
> conductance 150 μ mhos/cm. Fish were obtained from a commercial fish
> hatchery and maintained at 22 degree C.
>
> Ten fish were exposed to each concentration. Fish were 8 months old
> and had a mean length of 38 mm and a mean weight of 810 mg.
> Temperature and dissolved oxygen, and pH were determined initially,
> after 48 hours, and at the end of the test (96 hours). The initial pH
> of the test solutions at concentrations close to the LC50 value ranged
> between 4.5 and 5.0; the pH at 48 and 96 hours were measured but not
> reported..
>
> Mortality and behavioral effects of the test material were recorded.
>
> The LC50 was determined by Thompson's moving average methodology.
>
> Year: 1976
>
> GLP: no
>
> Test substance: n-propionic acid, purity not specified
>
> Remark: Test procedures followed USEPA methods with exception that
> replicate concentrations were not used.
>
> Result: 24 hr LC50 (95%conf limits): 107.4 (88.7-130) mg/l
>
> 48 hr LC50 (95%conf limits): 95.7 (79.1-115.9) mg/l
>
> 96 hr LC50 (95%conf limits): 85.3 (73.0-99.7) mg/l
>
> Remark: The test was conducted without preconditioning, i.e., pH
>
> buffering of the exposure concentrations. Toxic effects observed may
> have been due, in part, to the increase in hydrogen ion concentration.
>
> Reliability: score = 2, valid with restriction; purity of test
> material not specified; no analytical monitoring
>
> Reference: U.S. Environmental Protection Agency. Office of Pesticides
> Programs. Environmental Fate and Effects. Registration No. 10352-11.
>
> Union Carbide Corporation. 1976. Acute Toxicity of Propionic Acid
> (100%) to the Bluegill Sunfish, *Lepomis macrochirus* Rafinesque and
> Rainbow Trout, *Salmo gairdneri* Richardons. Unpublished reported
> dated April 23, 1976. Aquatic Environmental Sciences. Union Carbide
> Corporation, Tarrytown, NY. Prepared for Union Carbide Corporation
> Chemicals and Plastics Division, South Charleston, West Virginia.

\(c\) Type: static

> Species: *Salmo gairdneri* (rainbow trout)
>
> Unit: mg/l
>
> Exposure Period: 96 hours
>
> LC0: 37.0
>
> LC50: 67.1
>
> LC100: 87.0
>
> Analyt. Monitoring: none
>
> Method: USEPA. 1975. Methods for Acute Toxicity Tests with Fish,
> Macroinvertebrates and Amphibians. EPA-660/3-75-009.
>
> Six exposure levels (37, 56, 87, 135, 210, 320 mg/ml) and a control
> were used to determine the toxicity of n-propionic acid to rainbow
> trout. Fresh stock solutions for the test were prepared by weighing
> the test material and dissolving it in a volumetric flask with
> distilled water. Test was started by introducing the test material
> into the test vessels, mixing with dilution water, and then
> introducing fish. Dilution water was reconstituted to pH 7.5, hardness
> 48 mg/l (as CaCO3), alkalinity 44 mg/l (as CaCO3), and specific
> conductance 170 μ mhos/cm. Test solutions were not neutralized. The
> initial pH of the test solutions at concentrations close to the LC50
> value ranged between 4.5 and 5.0; the pH at 48 and 96 hours were
> measured but not reported..
>
> Fish were cultured from eggs obtained from a commercial fish hatchery
> and maintained at 13 degree C.
>
> Ten fish were exposed to each concentration. Fish were 6 months old
> and had a mean length of 47 mm and a mean weight of 1100 mg.
> Temperature and dissolved oxygen, and pH were determined initially,
> after 48 hours, and at the end of the test (96 hours). Mortality and
> behavioral effects of the test material were recorded.
>
> The LC50 was determined by Thompson's moving average methodology.
>
> Year: 1976
>
> GLP: no
>
> Test substance: n-propionic acid
>
> Remark: Test procedures followed USEPA methods with exception that
> replicate concentrations were not used.
>
> Result: 24 hr LC50: 107 mg/l
>
> 48 hr LC50: 70 mg/l
>
> 96 hr LC50 (95%conf limits): 67.1 (61.6-73.2) mg/l
>
> Remark: The test was conducted without preconditioning, i.e., pH
>
> buffering of the exposure concentrations. Toxic effects observed may
> have been due, in part, to the increase in hydrogen ion concentration.
>
> Reliability: score = 2, valid with restriction; purity of test
> material not specified; no analytical monitoring
>
> Reference: U.S. Environmental Protection Agency. Office of Pesticides
> Programs. Environmental Fate and Effects. Registration No. 10352-11.
>
> Union Carbide Corporation. 1976. Acute Toxicity of Propionic Acid
> (100%) to the Bluegill Sunfish, *Lepomis macrochirus* Rafinesque and
> Rainbow Trout, *Salmo gairdneri* Richardons. Unpublished reported
> dated April 23, 1976. Aquatic Environmental Sciences. Union Carbide
> Corporation, Tarrytown, NY. Prepared for Union Carbide Corporation
> Chemicals and Plastics Division, South Charleston, West Virginia.

\(d\) Test material: Calcium propionate; CAS No.: 4075-81-4

> Remark: Calcium propionate is the calcium salt of propionic acid
>
> Type: static
>
> Species: *Leuciscus idus* (golden orfe, freshwater fish)
>
> Unit: mg/l
>
> Exposure Period: 96 hours
>
> NOEC: 5000
>
> LC0: 5000
>
> LC50: \>10,000
>
> LC100: \>10,000
>
> Analyt. Monitoring: none
>
> Method: German industrial standard test guideline DIN 38 412 L15, 1982
>
> Two exposure levels (5000 and 10,000 mg/L) and an untreated control
> were used to determine the toxicity of calcium propionate to
> freshwater fish. Test concentrations of calcium propionate were based
> on results of a range-finding test. The positive control was
> Chloroacetamide.
>
> Fish were supplied by Fischzucht Paul Eggers and had a mean body
> weight of 2.6 g (range 1.6 to 4.0 g) and a mean body length of 6.2 cm
> (range 4.9-7.4 cm). Fish were acclimated for 2 weeks in a flow-through
> system in charcoal-filtered tap water with oil-free aeration and fed a
> diet of Growing Feed F/B 50, ad libitum. There was no mortality during
> the acclimation interval, however fish were treated twice with 0.05
> mg/L malachite green chloride and once with 10mg/L tetracycline
> hydrochloride.
>
> The test water was reconsititued freshwater prepared according to DIN
> 38412, Part II, 1982, prepared from fully demineralised tap water
> (methodology included in full report). Test water pH was 8.0, other
> water parameters included the following:
>
> Total hardness: 2.5 mmol/L
>
> Acid capacity: 0.8 mmol/L
>
> Ratio Ca^+^/Mg^+^ ions: 4:1
>
> Ratio Na^+^/K^+^ ions: 10:1
>
> The total volume of test water was 10 liters, the test water was
> maintained at 21°C. Fish were acclimated to test water and temperature
> for 3 days prior to the test.. Fish were not fed for 1 day prior to
> exposure, and were not fed during the 96-hr test interval. The
> day:night photoperiod was maintained at 16:8 hours.
>
> The test solutions were prepared by weighing the test material and
> then adding it directly to test water without pre-treatment; fish were
> then placed into the all-glass aquaria test vessels (30x22x24 cm). The
> loading rate was 2.6 g fish per liter of test water.
>
> Groups of 10 fish were exposed to each nominal test concentration
> (5000 and 10,000 mg/L) and an untreated concurrent control for 96
> hours. Fish were observed for mortality and signs of toxicity at 1 and
> 4 hours after initiation of exposure, and again at 24, 48, 72, and 96
> hours. Test water was subject to slight aeration, oxygen content and
> pH were measured at 1, 24, 48, 72, and 96 hour.
>
> The LC0, EC50, EC100, NOEC and LOEC were determined directly from the
> raw data.
>
> Year: 1982
>
> GLP: no
>
> Test substance: calcium propionate, CAS No.4075-81-4, purity 99%,
> solubility \>500 g/L
>
> Results: A small amount of undissolved test substance was visible in
> the bottom of the test aquaria. The concentration of the test material
> was not confirmed analytically, and all results refer to nominal test
> concentrations of calcium propionate.
>
> Oxygen content was maintained at or above 8.0 mg/L for the entire
> test. One hour after test initiation, the pH values for test vessels
> were 7.5, 6.9, and 6.8 for control, 5000 mg/L, and 10,000 mg/L,
> respectively; pH values remained between 7.1 and 7.5 for all test
> vessels for the remainder of the test.
>
> There was no mortality among control fish or among fish exposed to
> 5000 mg/L calcium propionate. Mortality was 4/10 at 10,000 mg/L;
> deaths occurred at 48 hr (1), 72 hr (1), and 96 hr (2). No signs of
> toxicity were observed in controls or at any of the test
> concentrations tested.
>
> The 48-hr LC50 of the positive control (Chloroacetamide) was
> approximately 31 mg/L.
>
> Remark: The LC~0~ and the NOEC for calcium propionate for this study
> is 5000 mg/L; the LC~50~ is \>10,000 mg/L.
>
> Reliability: score = 2, valid with restrictions; no analytical
> monitoring.
>
> Reference: BASF AG. 1990a. Luprosil salt (Calcium propionate). Acute
> toxicity to fish, Golden orfe (Leuciscus idus L., golden variety).
> Department of Toxicology, unpublished data, report No. 10F0958/885187,
> 02 Jan 1990.

\(e\) Test material: n-propionic acid

> Method: estimated value using ECOSAR model
>
> Value: 20,394 mg/L
>
> Remark: An acute fish 96-h LC50 was calculated using ECOSAR, from the
> USEPA. The SAR for neutral organics-acids was used. The structure was
> determined from the CAS RN as stored in the accompanying database of
> SMILES notations within ECOSAR. Data used for the calculation were
> water solubility 1,000,000 mg/L, log P 0.33, melting point -21.5
> deg.C, and molecular weight of 74.08 g/mol.
>
> Reliability: Score=2, valid with restrictions; accepted calculation
> method
>
> Reference: U.S. EPA ECOSAR model (v. 0.99h). 2000. EPISuite v3.12,
> U.S. Environmental Protection Agency.

# **4.2 ACUTE TOXICITY TO AQUATIC INVERTEBRATES** 

# **A. Daphnia**

(a) Preferred value Critical Study for SIDS Endpoint (score = 2)

> Type: Static

Species: *Daphnia magna* Strauss (Crustacea)

> Unit: mg/l
>
> Exposure Period: 48 hours

EC0:

> EC50: 22.7
>
> EC100:
>
> Analyt. Monitoring: no data
>
> Method other: other, American Public Health Association. 1971.
> Standard Methods for the Examination of Water and Wastewater., 3^rd^
> Edition.
>
> GLP: no data
>
> Year: 1979
>
> Test substance: n-propionic acid, purity [\<]{.underline} 100%
>
> Method: Groups of *Daphnia magna* Straus were exposed at nominal
> concentrations of 3.2, 5.6, 10.0, 18.0, and 32.0 mg/l. Four replicates
> of five organisms were exposed to each concentration and an untreated
> control. Tests were performed using natural soft lake water. The LC50
> and 95% confidence limits were determined by the method of Spearman
> and Karber (Finney, 1977).
>
> Result: 24 hr LC50 (95% conf limits): 33.1 (28.7-38.1) mg/l
>
> 48 hr LC50 (95% conf limits): 22.7 (21.0-24.6) mg/l
>
> Remark: The test was conducted without preconditioning, i.e., pH
>
> buffering of the exposure concentrations. Toxic effects observed may
> have been due, in part, to the increase in hydrogen ion concentration.
>
> Reliability: score = 2, reliable with restriction; no analytical
> monitoring
>
> Reference: Union Carbide Corporation. 1979b. AES Project No. 7619-500.
> July 2, 1979.

\(b\) Test material: Calcium propionate; CAS No.: 4075-81-4

> Remark: Calcium propionate is the calcium salt of propionic acid
>
> Type: static
>
> Species: *Daphnia magna* Straus (Crustacea)
>
> Unit: mg/l
>
> Exposure Period: 48 hours
>
> NOEC: 250
>
> EC0: 250
>
> EC50: \>500
>
> Analyt. Monitoring: none
>
> Method: EEC directive 79/831 EEC, Annex V, C2
>
> Multiple exposure levels and an untreated control were used to
> determine the toxicity of calcium propionate to Daphnia. Test
> concentrations of calcium propionate ranged between 31.25 and 500
> mg/L, using a spacing factor of 2.0.
>
> Test organisms were originally obtained from the Institute de
> Recherche Chimique Appliquee, France, with cultures subsequently
> maintained in the test laboratory. Daphnids were between 2 and 24 hr
> old at the beginning of the exposure interval.
>
> Dilution water was prepared according to the test guideine
> DIN38412.L11. The test medium of the highest test concentration (500
> mg/L, nominal) was prepared by adding 500 mg of the test material to 1
> liter of culture medium. This test medium was serially diluted with
> culture medium to obtain the desired test concentrations. The
> concurrent control consisted of untreated culture medium.
>
> The total volume of test water was 10 ml, the test water was
> maintained between 19 and 21°C. Daphnids were not fed during the 48-hr
> test interval. The day:night photoperiod was maintained at 16:8 hours
> using diffuse light. The exposure vessel for each replicate was a
> glass flat-bottomed tube.
>
> Groups of 20 daphnids (5 per replicate x 4 replicates) were exposed to
> each nominal test concentration and an untreated concurrent control
> for 48 hours. Daphnids were observed for signs of toxicity or
> immobility immediately after exposure (0 hr) at 3, 6, 24, and 48
> hours. Test solutions were monitored for oxygen content and pH at 0
> and 48 hours.
>
> The EC0, EC50, and NOEC were determined directly from the raw data.
>
> Year: 1989
>
> GLP: no
>
> Test substance: calcium propionate, CAS No.4075-81-4, purity 99%,
> solubility \>500 g/L.
>
> Results: Temperature during the test was maintained between 19 and
> 21°C; pH values ranged between 7.8 and 8.1. Oxygen content in control
> cultures was 9.08 mg/L at test initiation (0 hr) and 8.41 at the end
> of the 48-hr exposure interval. Oxygen content in test cultures ranged
> between 9.08 and 9.21 at 0 hr and between 7.02 and 7.86 at 48 hr.
>
> There were no signs of toxicity observed at any time during the test
> in controls or in test cultures exposed to 31.25, 62.5, 125, or 250
> mg/L calcium propionate. In cultures exposed to 500 mg/L, no signs of
> toxicity were observed until 24 hr, when 25% of exposed daphnids were
> immobile; the percent immobility increased to 30% at 48 hr.
>
> Remark: The LC~0~ and the NOEC for calcium propionate for this study
> is 250 mg/L; the LC~50~ is \>500 mg/L.
>
> Reliability: score = 2, valid with restrictions; no analytical
> monitoring.
>
> Reference: BASF AG. 1989a. Determination of acute effects of Calcium
> propionate on water flea *Daphnia magna Straus*. Department of
> Ecology, unpublished data, report No. 1/1540/2/88, 16 Mar 1989.

\(c\) Test material: n-propionic acid

> Method: estimated value using EcoSAR model
>
> Value: 19,472 mg/L
>
> Remark: An acute daphnid 48-h LC50 was calculated using ECOSAR, from
> the USEPA. The SAR for neutral organics-acids was used. The structure
> was determined from the CAS RN as stored in the accompanying database
> of SMILES notations within ECOSAR. Data used for the calculation were
> water solubility 1,000,000 mg/L, log P 0.33, melting point -21.5
> deg.C, and molecular weight of 74.08 g/mol.
>
> Reliability: Score=2, valid with restrictions; accepted calculation
> method
>
> Reference: U.S. EPA ECOSAR model (v. 0.99h). 2000. EPISuite v3.12,
> U.S. Environmental Protection Agency.

# **B. Other**

\(a\) Type: LD50

> Species: *Aedes aegypti* (Diptera, mosquito)
>
> Unit: % v/v
>
> Exposure Period: 4 hours
>
> LC0:
>
> LC50: 0.08% (v/v) or 800 mg/L
>
> Test substance: n-propionic acid
>
> Year: 1983
>
> GLP: no data
>
> Method: *Aede aegypti* eggs were hatched in solutions derived from dog
> food and yeast extract and the resultant 2^nd^ and 3^rd^ instar larvae
> were transferred to glass jars containing the test material; solutions
> were maintained at 22-24 degree C during the 4-hr test interval.
> Groups of 10-20 larvae were transferred to 50 ml of each test solution
> and mortality was assessed after 4 hr. Chemicals tested were reagent
> grade or better. Each test material was bioassayed in three separate
> tests.
>
> Result: No mortality was observed in control (untreated) larval
> cultures. In general, organic acids were more toxic than their
> corresponding alcohols and aldehydes. The 4 hr LC50 for propionic acid
> in mosquito larvae was 800 mg/L. Results for other saturated organic
> acids are listed below.
>
> [Test material 4-hr LC50 (mg/L)]{.underline}
>
> Propionic acid 800
>
> Butyric acid 3400
>
> Isobutyric acid 1700
>
> Pentanoic (valeric) acid 1500
>
> Reliability: score = 4, not assignable; study interval inadequate for
> assessment of toxicityReference: Kramer, V.C., Schnell, D.J., and
> Nickerson, K.W. 1983. Relative toxicity of organic solvents to Aedes
> aegypti larvae. J. Invertebr. Pathol. 42:285-287.

# **TOXICITY TO AQUATIC PLANTS e.g. Algae**

> \(a\) preferred result and critical study for SIDS endpoint
> reliability = 2

Species: *Scenedesmus subspicatus* CHODAT (Algae)

Endpoint: biomass

> Unit: mg/l
>
> Exposure Period: 96 hours
>
> EC20: 12.3
>
> EC50: 42.9
>
> EC90%: 79.4
>
> Analyt. Monitoring: no data available
>
> Method other: Performed according to DIN 38412 part 9, comparable to
> OECD
>
> Method 201.
>
> Algal growth criterion was chlorophyll a fluorescence at 685 nm. Ten
> ml tubes flat bottom reagent tubes were inoculated with stock cultures
> to an initial density of 10,000 cells/ml. The preparation of the test
> medium was specified in the report. Initial pH was 8.0. Tubes were
> cultured at 20±2 °C and kept under 120 uE/m2s illumination.
> Concentrations of test substance were 0, 0.125, 0.25, 0.49, 0.98,
> 1.95, 3.91, 7.81, 15.63, 31.25, 62.5, and 125 mg/l. Tubes were taken
> for chlorophyll a measurements daily for 96 hours.
>
> EC values were determined as follows: a dose/response curve was
> prepared and the EC50 value calculated from the curve. The dose refers
> to the nominal test substance concentration (mg/L) and the response
> refers to the % inhibition of cell density measured as fluorescence at
> 685 nm. Effective concentrations for growth inhibition at 72 hours and
> 96 hours were calculated. After 72 hours, the EC20, EC50, and EC90
> were 33.5, 45.8, and 62.3 mg/L, respectively. After 96 hours, the
> EC20, EC50, and EC90 were 12.3, 42.9, and 79.4 mg/L. The improvement
> in EC50 with length of test was the due to a stimulatory effect at the
> lower concentrations.Year: 1987
>
> GLP: no data
>
> Test substance: Propionic acid, purity not specified
>
> Remark: After 24 hours, the EC20, EC50, and EC90 were 37.6, 58.8, and
>
> \>100 mg/L, respectively.
>
> After 48 hours, the EC20, EC50, and EC90 were 33.5, 45.8, and
>
> 86.9 mg/L.
>
> After 72 hours, the EC20, EC50, and EC90 were 33.5, 45.8, and
>
> 62.3 mg/L, respectively.
>
> After 96 hours, the EC20, EC50, and EC90 were 12.3, 42.9, and
>
> 79.4 mg/L, respectively.
>
> The effect values were re-calculated according to OECD 201 and the
> following was obtained:
>
> For endpoint growth rate: 72-hr ErC50 = 48.7 mg/L
>
> For endpoint biomass: 72-hr EbC50 = 43.3 mg/L
>
> Reliability: score = 2, valid with restriction; OECD guideline study,
> however purity of the test material not specified, and no analytical
> monitoring.
>
> Reference: BASF AG. 1987. Algal Growth Inhibition Test. Project report
>
> 1103/87. Ludwigshafen, Germany.

\(b\) Test material: Calcium propionate; CAS No.: 4075-81-4

> Remark: Calcium propionate is the calcium salt of propionic acid
>
> Type: static
>
> Species: *Scenedesmus subspicatus* CHODAT (Algae)
>
> Endpoint: growth rate/biomass
>
> Unit: mg/l
>
> Exposure Period: 72 hours
>
> EC50: 500
>
> EC20: \>500
>
> Analyt. Monitoring: none
>
> Method: OECD Guideline 201, Algae Growth Inhibition Test
>
> Multiple exposure levels and an untreated control were used to
> determine the toxicity of calcium propionate to algae. Test
> concentrations of calcium propionate ranged between 7.812 and 500
> mg/L, using a spacing factor of 2.0.
>
> The test species *Scenedesmus subspicatus* CHODAT, Strain
>
> SAG 86.81, was supplied by Sammlung fur Algenkulturen,
>
> University of Gottingen, with cultures subsequently maintained
>
> in the test laboratory.
>
> Dilution water was prepared according to the OECD Guideine 201.The
> test medium of the highest test concentration of calcium propionate
> (500 mg/L, nominal) was prepared by adding 500 mg of the test material
> to 1 liter of culture medium. This test medium was then serially
> diluted with culture medium to obtain the desired test concentrations.
> The concurrent control consisted of untreated culture medium.
>
> Algal growth criterion was chlorophyll-a-fluorescence at 685 nm. Ten
> ml tubes flat bottom reagent tubes were inoculated with stock cultures
> to an initial density of 10,000 cells/ml. A total of three replicates
> were used for each test concentration and control. Cells were exposed
> for 72 hours. Replicate test vessels that contained test medium but no
> algal cells (uninoculated) were subject to the same test conditions.
> Fluorometric values were determined for each concentration at 0, 24,
> 48, and 72 hr; pH was monitored at 0 and 72 hr for inoculated as well
> as uninoculated test cultures. Oxygen concentration was not reported.
> Culture vessels were maintained at 20°C under continuous white light.

Year: 1989

GLP: no

Test substance: Calcium propionate, CAS No. 7075-81-4, purity 99%, water
solubility \>500 g/L.

> Result: The temperature of the culture vessels was maintained at 20°C.
> pH values ranged between 7.76 and 10.07 (see below).

pH values in test and control cultures at 0 and 72 hours

+----------------------+-------------+----------------+---------------+
| Nominal              | 0 hour      | 72 hours       |               |
|                      |             |                |               |
| Concentration        |             |                |               |
|                      |             |                |               |
| (mg/L)               |             |                |               |
+----------------------+-------------+----------------+---------------+
|                      |             | uninoculated   | inoculated    |
+----------------------+-------------+----------------+---------------+
| Control              | 7.80        | 8.17           | 9.88          |
+----------------------+-------------+----------------+---------------+
| 7.812                | 8.14        | 8.13           | 9.81          |
+----------------------+-------------+----------------+---------------+
| 15.625               | 8.06        | 8.02           | 9.87          |
+----------------------+-------------+----------------+---------------+
| 31.25                | 8.00        | 8.05           | 10.02         |
+----------------------+-------------+----------------+---------------+
| 62.5                 | 8.03        | 8.03           | 10.07         |
+----------------------+-------------+----------------+---------------+
| 125                  | 7.98        | 7.96           | 9.90          |
+----------------------+-------------+----------------+---------------+
| 250                  | 7.88        | 7.91           | 9.75          |
+----------------------+-------------+----------------+---------------+
| 500                  | 7.76        | 7.92           | 9.72          |
+----------------------+-------------+----------------+---------------+

> Fluorometric measurements were used to determine the effect of calcium
> propionate on biomass after 72 hr exposure.
>
> Fluorometric values after 72 hours

+--------------------------------------+-------------------------------+
| Nominal                              | \% of control                 |
|                                      |                               |
| concentration                        |                               |
|                                      |                               |
| (mg/L)                               |                               |
+--------------------------------------+-------------------------------+
| Control                              | NA                            |
+--------------------------------------+-------------------------------+
| 7.812                                | 101.19                        |
+--------------------------------------+-------------------------------+
| 15.625                               | 101.91                        |
+--------------------------------------+-------------------------------+
| 31.25                                | 116.35                        |
+--------------------------------------+-------------------------------+
| 62.5                                 | 108.58                        |
+--------------------------------------+-------------------------------+
| 125                                  | 96.51                         |
+--------------------------------------+-------------------------------+
| 250                                  | 83.29                         |
+--------------------------------------+-------------------------------+
| 500                                  | 85.78                         |
+--------------------------------------+-------------------------------+

> Probit analysis was used to determine the EC50. Based on the results
> of this assay, the EC50b for biomass is \>500 mg/L, the EC50r for
> growth rate is \>500 mg/L.
>
> Reliability: score = 2, valid with restriction; no analytical
> measurement of test solutions.
>
> References: BASF AG . 1989b. Luprosil salt (Calciumpropionate). Algal
>
> growth inhibition test. Department of Ecology, unpublished data,
> report No. 2/1540/88, 25 Sep 1989.
>
> BASF AG. 2007. Department for Product Safety, recalculation of EbC50
> and ErC50 values of algal growth test from study 2/1540/88 by ECT
> Oekotoxikologie GmbH, unpublished data, 04 Sep 2007
>
> \(c\) Test material: n-propionic acid
>
> Method: estimated value using EcoSAR model
>
> Value: 11,057 mg/L
>
> Remark: An acute algal 96-h EC50 was calculated using ECOSAR, from the
> USEPA. The SAR for neutral organics-acids was used. The structure was
> determined from the CAS RN as stored in the accompanying database of
> SMILES notations within ECOSAR. Data used for the calculation were
> water solubility 1,000,000 mg/L, log P 0.33, melting point -21.5
> deg.C, and molecular weight of 74.08 g/mol.
>
> Reliability: Score=2, valid with restrictions; accepted calculation
> method

Reference: U.S.EPA ECOSAR model (v. 0.99h). 2000. EPISuite v3.12, U.S.
Environmental Protection Agency.

# **4.4 TOXICITY TO BACTERIA** 

> No data available

# **4.5 CHRONIC TOXICITY TO AQUATIC ORGANISMS**

> No data available

# **4.5.1 CHRONIC TOXICITY TO FISH** 

> No data available

# **4.5.2. CHRONIC TOXICITY TO AQUATIC INVERTEBRATES**

No data available

# **4.6 TOXICITY TO TERRESTRIAL ORGANISMS**

No data available

# **4.6.1 TOXICITY TO SOIL DWELLING ORGANISMS**

\(a\) Critical Study for SIDS Endpoint

> Type: EC50, loss of mobility/paralysis
>
> Species: *Meloidogyne arenaria*, plant parasitic nematode
>
> Unit: mM and equivalent ug/L
>
> Exposure Period: 24 hours
>
> EC0:
>
> EC50: 0.50 mM, equivalent to 37 mg/L
>
> Test substance: n-propionic acid, purity not specified
>
> Year: 1994
>
> GLP: no data
>
> Method: Second-state *Meloidogyne arenaria* juveniles were extracted
> daily from galled tomato plant roots in order to use individuals
> hatched within a 24-hour period. Acids were purchased from Aldrich
> Chemical Company or Sigma Chemical Company and used without additional
> purification. In vitro tests were performed using 24-well Nunclone
> plates. Each well contained a1ml aqueous solution of the test compound
> and 20 ul of nematode suspension (50 to 100 nematodes). Each treatment
> dose was replicated 4 times. A series of dilutions for each acid was
> prepared from 100 mM to 0.01 mM in distilled water. The number of live
> and paralyzed nematodes were counted under a binocular microscope
> after 24 hours. Toxicity was determined according to the mean
> percentage of dead or paralyzed nematodes after 24 hours. The
> confidence limits of each concentration, TC~50~ values, were
> determined by probit analysis method (Student's test, p = 0.05).
> Nematodes exposed to distilled water or in a 1% solution of ethanol
> served as controls.
>
> Results: Test results suggest that saturated aliphatic acids display
> comparable toxicity on a when tested on second-stage juveniles of the
> parasitic plant nematode, *Meloidogyne arenaria.*
>
> Toxicity of short chain fatty acids to larval nematodes
>
> [Test material TC50 (mM) TC50 (mg/L)]{.underline}
>
> Propionic acid 0.50 37
>
> Butyric acid 0.40 35
>
> Pentanoic acid 0.40 41
>
> Hexanoic acid 0.50 58
>
> [Heptanoic acid 0.40 52 .]{.underline}
>
> TC: toxic concentration, based on number of dead or
>
> immobile (paralysed) nematodes
>
> Remark: The authors tested the effect of propionic acid on a variety
> of nematodes species. They report that propionic acid and other
> carboxylic acids demonstrated a selective effect on some
> plant-parasitic nematodes, but did not adversely effect the
> saprophagous species, which constitute an important part of the useful
> microfauna of the soil. The TC50 for these species, was reported as
> greater than 100 mM, or 10.2 g/L.
>
> Reliability: score = 2, valid with restriction; purity of test
> material not specified.
>
> Reference: Djian, C., Ponchet, M., and Cayrol, J.C. 1994. Nematocidal
> properties of carboxylic acids and derivatives. Pesticide Biochem.
> Biophysiol. 50: 229-239.

# **4.6.2 TOXICITY TO TERRESTRIAL PLANTS**

\(a\) Critical Study for SIDS Endpoint

> Test substance: n-propionic acid, purity not specified
>
> Type: EC50, inhibition of fruit germination
>
> Species: *Lactuca sativa L. (*Artic King lettuce)
>
> Unit: mM and equivalent mg/L
>
> Exposure Period: 72 hours
>
> EC0:
>
> EC50: 1.7 mM, equivalent to 125.8 mg/L
>
> Test substance: propionic acid, purity not specified
>
> Year: 1975
>
> GLP: no data
>
> Method: Seeds of *Lactuca sativa* were sown in polystyrene pots (2.8 x
> 3.5 cm). Each pot contained 10 ml of 0.5% agar in which the test
> substance was dissolved. Pots were floated in water baths under
> uniform light conditions and maintained at 29 [+]{.underline} 0.5 ºC.
> L. Twenty lettuce fruits were sown in each pot; each set contained
> five replicates; germination was counted after 72 hours. Test
> solutions were prepared and then mixed with molten 1% agar solutions
> to provide the germination medium. The pH of the germination solution
> was measured at test initiation. Test compounds were used as received
> from the manufacturer and were used without further purification.
>
> Results: Test results suggest that inhibition of lettuce seed
> germination increases as carbon length increases; this effect appears
> to be independent of pH.
>
> [Effect of Fatty Acids on Inhibition of Lettuce Seed
> Germination]{.underline}
>
> EC50^2^ EC50 pH at
>
> [Test material (C#)^1^ (mM) (mg/L) EC50]{.underline}
>
> Propionic acid (C3) 1.7 ^[+]{.underline}^ 0.6 125.8 5.75
>
> Butyric acid (C4) 2.1 ^[+]{.underline}^ 0.8 184.8 3.44
>
> Pentanoic acid (C5) 1.3 ^[+]{.underline}^ 0.3 132.6 3.55
>
> Hexanoic acid (C6) 1.0 ^[+]{.underline}^ 0.2 116.0 3.40
>
> Heptanoic acid (C7) 0.7 ^[+]{.underline}^ 0.06 91.0 3.20
>
> [Octanoic Acid (C8) 0.7 ^+^ 0.02 100.8 3.70]{.underline}
>
> 1: number of carbons in test material
>
> 2: EC50: concentration at which a 50% inhibition of germination was
> observed relative to controls, [+]{.underline} 95 % confidence limit
> (*p* = 0.05)
>
> Reliability: score = 2, valid with restriction; purity of test
> material not specified.
>
> Reference: Reynolds, T. 1975a. Characterization of osmotic restraints
> on lettuce fruit germination. Annals of Botany 39: 791-796. *and*
>
> Reynolds, T. 1975b. pH Restraints on lettuce fruit germination. Annals
> of Botany 39: 797-805.

# **4.6.3 TOXICITY TO OTHER NON MAMMALIAN TERRESTRIAL SPECIES (INCLUDING AVIAN)**

No data available

# **4.7 BIOLOGICAL EFFECTS MONITORING (INCLUDING BIOMAGNIFICATION)**

No data available

# **4.8 BIOTRANSFORMATION AND KINETICS**

No data available

# **4.9 ADDITIONAL REMARKS**

None

# **5.0 TOXICITY**

# **5.1 ACUTE TOXICITY**

# **5.1.1 ACUTE ORAL TOXICITY**

\(a\) Critical Study for SIDS Endpoint (reliability score = 2)

> Type: LD50

Species: rat (male)

Value: 426 (305 -- 593) mg/kg bw

> Method: Groups of five male Carworth-Wistar rats received 8.0, 4.0, or
> 2.0 ml/kg bw (0, 1987, 3973, or 7947 mg/kg bw) n-propionic acid,
> administered as a 10% aqueous solution, by stomach tube. Rats were not
> fasted prior to dosing. Five rats were included in each group. Animals
> were observed for signs of toxicity after dosing, and throughout the
> 14-day observation interval. Animals were weighed prior to dosing and
> at the end of the observation interval. Animals that died on study
> were subjected to necropsy; surviving animals were sacrificed at the
> end of the observation interval and necropsied. Thompson\'s method of
> calculating the LD50 was applied to the 14-day mortality data.
>
> Year: 1957
>
> GLP: no
>
> Test substance: n-propionic acid, purity not specified
>
> Results: The peroral LD50 (and 95% confidence limits) for male
> Carworth-Wistar rats fed a solution of 10% n-propionic acid was 4.29
> (3.07-5.98) ml/kg bw, or 4.26 (3.05-5.93) g/kg bw body weight of the
> test solution. All rats that received 8.0 ml/kg died, 2 of 5 rats died
> in the 4.0 ml/kg bw group. All deaths occurred on the day of dosing
> (day 0) or on day 1. There was no mortality among rats that received
> the lowest dosage of 2.0 ml/kg. All but one surviving animal gained
> weight. Necropsy of animals that died on study revealed hemorrhaged
> and congested lungs and gastrointestinal tracts, and \"burned\"
> surfaces of kidney, liver, spleen and adrenal where contact was made
> with the gastrointestinal tract.
>
> Remark: Based on the results of the assay that employed a test
> solution of 10% propionic acid, the LD50 for undiluted propionic acid
> can be extrapolated to be 426 mg/kg bw, with a 95% confidence interval
> of 305 and 593 mg/kg bw.
>
> Reliability: score = 2, valid with restrictions; purity of test
> material not specified, female rats not tested
>
> Reference: Smyth H.F. Jr., Carpenter, C.P., Weil, C.S., Pozzani, C.,
> and Striegel, J.A. 1962. Range Finding Toxicity Data. Am. Ind. Hyg.
> Assoc. J. 23: 95-107.
>
> *and*
>
> Union Carbide Corporation. 1957. Range Finding Tests on Propionic
> Acid. Mellon Institute Research Report 20-67, dated April 11, 1957.

\(b\) Type: LD50

Species: rat (female)

Value: 354 ml/kg (351 mg/kg)

> Method: Groups of non-fasted female Harlan-Wistar rats (90-120 g)
> received increasing dose levels of undiluted n-propionic acid,
> administered by stomach tube. The number of animals dosed per group is
> not reported. Animals were observed for signs of toxicity after
> dosing, and throughout the 14-day observation interval. Animals were
> weighed prior to dosing and at the end of the observation interval.
> Thompson\'s method of calculating the LD50 was applied to the 14-day
> mortality data.
>
> Year: 1974
>
> GLP: no
>
> Test substance: n-propionic acid, purity not specified
>
> Remark: The peroral LD50 for female rats was 354 ml/kg or 351 mg/kg.
>
> Reliability: score = 2, valid with restrictions; purity of test
> material not specified, male rats not tested
>
> Reference: Union Carbide Corporation. 1974b. Toxicity and Irritation
> Assay Results of Some Food, Drug or Cosmetic Product Chemicals.
> Carnegie-Mellon Institute Research Report 37-77, dated September 3,
> 1974.

\(c\) Type: LD50

Species: rat (male and female)

Strain: Sprague Dawley

Value: 3470 (2988 - 4020) mg/kg bw

> Method: Standard BASF Test; equivalent to OECD Test Guideline 401.
> Groups of five male and five female Sprague Dawley rats received 2000,
> 2500, 3200, 4000, 5000, or 6400 ml/kg bw n-propionic acid (equivalent
> doses: 1986, 2483, 3178, 3972, 4965, and 6355 mg/kg bw). Water is
> listed as the vehicle. The volume of test material administered is not
> specified. It is not known if animals were fasted prior to dosing. The
> 3200 mg/kg group contained additional animals for a final group size
> of 10 males and 10 females. The mean weight of test animals was 161 g
> for males and 148 g for females. Animals were observed for signs of
> toxicity after dosing and at 1, 24, and 72 hr, and at 7 and 14 days
>
> Animals that died on study were subjected to necropsy, and surviving
> animals were sacrificed at the end of the observation interval and
> necropsied. The Litchfield and Wilcoxon method of calculating the LD50
> was applied to the 14-day mortality data.
>
> Year: 1969
>
> GLP: no
>
> Test substance: n-propionic acid, purity not specified
>
> Results: The peroral LD50 (and 95% confidence limits) for Sprague
> Dawley rats fed n-propionic acid was 3490 (3009-4048)ml/kg bw, or 3470
> (2988-4020) mg/kg bw. All rats that received 6400 ml/kg died;
> mortality was 70%, 80%, and 40% in the 5000, 4000, and 3200 ml/kg
> groups, respectively. There was 10% mortality among rats that received
> the lowest dose levels of 2500 and 2000 ml/kg bw. All but one death
> occurred within 24 hours of dosing. Clinical signs included squatting
> posture, agitation or apathy, dyspnea, cyanosis, and ruffled fur;
> among survivors, these signs were reversible within 5-14 days.
> Necropsy of animals that died on study revealed a large amount of
> liquid in the abdomen and discoloration around the snout. Superficial
> liver necrosis was observed in one animal. Reduced retroperitoneal fat
> pads were observed in animals that were sacrificed at the end of the
> observation interval; one animal displayed a swollen intestine.
>
> Reliability: score = 2, valid with restrictions; purity of test
> material not specified
>
> Reference: BASF AG. 1969. Report on the acute per oral toxicity of
> propionic acid on rats. Department of Toxicology, translation of the
> unpublished report No. XIX/264, dated 27 Oct. 1969.

# **5.1.2 ACUTE INHALATION TOXICITY**

\(a\) Critical study for SIDS endpoint (score = 2)

Type: LC0

Species: rat

Value: 36 ppm (0.14 mg/L)

Exposure interval: 8 hours

> Method: A group of 6 rats was exposed for 8 hr to a dynamically
> generated vapor atmosphere containing n-propionic acid at a nominal
> concentration of 36 ppm. The vapor-air mixture was generated by
> passing 2.5 liter/min of dried air at room temperature through a
> fritted glass disc immersed to a depth of at least 1-inch in
> approximately 50 ml of the test material. After exposure, rats were
> observed for 14 days. Animals were weighed prior to exposure and at
> the end of the 14-day post-exposure observation interval.
>
> Year: 1957
>
> GLP: no
>
> Test substance: n-propionic acid, purity not specified
>
> Remark: There was no mortality among rats exposed to 36 ppm
> n-propionic acid for 8 hr. Nasal, ocular, and skin irritation were
> observed. All animals gained weight during the 14-day observation
> interval.
>
> Reliability: score = 2; valid with restriction: purity of test
> material not specified, sex of animals tested not specified.
>
> Reference: Union Carbide Corporation. 1957. Range Finding Tests on
> Propionic Acid. Mellon Institute Research Report 20-67, dated April
> 11, 1957. *and*
>
> Smyth H.F. Jr., Carpenter, C.P., Weil, C.S., Pozzani, C., and
> Striegel, J.A. 1962. Range Finding Toxicity Data. Am. Ind. Hyg. Assoc.
> J. 23: 95-107.

\(b\) Critical Study for SIDS Endpoint

> Type: LC50

Species: rat (male/female)

Strain: Sprague Dawley

Value: \> 19.7 mg/L

Exposure interval: 1 hour

> Method: Groups of male and female (10 per sex) Sprague Dawley rats
> (200-300 g) were exposed using a head-nose inhalation system for 1 hr
> to an atmosphere containing n-propionic acid at a measured
> concentrations of 2.7 or 19.7 mg/L. There was no control group. The
> method of atmosphere generation and analysis of the test atmosphere
> concentration are not described. A concentration of 19.7 mg/L was
> reported as the maximum achievable concentration. Particle size in the
> atmosphere was measured, indicating that animals were exposed to a
> vapor/aerosol (MMAD 50% = 2.8 μm). Animals were observed during
> exposure. After exposure, rats were observed for 14 days. Animals were
> weighed prior to exposure and at the end of the 14-day post-exposure
> observation interval. Animals that died on study were subjected to
> necropsy; surviving animals were sacrificed at the end of the
> observation interval and necropsied.
>
> Year: 1979
>
> GLP: no
>
> Test substance: n-propionic acid, purity not specified
>
> Results: One female (1/10) died after exposure to 19.7 mg/L. Necropsy
> of this animal revealed discolored lungs, pulmonary edema and partial
> atelectasis with intestines filled with gas. No other mortality was
> observed. Clinical signs in high dose animals during exposure included
> slightly reduced respiration frequency, gasping, narrowed eyelids,
> salivation, nasal secretion, and slight corneal opacity; fur wetted
> with urine was also observed. Signs observed in the low dose animals
> included narrowed eyelids and fur wetted with urine. After exposure,
> high dose animals displayed gasping, reduced respiratory frequency
> (females only), narrowed eyelids, swollen nasal areas, and corneal
> opacity, which persisted in one animal until the end of the
> observation interval. Both treatment groups displayed similar body
> weight gains one week after exposurr, however high dose females did
> not gain weight during week 2, while low-dose females displayed a 10%
> increase in weight during this interval. Necropsy of animals that were
> sacrificed at the end of the observation interval revealed multiple
> petechia in the lung in 4/19 animals in the high dose group.
>
> Reliability: score = 2; valid with restriction: purity of test
> material not specified, .
>
> Reference: BASF AG (sponsor of INBIFO study). 1979. Determination of
> the acute inhalation toxicity LC50 of propionic acid as vapour on male
> and female rats. BASF AG translation of the unpublished report BASF
> No. 77/523, dated 5 Nov. 1979.

# **5.1.3 ACUTE DERMAL TOXICITY**

\(a\) Preferred value and critical study for SIDS endpoint (score = 2)

Type: LD50

Species: rabbit (male)

Value: 490 (367 -- 665) mg/kg bw

> Method: Groups of four male New Zealand white rabbits received 0.3125
> or 0.625 ml/kg n-propionic acid, applied undiluted, to intact
> (non-abraded) skin. Fur was removed from the trunk of each rabbit
> prior to application of the test material. Rabbits were immobilized
> during the 24-hr skin contact interval. Propionic acid was applied to
> the dorsal surface of the trunk and spread over as large an area as
> possible. The test material was retained on the skin beneath an
> impervious sheet of Vinylite, which was wrapped around the trunk of
> each animal. After treatment, all wrappings were removed; animals were
> observed for signs of toxicity after dosing, and throughout the 14-day
> observation interval. Animals that died on study were subjected to
> necropsy; animals sacrificed at the end of the observation interval
> were also necropsied. Thompson\'s method of calculating the LD50 was
> applied to the 14-day mortality data.
>
> Year 1957
>
> GLP: no
>
> Test substance: n-propionic acid, purity not specified
>
> Remark: The dermal LD50 (and 95% confidence limits) for male New
> Zealand white rabbits was 0.5 (0.37-0.67) ml/kg bw, or 490 (367-665)
> mg/kg bw. Mortality was 3/4 for the group receiving 0.625 ml/kg. There
> were no deaths among animals that received 0.3125 ml/kg. All deaths
> occurred on the day of dosing. Covered application produced necrosis
> of the skin. Necropsy of animals that died revealed petechial
> hemorrhage of the lungs, mottled livers, congested kidneys, and
> hemorrhage of the intestines; the urine of one animal contained blood.
> All but two of the surviving animals gained weight during the 14-day
> observation interval
>
> Reliability: score = 2, valid with restriction; purity of test
> material not specified, only two doses tested..
>
> Reference: Smyth H.F. Jr., Carpenter, C.P., Weil, C.S., Pozzani, C.,
> and Striegel, J.A. 1962. Range Finding Toxicity Data. Am. Ind. Hyg.
> Assoc. J. 23: 95-107.
>
> *and*
>
> Union Carbide Corporation. 1957. Range Finding Tests on Propionic
> Acid. Mellon Institute Research Report 20-67, dated April 11, 1957.

\(b\) Type: LD50

Species: rat (female)

Value: 1.68 ml/kg bw (1669 mg/kg bw)

> Method: Groups female Harlan-Wistar rats (120-180 g) received
> increasing doses of n-propionic acid, applied undiluted to intact
> (non-abraded) skin. Fur was removed from the trunk of each rat prior
> to application of the test material. Rats were immobilized during the
> 4-hour skin contact interval. Propionic acid was applied to the dorsal
> surface of the trunk and spread over as large an area as possible. The
> test material was retained on the skin beneath an impervious sheet of
> Vinylite, which was wrapped around the trunk of each animal. After
> treatment, all wrappings were removed; animals were observed for signs
> of toxicity after dosing, and throughout the 14-day observation
> interval. Thompson\'s method of calculating the LD50 was applied to
> the 14-day mortality data.
>
> Year 1974
>
> GLP: no
>
> Test substance: n-propionic acid, purity not specified, test doses not
> specified
>
> Remark: The 4-hour dermal LD50 for female rats was 1.68 ml/kg, or 1669
> mg/kg. Irritation of the skin at the site of application was not
> reported.
>
> Reliability: score = 2, valid with restriction; purity of test
> material not specified.
>
> Reference: Union Carbide Corporation. 1974b. Toxicity and Irritation
> Assay Results of Some Food, Drug or Cosmetic Product Chemicals.
> Carnegie-Mellon Institute Research Report 37-77, dated September 3,
> 1974.

# **5.1.4 ACUTE TOXICITY, OTHER ROUTES OF ADMINISTRATION**

\(a\) Type: LD50

Species: rat

Route of Admin: intraperitoneal injection (IP)

Value: 200-400 mg/kg bw

Method other: no data available

> Year: 1974
>
> Test material: n-propionic acid, purity not specified
>
> Remark: Groups of rats received intraperitoneal injections of a 1%
> aqueous solution of propionic acid. Dosages administered ranged from
> 25 mg/kg bw to 400 mg/kg bw. Dosed animals displayed weakness and
> ataxia. Deaths occurred within 2 days of administration. The LD50 for
> IP injection for propionic acid was determined to be between 200 and
> 400 mg/kg bw
>
> Reliability: score = 4, not assignable; documentation insufficient for
> assessment
>
> Reference: Eastman Kodak Company. 1974. Unpublished report. Propionic
> Acid. Health and Safety Laboratory Report 74-153.

# **5.2 CORROSIVENESS/IRRITATION**

# **5.2.1 SKIN IRRITATION/CORROSION**

> \(a\) Critical Study for SIDS Endpoint (score = 2)
>
> Species: rabbit, male

Result: severe irritation and necrosis

> Classification: corrosive
>
> Method other:
>
> Year: 1957
>
> GLP: no
>
> Test substance: n-propionic acid , purity not specified
>
> Remark: Undiluted propionic acid (0.01 ml or approximately 10
> mg/animal) was applied to clipped skin of male New Zealand white
> rabbits and allowed to remain on the skin for 24 hours under
> non-occluded conditions. Necrosis was evident after 24 hours. In a
> follow-up study, application of a 10% aqueous solution of propionic
> acid for 24 hours under non-occluded conditions produced moderate to
> marked erythema (Grade 6 on a scale of 10).
>
> Reliability: score = 2, valid with restriction; purity of test
> material not specified
>
> Reference: Smyth H.F. Jr., Carpenter, C.P., Weil, C.S., Pozzani, C.,
> and Striegel, J.A. 1962. Range Finding Toxicity Data. Am. Ind. Hyg.
> Assoc. J. 23: 95-107.
>
> *and*
>
> Union Carbide Corporation. 1957. Range Finding Tests on Propionic
> Acid. Mellon Institute Research Report 20-67, dated April 11, 1957.

\(b\) Species: guinea pig

Result: severe irritation and necrosis

> Classification: corrosive
>
> Method other:
>
> Year: 1974
>
> GLP: no
>
> Test substance: n-propionic acid, purity not specified
>
> Method: A volume of 0.5 ml of undiluted propionic acid was
> administered and allowed to remain on the skin of 5 guinea pigs. Skin
> reaction was observed and recorded at 2, 24, and 48 hr after
> application. Animals were weighed prior to treatment, and again at the
> end of a 14-day observation interval.
>
> Results: At 2 hours after dermal administration, slight to moderate
> edema, moderate to severe erythema, and necrosis was observed. After
> 24 hr, the application site was necrotic with erythema around the
> periphery. At 48 hr, eschar covered most of the treatment site on all
> animals; there was also petechial hemorrhages, erythema, and scattered
> areas of necrosis. All animals lost weight during the 14-day
> observation interval.
>
> Reliability: score = 2, valid with restriction, purity of test
> material not specified
>
> Reference: Eastman Kodak Company. 1974. Unpublished report. Propionic
> Acid. Health and Safety Laboratory Report 74-153.

# **5.2.2 EYE IRRITATION/CORROSION**

> \(a\) Critical Study for SIDS Endpoint (score = 2)

Species: rabbit, male, New Zealand White

Result: severe irritation

Classification: corrosive

> Method: other .
>
> Year: 1957

GLP: no

> Test substance: n-propionic acid, purity not specified
>
> Remark : Instillation of 0.005 ml of undiluted propionic acid burned
> rabbit eyes severely (Grade 9 on a scale of 10) An excess amount (0.1
> ml) of a 5% aqueous solution instilled into the eye caused less severe
> burns. In a follow-up study, five rabbits were treated with 0.1 ml of
> 1% propionic acid as an aqueous solution; 3 of 5 eyes were unaffected,
> while 2 of 5 had trace injuries.
>
> Reliability: score = 2, valid with restrictions; limited description
> of methodology, purity of test material not specified.
>
> Reference: Union Carbide Corporation. 1957. Range Finding Tests on
> Propionic Acid. Mellon Institute Research Report 20-67, dated April
> 11, 1957.

# **5.3 SKIN SENSITISATION**

> No data available

# **5.4 REPEATED DOSE TOXICITY** 

(a) Critical Study for SIDS Endpoint (score = 1)

Species: dog

Strain: Beagle

> Sex: male and female

Route of Admin: oral (in feed)

Exposure Period: 3 months

Freq. of Treatment: daily

Post Exposure

> Observation Period: 6 weeks
>
> Doses: 0, 3000, 10,000 or 30,000 ppm in diet
>
> Control Group: yes
>
> NOAEL: 10,000 ppm (1.0% in diet)
>
> LOAEL: 30,000 ppm (3 % in diet)
>
> Method: Laboratory bred Beagle dogs (male and female, 4-8 months old)
> were house singly in separate indoor kennels (floor area 1.5 m^2^)
> with constant access to an outdoor kennel (floor area 4.5 m^2^) during
> both adaptation and administration intervals. Body weights were
> determined weekly and food consumption was measured daily beginning 7
> days prior to initiation of the study. Dogs were offered a daily food
> ration of 700 g; this ration consisted of 350 g pulverized food
> pellets mixed into a paste in each individual food dish by the
> addition of 350 g water (all dogs during 7-day adaptation interval,
> control dogs during the administration interval ), or 350 g of the
> appropriate propionic acid aqueous solution.
>
> Groups of Beagle dogs were assigned to 4 different test groups and fed
> a diet containing 0, 0.3, 1.0, or 3.0% n-propionic acid. Groups of 16
> dogs (8 males and 8 females) received the control or the high dose (3%
> propionic acid) diet, while groups of 8 dogs (4 males and 4 females)
> received 0.3% and 1.0% propionic acid in the diet. Dogs received the
> test diet for approximately 3 months (106 days for males, 99 days for
> females) when they were sacrificed and subject to necropsy. Four males
> and four females from the control and high dose (3% propionic acid)
> were assigned to the recovery groups and fed the control diet for 6
> weeks.
>
> Purity and stability of the test material were analyzed at the start
> of the study, after 10 weeks, and at the end of the administration and
> recovery intervals. The concentration of the test material for each
> test concentration was analyzed in duplicate at the start of the
> study, after about 6 weeks, and at the end of the administration
> interval. The stability of the test material in the food was evaluated
> prior to initiation of the study.
>
> During the administration interval, dogs were offered food once per
> day in late morning; left over diet was removed the following day and
> the amount subtracted from the initial amount. During the recovery
> interval, dogs were offered food once per day mid-day for a period of
> two hours; left-over food was removed and weighed.
>
> All dogs were weighed once per week before eating. Animals were
> observed daily and examined at least once per day for clinical signs
> of toxicity. Before initiation and at the end of the administration
> interval of the study, an ophthalmological examinations were conducted
> on control and high (3% propionic acid) animals. Samples were
> collected for hematological, urinalysis, and clinical chemistry
> evaluations prior to initiation and then again during the
> administration and recovery intervals.
>
> All animals were sacrificed under anesthesia by exsanguinations from
> the cervical and brachial vessels. Animals were necropsied and all
> gross lesions recorded. The following organs were removed and weighed:
> liver, kidneys, adrenal glands, thyroid (including parathyroid)
> glands, testes and ovaries. All major organs and tissues, as well as
> the sternum with marrow, mesenteric and axillary lymph nodes, salivary
> glands, and peripheral nerve (ischiadicus) were prepared for
> histological examination.
>
> The digestive tract from each animals was removed, fixed and prepared
> for histological examination:
>
> Tongue:
>
> 1\) Tip of the tongue,
>
> 2\) Base of the tongue.
>
> Esophagus:
>
> 1\) Cross-section approsimately 5 cm caudal of the arytenoids
> cartilage;
>
> 2\) Cross-section from middle third
>
> 3\) Longitudinal section through transition to the cardiac gland

Stomach:

> 1\) Longitudinal section from transition of the esophagus into the
> stomach comprising the caudal part of the esophagus and cardiac gland
> zone of the stomach;

2\) Longitudinal section from the pale fundic gland region;

3\) Longitudinal section from the dark fundic gland region;

4\) Longitudinal section from the pyloric gland region;

> 5\) Longitudinal section from the transition of the pyloric gland
> region into the duodenum
>
> Small intestine (duodenum, jejunum, ileum:
>
> Segments of approximately 5 to 7 cm from each region were prepared and
> cross sectioned, including cross section of cranial segment and
> transition from pyloric gland zone into duodenum.
>
> Large intestine:
>
> Segments of cecum, colon and rectum were prepared and cross sectioned.
>
> [Statistical evaluation]{.underline}: The statistical evaluation of
> variables included calculation of mean and standard deviations.
> Comparison of change was carried out using a Kruskal & Wallis test or
> a Mann-Whitney U test for the comparison of several dose groups with a
> control group. The minimum level of significance was determined to be
> p [\<]{.underline} 0.05.
>
> The Kruskal-Wallis one-way analysis of variance by ranks. *in*:
> Siegel, S. 1956. Nonparametric Statistics for the Behavior Sciences.
> London: McGraw Hill Book Company. P. 184-194.
>
> The Mann-Whitney U Test. *in*: Siegel, S. 1956. Nonparametric
> Statistics for the Behavior Sciences. London: McGraw Hill Book
> Company. P. 116-127.
>
> Results: Based on food consumption, the mean daily dose administered
> to high dose (3% propionic acid in diet) males ranged between 2491
> mg/kg bw at the start of the study, to 1848 mg/kg bw at the end of the
> administration interval. For high dose females, the mean daily dose
> ranged between 2209 and 1832 mg/kg bw at the start and end of the
> study, respectively. The mean daily dose administered to mid-dose (1%
> propionic acid in diet) males ranged from 835 to 660 mg/kg bw;
> mid-dose females received mean daily doses between 844 and 696 mg/kg
> bw. The mean daily dose for low-dose males was between 249 and 196
> mg/kg; for females 252 and 210 mg/kg bw.
>
> There were no deaths and during the administration and recovery
> intervals, dogs did not display any clinical signs of toxicity. Four
> females in the high dose group displayed a marked and prolonged lack
> of appetite, while an additional 2 females and 4 males in the high
> dose group displayed a slight reduction in appetite. This decrease in
> food consumption was attributed to the presence of the test material.
> The decrease in food consumption did not significantly effect body
> weight gain. There were no differences in body weights or body weight
> gains between groups during the 3-month administration interval and
> the 6-week recovery interval.
>
> There were no significant changes in hematology or urinalysis
> parameters. An approximately 30% decrease in alkaline phosphatase
> activity in high dose dogs was determined to be an artifact caused by
> interference with the detection method produced by the propionyl
> Coenzyme A, a metabolite of propionic acid.
>
> Necropsy of dogs at the end of the administration interval revealed no
> gross lesions. The digestive tract (tongue, stomach, duodeum, jejunum,
> ileum, cecum, colon, and rectum) and other organs and tissues examined
> displayed no changes in the incidence or severity of lesions that
> could be ascribed to feeding of the test material. The esophagus,
> which was examined at three different levels, displayed epithelial
> hyperplasia of varying severity (slight) and extent (focal) in the
> majority of animals in controls and test groups.
>
> Control animals: a total of 5/8 displayed focal areas of epithelial
> hyperplasia in the esophagus at one or two levels, and only 1/8
> displayed diffuse hyperplasia at one level.
>
> Low dose animals (3000 ppm in the diet): a total of 5/8 displayed
> focal areas of epithelial hyperplasia in the esophagus at one level,
> and only 1/8 displayed diffuse hyperplasia at one level.
>
> Mid-dose animals (10,000 ppm): a total of 4/8 displayed focal areas of
> epithelial hyperplasia in the esophagus at one or two levels, and 2/8
> displayed diffuse hyperplasia (1/8 at one level, 1/8 at two levels).
>
> High dose animals (30,000 ppm): a total of 7/8 displayed focal areas
> of hyperplasia (2/7 at one level, 5/7 at two levels), and 4/8
> displayed diffuse epithelial hyperplasia. Among the 4/8 animals
> displaying diffuse epithelial hyperplasia, 3 animals displayed
> epithelial changes at all three levels of the esophagus, the severity
> of these changes was graded as slight to moderate.
>
> In the lower dose groups (0.3% and 1.0% propionic acid), focal
> hyperplasia was the primary lesion observed, and the incidence was
> similar to that observed in control animals. In the 3% (30,000 ppm)
> group, however, there was an increase in diffuse epithelial
> hyperplasia which appeared at multiple levels of the esophagus. Among
> animals in the recovery group, the incidence and severity of
> hyperplasia in the high dose animals was comparable to controls.
>
> Remark: Based on these results, the LOAEL for this study is 3%
> propionic acid in the diet; the NOAEL is 1% propionic acid.

Reliability: score = 1, valid without restriction; GLP study

> Reference: BASF. 1988. Study of the toxicity of propionic acid in
> Beagle dogs. Administration in the diet over 3 months and a 6-week
> recovery period. Project No. 31D0473/8590. Study conducted by the
> Department of Toxicology of BASF Aktiengesellschaft, 6700
> Ludwigshafen/Rhein, FRG. Report dated July 8, 1988.

\(b\) Critical Study for SIDS Endpoint

> Species: rat

Strain: Sprague-Dawley

> Sex: male and female

Route of Admin: oral (in feed)

Exposure Period: 3 months (91 days)

Freq. of Treatment: daily

Post Exposure

> Observation Period: 6 weeks (42 days)
>
> Doses: 0, 6200, 12500, 25000, and 50000 ppm in diet (equivalent to 0,
> 0.62, 1.25, 2.5, and 5%)
>
> Control Group: yes
>
> NOAEL: 25,000 ppm (2.5% in the diet or approximately 1600 mg/kg bw)
>
> LOAEL: 50,000 ppm (5% in the diet or approximately 3300 mg/kg bw)
>
> Method: Groups of male(135-136 g) and female (128-129 g) Sprague
>
> Dawley rats were offered a daily food ration containing 0, 6200,
> 12500, 25000, or 50000 ppm propionic acid (0, 0.62, 1.25, 2.5, and
> 5%). The method of food preparation is not described, and it is not
> clear if the concentration of the test material in the food was
> measured. Each group consisted of 20 animals per sex per dose and an
> additional 10 post-exposure animals were included in the control,
> 0.62, and 5% groups. Rats received the test diet for approximately 3
> months (91 days) when they were sacrificed and subject to necropsy.
> Ten rats from the control, low dose (0.62%), and high dose (5%
> propionic acid) were assigned to the post-exposure recovery groups and
> fed the control diet for 6 weeks.
>
> Clinical observations and food consumption were monitored daily. Rats
> were weighed weekly. Hematological examinations were performed with 10
> animals per dose per sex on day 19-21 and day 75-78. Urinalysis was
> performed on day 14-17 and day 70-73. At the end of the study, weights
> of liver, kidneys and heart were determined. Organs examined at
> necropsy (macroscopic and histological) included tissues from the CNS,
> heart, lung, thyroid, liver, kidneys, adrenals, spleen, pancreas,
> stomach, intestine, urinary bladder, testes/ovaries and intestine
> lymph nodes.

Test substance: propionic acid, technical grade (purity not specified)

> Results: There was no mortality among control or treated rats:
>
> [Body weight]{.underline}: Males showed a dose-dependent reduced
> weight gain with a clear reduction in the 5% treatment after day 7-14,
> resulting in a reduced body weight at the end of the study by 6%,
> whereas the body weight/ body weight gain in females was not affected
> or slightly decreased. Animals of all treatments showed comparable
> body weight gain in the post exposure period; however, the differences
> in body weights remained.
>
> [Food consumption]{.underline}: comparable to the control, but
> slightly reduced in males of the 5% treatment. Animals of all
> treatments showed comparable food consumption in the post exposure
> period. Food consumption was monitored for each group, the average
> dose received was estimated to be approximately 500, 1000, 1600, and
> 3300 mg/kg bw for rats receiving propionic acid in the diet at 0.062%,
> 1.25%, 2.5%, and 5.0%, respectively.
>
> [Clinical signs]{.underline}: no clinical signs in any animal of the
> treatment groups.
>
> [Hematological findings]{.underline}: no differences to the control in
> any treatment.
>
> [Clinical biochemistry findings]{.underline}: no differences beyond
> physiological variations between the control and any treatment.
>
> [Organ weight changes]{.underline}: there were no differences relative
> to controls in the absolute weights of liver, kidneys and heart in any
> of the treatment groups. No differences to the control were observed
> in the relative liver and heart weights in males of all treatment
> groups. In males of the 5% treatment group, the relative weight of the
> kidneys was decreased by 12%. In contrast, in all treated females the
> relative weight of kidneys was slightly increased, whereas the
> relative liver and heart weights of females was increased only in the
> 5% treatment by 9 and 5%, respectively.
>
> Relative to the heart weight, the weights of liver and kidneys of the
> treatment groups were comparable to the control.
>
> There were no differences between control and treated groups in
> absolute and relative organ weights of the animals sacrificed after
> the post exposure period.
>
> [Gross pathology]{.underline}: no substance related differences to the
> control in any treatment
>
> [Histopathology]{.underline}: Changes of the mucosa of the forestomach
> were observed in all treatment groups, increasing in incidence and
> severity. In the 5% treatment group these changes were considered
> substance related (proliferation acanthosis and retention
> hyperkeratosis). Considering the examinations of the animals after the
> post exposure period, this effect should be regarded as reversible.
> All other examined organs did not show substance related changes in
> any treatment.
>
> [Conclusion]{.underline}: the mucosa of the fore stomach should be
> regarded as the target organ after repeated ingestion of propionic
> acid. All observed effects were reversible within 42 day.
>
> Reliability: score = 2, valid with restrictiond; purity of test
> material, method of diet preparation not specified, food consumption
> data not available.
>
> Reference: BASF AG. 1971. 90-day feeding study on rats with propionic
> acid. Department of Toxicology, translation of the unpublished report
> No. XX/200, dated 30 July 1971.

\(c\) Species: rat

Strain: Wistar

> Sex: male

Route of Admin: oral (in pelleted feed)

Exposure Period: 24 weeks

Freq. of Treatment: daily

Post Exposure

> Observation Period: none
>
> Doses: 0 or 4% in feed
>
> Control Group: yes
>
> NOEL:
>
> LOEL: NA
>
> Method: Groups of six male Wistar rats were fed either a control diet,
> or a [pelleted]{.underline} diet containing propionic acid for 24
> weeks. Rats were housed two to a cage and allowed free access to food
> and water. Body weights were determined at the start of the study and
> weekly thereafter. Food consumption was determined daily by weighing
> the containers after filling and prior to filling on the following
> day. Propionic acid was incorporated into the powdered diet using a
> household mixer. Pellets of approximately 10 g were pressed and
> air-dried for at least 3 days and stored for no more than 10 days. The
> concentration of propionic acid in the diet was determined in
> triplicate by capillary gas-liquid chromatography after vacuum
> distillation using a Perkin Elmer 900 GC equipped with a flame
> ionization detector. At the end of the study, rats were killed and the
> entire stomach removed and opened along the greater curvature. Parts
> of the food bolus within the forestomach were collected and stored at
> -20 degrees C. The stomach was flattened and fixed for microscopic
> examination.
>
> Year: 1993

GLP: no

> Test substance: n-propionic acid, initial purity not specified
>
> Analytical monitoring: yes
>
> Remark: The NOEL for forestomach changes was 2.4-3.1% when fed in a
> [pelleted]{.underline} diet.
>
> Results: Groups of male Wistar rats were fed a [pelleted]{.underline}
> diet containing propionic acid for 24 weeks. The behavior and general
> health of treated rats were similar to those of the controls. The
> initial concentration of propionic acid in the pelleted diet was
> determined to be 8.2 +/- 0.8%; this decreased to 3.1 +/- 0.7% on day 4
> (first day of use) and 2.4 +/- 0.7 on day 10 (last day of use). Rats
> fed a pelleted diet containing 2.4-3.1% propionic acid for 24 weeks
> displayed no forestomach changes. Macroscopic and histopathological
> examination revealed no adverse effects on the gastric mucosa.
>
> Reliability: score = 2, valid with restrictions: initial purity of
> test material not specified, study evaluated only forestomach effects
>
> Reference: Bueld, J.E. and Netter, K.J. 1993. Factors affecting the
> distribution of ingested propionic acid in the rat forestomach. Fd.
> Chem. Toxic. 31: 169-176.

\(d\) Species: rat

Strain: Wistar

> Sex: male

Route of Admin: oral (in powdered feed)

Exposure Period: 12 weeks

Freq. of Treatment: daily

Post Exposure

> Observation Period: none
>
> Doses: 0 or 4% in diet
>
> Control Group: yes
>
> NOEL:
>
> LOEL: NA
>
> Method: Groups of six male Wistar rats were fed either a
> [powdered]{.underline} diet, a powdered diet containing propionic
> acid, a powdered diet containing propionic acid and 1% L-carnitine, or
> a powdered diet containing 1% L-carnitine, for 12 weeks. Rats were
> housed two to a cage and allowed free access to food and water. Body
> weights were determined at the start of the study and weekly
> thereafter. Food consumption was determined daily by weighing the
> containers after filling and prior to filling on the following day.
> Spillage was minimized by container design. Food containers were
> completely emptied and refilled with fresh diet each day. Propionic
> acid was incorporated into the powdered diet using a household mixer.
> The concentration of propionic acid in the diet was determined in
> triplicate by capillary gas-liquid chromatography after vacuum
> distillation using a Perkin Elmer 900 GC equipped with a flame
> ionization detector. At the end of the study, rats were killed and the
> entire stomach removed and opened along the greater curvature. Parts
> of the food bolus within the forestomach were collected and stored at
> -20 degrees C. The stomach was flattened and fixed for microscopic
> examination.
>
> Year: 1993

GLP: no

> Test substance: n-propionic acid, initial purity not specified.
>
> Analytical monitoring: yes
>
> Remark: Rats fed a [powdered]{.underline} diet containing propionic
> acid for 12 weeks displayed severe changes in the forestomach but not
> in the glandular stomach. No effects were observed when rats were fed
> the same diet but in [pelleted]{.underline} form.
>
> Results: Groups of male Wistar rats were fed a [powdered]{.underline}
> diet for 12 weeks. The behavior and general health of treated rats
> were similar to those of the controls. There was no morbidity or
> mortality in any group. Relative to controls, food consumption showed
> a trend toward a slight reduction in mean intake in groups fed a
> powdered diet containing 4% propionic acid or 4% propionic acid and 1%
> L-carnitine. There was an increase in food consumption in rats fed a
> powdered diet containing 1% carnitine; this group displayed a
> significantly greater increase in mean body weight when compared to
> controls and other treated groups. There were no significant
> differences in body weight gain among the other groups. The
> concentration of propionic acid in powdered diet was determined to be
> 4.4 +/-0.3% at feeding time, 3.5 +/-0.2% after six hr, and 2.9 +/-0.5%
> after 24 hr. After 12 weeks, rats fed a powdered diet containing
> 2.9-4.4%propionic acid displayed severe changes in the forestomach but
> not in the glandular stomach. Crater-like growths with marginal
> hyperplasia and central ulceration were found in the forestomach of
> all animals, particularly in the prefundic region proximate to the
> glandular stomach. Rats fed a powdered diet containing 2.9-4.4%
> propionic acid and 1% L-carnitine for 12 weeks displayed similar
> forestomach changes, suggesting that the addition of L-carnitine did
> not affect the occurrences of hyperplasia. No changes in the
> forestomach and glandular stomach were observed in animals fed the
> control powdered or a powdered diet containing 1% L-carnitine.

Remark: Results obtained from this study suggests that the type of diet

> used (pelleted vs. powdered) affects the incidence and severity of
> forestomach changes produced in response to feeding propionic acid in
> the diet.
>
> Reliability: score = 2, valid with restrictions: initial purity of
> test material not specified, study evaluated only forestomach effects
>
> Reference: Bueld, J.E. and Netter, K.J. 1993. Factors affecting the
> distribution of ingested propionic acid in the rat forestomach. Fd.
> Chem. Toxic. 31: 169-176.

\(e\) Species: rat

Strain: Wistar

> Sex: male

Route of Admin: oral (in ground feed)

Exposure Period: 20 weeks or lifetime

Freq. of Treatment: daily

Post Exposure

> Observation Period: none
>
> Doses: 0, 0.4, or 4%
>
> Control Group: yes
>
> NOEL:
>
> LOEL:
>
> Method: Groups of male Wistar rats received 0, 0.4% or 4.0% propionic
> acid mixed in ground rat feed. There were 30 rats in each group; the
> feeding regimen was initiated when rats were 3 weeks old. After 20
> weeks, 10 rats from each group were sacrificed. The remaining animals
> were maintained on their respective diets and observed until death.
> Animals sacrificed and dying on study were subject to necropsy. Organs
> (stomach, intestine, esophagus, liver, kidneys, spleen, heart, lungs,
> adrenals, pancreas, thyroid, and brain) were fixed in 5% formalin,
> then prepared for histopathological examination.
>
> Year: 1985

GLP: no data

> Test substance: n-propionic acid, purity not specified
>
> Remark:
>
> Results: No changes were grossly visible in the stomach of animals
> that received feed with 0.4% propionic acid and sacrificed at 20
> weeks; the limiting ridge, however, was slightly swollen in all
> animals. Hyperplasia and hyperkeratosis was observed histologically.
> Similar changes were observed among rats in this group that were
> sacrificed by 2 yr; there were no changes in the mucosa of the
> glandular stomach. Among rats fed a ground diet of rat feed containing
> 4% propionic acid and sacrificed at 20 weeks, 6 of 10 displayed
> elevations in the forestomach mucosa in the area of limiting ridge.
> Histological examination of these areas revealed marked squamous
> hyperplasia of the epidermis with incipient ulceration and hyperplasia
> of the mucosal papillae. Hyperkeratosis and hyperplasia were observed
> in the forestomach mucosa of the remaining animals. Animals that died
> on study or were sacrificed by 2 yr displayed hyperplasia with
> ulceration and/or dyskeratosis, and papillomatous elevations. One
> papilloma with unspecified "carcinomatous changes" was also observed.
> The limiting ridge exhibited extensive hyperplastic changes in all
> animals in the 4% group. Erosive changes were also detected in the
> glandular region of the stomach but were not corroborated
> histologically. Control animals did not exhibit any pathological
> changes of the stomach or forestomach mucosa.
>
> Reliability: score = 2, valid with restrictions: purity of test
> material not specified; concentration of test material in feed not
> verified, study evaluated only forestomach effects
>
> Reference: Griem, W. 1985. Tumorigenic effect of propionic acid on the
> forestomach mucosa in rats in feeding experiments.
> Bundesgesundheitsgblatt 28: 322-327.

\(f\) Species: rat

Strain: Fischer 344

> Sex: male

Route of Admin: oral (in powdered feed)

Exposure Period: 9, 15, 21, 27 days

Freq. of Treatment: daily

Post Exposure

> Observation Period: none
>
> Doses: 0 or 4% in diet
>
> Control Group: yes
>
> NOEL: NA
>
> LOEL: NA
>
> Method: Groups of seven male weanling F-344 rats were housed
> individually and fed a powdered diet containing 4% propionic acid for
> 9, 15, 21 or 27 days. Control rats received only the powdered diet.
> Animals were weighed daily and food consumption was determined daily.
> One hour before sacrifice, rats were injected i.p. with 0.25 uCi/g
> radiolabeled thymidine. Each rat was dissected; the stomach was
> removed and fixed in 10% buffered formalin. After fixation, the
> forestomach was opened, cleaned of contents, and sectioned. Slides
> were prepared for histopathology; 5 um sections were prepared for
> radioautography using Kodak NTB emulsion. Labeled squamous epithelial
> cells were counted in both the prefundic (1000 cells immediately
> adjacent to the fundic mucosa) and mid-region of the forestomach (2000
> to 4000 cells from the tissue immediately opposite the opening between
> the forestomach and glandular stomach). The radiolabelling index was
> determined at each time point for both treated and control rats. The
> ratio of treated to control was also determined for each group.
>
> Year: 1986

GLP: no

> Test substance: n-propionic acid, purity not specified.
>
> Remark: Rats fed a powdered diet containing 4% propionic acid did not
> display histopathological effects on the forestomach epithelium until
> feeding day 27. The authors suggest that the delayed proliferative
> effect observed may reflect an inflammatory reaction to changes in
> forestomach pH.
>
> Results: Weanling male F-344 rats were fed a powdered diet containing
> 4% propionic acid for up to 27 days. Rats were sacrificed and stomachs
> examined and prepared for autoradiography on feeding day 9, 15, 21 and
> 27. Gross and light microscopic examination revealed no changes to the
> forestomach mucosa among rats fed propionic acid for 9 days. In
> contrast, rats fed propionic acid for 27 days showed thickening of the
> mucosa with acanthosis, hyperkeratosis, prominent ret pegs and
> papillae formation along the lesser curvature of the forestomach.
> Changes in the epithelium were accompanied by submucosal edema and
> infiltration of eosinophils and lymphocytes. These changes appeared to
> be inflammatory reactions and were not associated with epithelial
> atypias. There was no increase in the radiolabelling index in the
> prefundic region of the stomach when compared to controls. In
> contrast, a two-fold increase in the radiolabeled thymidine index was
> observed in the main body of the forestomach epithelium in animals fed
> propionic acid for 21 and 27 days.
>
> Reliability: score = 2, valid with restrictions: purity of test
> material not specified; concentration of test material in feed not
> verified
>
> Reference: Rodrigues C., Lok, E., Iverson, F., Page, D. et al. 1986.
> Short term effects of various phenols and acids on the Fischer 344
> male rat forestomach epithelium. Toxicology 38, 103-117.

\(g\) Species: mouse

Strain: CD-1 (ICR) BR

> Sex: female

Route of Admin: dermal

Exposure Period: 101 days

Freq. of Treatment: once daily, 5 days per week

> Post Exposure
>
> Observation Period: none
>
> Doses: 6, 8, or 10% (first 3 weeks)
>
> 8, 10, or 14% (for remainder of study)
>
> Control Group: yes, solvent control from parallel study
>
> NOAEL:
>
> LOAEL: 8%
>
> Method: Groups of 10 CD-1 (ICR) BR female mice (49 days old, 25.2-30.2
> g) received 50 μl of unbuffered propionic acid dissolved in water.
> Doses of 6%, 8% or 10% were applied to the shaved skin of the
> interscapular area once per day, 5 days per week. Because of the
> absence of the expected strong dermal changes in the highest dose
> group (10%) and the absence of irritation effects in the low (6%) and
> mid dose group (8%), the dosage of the 6% group was increased to 14%
> after 3 weeks (16 applications).
>
> Animals were monitored daily for clinical signs; body weights were
> measured weekly. The skin of each animal was examined and palpated
> each week. At necropsy, the intrascalular skin was examined and
> submitted for histological evaluation.

Test substance: n-propionic acid, purity 99.7%

> Results: There was no mortality among treated mice:
>
> Clinical signs
>
> [6/14% treatment]{.underline}: skin alterations in 10/10; skin defects
> in 3/10; crust formation in 1/10, eschar formation in 5/10, erythema
> in 1/10.
>
> [10% treatment:]{.underline} skin alterations in 6/10 animals; skin
> defects in 1/10; crust formation in 2/10, eschar formation in 1/10,
> scale formation in 2/10.
>
> [8% treatment]{.underline}: no skin alterations in any of the animals.
>
> Histopathology
>
> [6/14% treatment]{.underline}: crust formation and/ or ulceration in
> 5/10, skin alterations in 4/10 (acanthosis, fibrous condensation of
> the stratum reticulare of the corium connective tissue).
>
> [10% treatment]{.underline}: crust formation in 2/10, skin alterations
> in 4/10 (acanthosis, fibrous condensation of the stratum reticulare of
> the corium connective tissue); no histological alterations in 4/10.
>
> [8% treatment]{.underline}: crust formation and/ or ulceration in
> 2/10, skin alterations in 3/10 (acanthosis, fibrous condensation of
> the stratum reticulare of the corium connective tissue); no
> histological alterations in 5/10.
>
> [Solvent control: no data submitted.]{.underline}
>
> [Conclusion]{.underline}: the non-irritating concentration for
> propionic acid in this study is less than 8%.
>
> Reliability: score = 2, valid with restriction, range-finding study,
> males not tested.
>
> Reference: BASF AG. 1990b. Study of the dermal effects of propionic
> acid after a 3-month epicutaneous application in female mice.
> Department of Toxicology, translation of the unpublished report No.
> 39C0473/85127, dated 19 Nov. 1990.

\(h\) Test substances: n-propionic acid, purity 99%

> n-butyic acid, purity 99%
>
> Remark: Butyric acid is the 4-carbon structural analogs of propionic
> acid.
>
> Species: rat, mouse, hamster

Strain: Sprague Dawley rat, C3B6F1 mouse, Syrian golden hamster

> Sex: male and female

Route of Admin: mixed into powdered feed

Exposure Period: 7 days

Freq. of Treatment: daily

Post Exposure

> Observation Period: none
>
> Doses: 0, and 4% (w/w, equivalent to 40 mg/g diet)

Control Group: yes

> NOEL: NA
>
> LOEL: 4%
>
> Method: Groups of male and female rats, mice, and hamsters
> (5/sex/group) were fed powdered rodent breeding diet (LAD-2) for
> several days and then assigned to treatment groups to receive 1)
> untreated or control diet or 2) diet containing 4% n-butyric acid or
> 3) diet containing 4% n-propionic acid. Food and water were available
> ad libitum. Animals were monitored throughout the study for changes in
> condition or behavior. After 7 days, animals were killed and a
> complete necropsy performed on each animal which included examination
> of cranial, thoracic and abdominal cavities. All gross abnormalities
> were recorded. The stomach of each animal was removed, opened along
> the greater curvature, the contents removed, and the tissue fixed in
> 10% buffered formalin. Microscopic examinations of slides for each
> species were performed in random order, one parameter at a time, and
> without knowledge of treatment.
>
> Year: 1991
>
> GLP: no data
>
> Test substance: n-butyic acid, purity 99%

n-propionic acid, purity 99%

> Results: No significant clinical signs were observed and there was no
> mortality among test animals. Diet containing propionic and butyric
> acid appeared to be somewhat unpalatable to animals of all three
> species, especially during the first few days of the study when the
> food had pungent odor. No gross abnormalities were noted in control
> animals. In rats treated with 4% propionic acid, stomach walls were
> thickened in several animals; the mucosal surface of the stomach was
> discoloured in several rats. Stomachs of hamsters receiving propionic
> acid were normal. Histopathological changes occurred in both treated
> groups, but were more frequent in animals fed butyric acid (see tables
> below). The authors suggest that even when statistical significance
> was not achieved, differences between control and treated animals
> should be considered biologically relevant.
>
> Incidence of Histopathological Changes in Rats Fed Propionic or
> Butyric Acid

[Forestomach Lesion Control Propionic Butyric]{.underline}

Generalized acanthosis 1/10\* 4/10 5/10\*\*

Basal cell hyperplasia 2/10 5/10 5/10

Increased mitotic figures 0/10 3/10 3/10

Edema of lamina propria 1/10 4/10 4/10

Epithelial vacuolation (slight) 7/10 3/10 3/10

Epithelial vacuolation (moderate) 1/10 5/10\*\* 5/10\*\*

Epithelial inflammatory infiltrate 1/10 1/10 3/10

[Ulceration with hyperplasia 0/10 0/10 4/10 .]{.underline}

\*animals displaying lesion/total animals treated and examined

\*\*significantly different from controls (P=\<0.05, chi-square test)

> Incidence of Histopathological Changes Rats Fed Propionic or Butyric
> Acid

[Limiting Ridge Lesion Control Propionic Butyric]{.underline}
Hyperkeratosis 3/9\* 3/8 2/6

Basal cell hyperplasia 5/9 5/8 4/6

Increased mitotic figures 0/9 2/8 1/6

Edema of lamina propria 2/9 1/8 3/6

Epithelial vacuolation (slight) 4/9 3/8 1/6

Epithelial vacuolation (moderate) 4/9 3/8 3/6

[Epithelial inflammatory infiltrate 4/9 4/8 5/6 .]{.underline}

\*animals displaying lesion/total animals examined

> Forestomach lesions in mice fed propionic acid included generalized
> acanthosis (6/10), basal cell hyperplasia (5/10), and epithelial
> vacuolation (7/10). Mice fed butyric acid had a higher incidence of
> acanthosis (10/10), basal cell hyperplasia (8/10), and increased
> mitotic figures (5/10). Hamsters fed propionic acid displayed an
> increase in nuclear vacuolation (3/8). Hamsters fed butyric acid
> increases in ancanthosis (8/10), basal cell hyperplasia (6/10),
> epithelial vacuolation (5/10), and submucosal edema 7/10).

Remark: The authors suggest that the data indicate that propionic and
butyric acids at 4% in a powdered diet can damage the forestomach
epithelium and induce proliferative responses after only 7 days. These
data tentatively support the hypothesis that tumors of the forestomach
could be induced by long-term feeding with propionic acid as a result
from repeated low-level damage and associated repair/proliferative
responses, and these acids may therefore constitute a non-genotoxic
carcinogenic effect.

> Comment: These results suggest that propionic acid and butyric acid,
> at a dose of 4% in powdered diet, are able to damage forestomach
> epithelium and induce a proliferative response after only 7 days.
>
> Reliability: score = 2, valid with restriction; concentrations of test
> materials in food not analyzed, only one doses tested, study evaluated
> only forestomach effects
>
> Reference: Harrison, P.T., Grasso, P. and Badescu, B. 1991. Early
> changes in the forestomach of rats, mice and hamsters exposed to
> dietary propionic and butyric acid. Fd. Chem. Toxic. 29: 367-371

\(i\) Test substances: n-propionic acid

n-butyric acid

n-pentanoic (valeric) acid

n-hexanoic (capronic) acid

> Remark: Butyric acid, pentanoic acid, and hexanoic acid are structural
> analogs of propionic acid.
>
> Species: rat

Strain: albino, mixed strain

> Sex: male and female

Route of Admin: mixed into rice diet

Exposure Period: up to 500 days

Freq. of Treatment: daily

Post Exposure

> Observation Period: none
>
> Doses: 0, and up to 10% of diet (v/w)

Control Group: yes

> NOEL: 10% in diet (hexanoic acid only)
>
> LOEL:
>
> Method: Short-chain aliphatic acids were fed to male and female albino
> rats (initial weight 50-80g) in a supplemented rice diet.
>
> [Butyric acid]{.underline}: a total of 120 male and female rats were
> initially exposed to 10 ml undiluted butyric acid mixed into 1 kg
> rice; the concentration of butyric acid was gradually increased to 100
> ml per kg rice. The rice diet was supplemented with dried beef liver,
> brewer's yeast and cod liver oil to avoid vitamin or nutritional
> deficiency. Rats were killed on day 50, 75, 100, 135, 150, 350, and
> the remainder (5 animals) on day 500. Stomachs of rats were removed
> and placed in a formalin fixative; after short fixation the stomachs
> were cut along the greater curature and examined for gross lesions.
> Those showing gross abnormalities were prepared for histological
> examination.
>
> [Propionic acid]{.underline}: a total of 5 rats were maintained on a
> rice diet to which 50 ml undiluted propionic acid was added to 1 kg
> rice. Rats were maintained on the rice diet supplemented with cod
> liver oil for 110 days, then sacrificed, and their stomachs removed
> and prepared as described above.
>
> [Valeric acid]{.underline}: a total of 10 rats were maintained on a
> rice diet to which 50 ml undiluted pentanoic (valeric) acid was added
> to 1 kg rice; the rice diet was supplemented with cod liver oil. One
> half the group was sacrificed after 115 days; the remainder were
> killed on day 150. Stomachs of rats were examined and prepared as
> described above for butyric acid.
>
> [Hexanoic (capric) acid]{.underline}: a total of 10 rats were
> maintained on rice diet to which 100 ml undiluted hexanoic acid was
> added to 1 kg rice; supplemented with cod liver oil. All rats were
> sacrificed on day 150 and their stomachs examined for gross lesions.
>
> Year: 1953
>
> GLP: no
>
> Test substance: propionic acid, purity not specified
>
> butyic acid, purity not specified
>
> pentanoic (valeric) acid, purity not specified
>
> hexanoic (capric) acid, purity not specified
>
> Results: Forestomach lesions were observed in rats which received
> propionic, butyric, and valeric acid in a rice diet; no lesions were
> noted in rats which received hexanoic acid. Four of 5 rats fed
> propionic acid in the diet survived until sacrifice on day 110; gross
> examination of the stomach revealed papillomatous lesions (polyps) in
> 3 animals. The majority of rats which received butyric acid in the
> diet for more than 50 days demonstrated forestomach lesions, including
> hyperkeratosis, hyperplasia, and papillomas. Papillomas with keratin
> cysts were also observed. Among rats fed valeric acid, 8 of 10
> displayed papillomas in the forestomach. Microscopic examination of
> forestomach lesions produced by aliphatic acids revealed extensive
> benign hyperplasia, hyperkeratosis of the squamous epithelium and
> development of numerous papilloma which occupied a large portion of
> the forestomach. Lesions were most severe in rats fed butyric acid,
> when compared to other acids fed for a comparable length of time. The
> glandular portion of the stomach remained normal, even in the presence
> of extensive damage in the forestomach.
>
> Remark: Rats were fed short-chain fatty acids (propionic, butyric,
>
> valeric, hexanoic) incorporated into the diet at concentrations up to
> 10% for periods of up to 500 days. All the acids induced forestomach
> changes including benign hyperplasia, hyperkeratosis, acanthosis, and
> polyps. No malignant changes were detected. In an earlier study (Mori,
> 1952), similar changes were observed in rats fed a rice diet with
> acetic acid.

Reliability: score = 4, not assignble, insufficient study details

> Reference: Mori, K. 1952. The production of gastric lesions in the rat
> by acetic acid feeding. Gann 43: 443-447. *and*
>
> Mori, K. 1953. The production of gastric lesions in the rat by the
> diet containing fatty acids. Gann 44: 421-426.

\(j\) Test substances: n-propionic acid

> Species: no information

Strain: no information

> Sex: no information

Route of Admin: inhalation

Exposure Period: no information

Freq. of Treatment: continuous

> Doses: 23, 100, 800, 2000, 5000 mg/m^3^

Control Group: no information

> NOEC: 0.26 mg/m^3^
>
> LOEL:
>
> Method: no information
>
> Year:
>
> GLP: no information
>
> Test substance: propionic acid, purity not stated
>
> Results: The lowest no effect concentration is 0.26 mg/m^3^. However,
> no effect concentrations determined by the reflex effect are lower
> than levels by the resorptive effect. The reflex effect threshold is
> 0.078 mg/m^3^ and an associated no effect concentration is 0.02
> mg/m^3^.
>
> Reliability: score = 4, not assignable; only limited information
> available in English Summary
>
> Reference: Tokanova, SE. 1982. Biological action and hygienic
> evaluation of prop... Gigiena I Sanitariia. 4: 10-3. April.

# **5.5 GENETIC TOXICITY IN VITRO**

# **A. BACTERIAL IN VITRO TEST**

> \(q\) Critical Study for SIDS Endpoint (score = 1)
>
> Test substance: n-propionic acid
>
> Type: Salmonella/microsome bacterial mutagenicity assay (Ames test)
>
> System of Testing: Salmonella typhimurium strains TA98, TA100, TA102,
> TA104, TA1535, TA1537, and TA1538
>
> Concentration: 0, 0.1, 0.33, 1.0, 3.3, 10 mg/plate

Metabolic Activation: with and without

> Result: with metabolic activation: negative

without metabolic activation: negative

> Propionic acid was not mutagenic when tested to a maximum
> concentration of 10 mg/plate, using the Salmonella typhimurium
> pre-incubation protocol. At least five doses were tested in
> triplicate, without metabolic activation, and with 10% and 30% liver
> S-9 from rat and hamster. Replicate testes were performed after the
> initial trial to confirm these results. Appropriate responses were
> obtained with negative and positive controls.
>
> Method: Propionic acid was tested as a coded chemical using the
> preincubation modification of the Salmonella/mammalian microsome
> mutagenicity assay using S. typhimurium tester strains TA97, TA98,
> TA100, TA102, TA104, TA1535, TA1537, and TA1538 in the presence and
> absence of Arochlor-induced liver S9 from Sprague Dawley rats and
> Syrian hamsters. Test concentrations of propionic acid (0, 100, 333,
> 1000, 3333, and 10,000 ug/plate) were prepared using distilled water
> as the solvent; a maximum of 0.5 ml solvent was added to each plate.
> Each dose was tested in triplicate without activation, and with 10%
> rat and hamster liver S-9. Concurrent positive and solvent controls
> were run with each trial. As a positive control, 2-aminoanthracene
> (2-AA) was tested on all strains in the presence of rat and hamster
> S-9. As positive controls in tests without S-9,
> 4-nitro-o-phenlenediamine was tested on TA98 and TA1538, sodium azide
> was tested on TA100 and TA1535, and 9-aminoacridine was tested on TA97
> and TA1537. The actual concentration for each positive control used
> for each strain was based on dose-response curves generated at the
> beginning of the study.
>
> After a negative result was obtained, propionic acid was retested
> without metabolic activation and with 30% S-9. Repeat experiments were
> performed at least one week following the initial trial. A material
> was considered mutagenic if it produced a reproducible, dose-related
> increase in revertants over the solvent control, under a single
> metabolic activation condition, in replicate trials. A material was
> considered questionable if the positive response was elicited at only
> one concentration, or if the response could not be reproduced. A
> chemical was designated as non-mutagenic only after it was tested
> without metabolic activation, and with 10% and 30% rat and hamster
> S-9.
>
> Year: 1992
>
> GLP: no data
>
> Test substance: n-propionic acid, purity 99+%
>
> Reliability: score = 1, valid without restriction; comparable to
> guideline study
>
> Reference: Zeiger, E, Anderson, B., Haworth, S., Lawlor, T. and
> Mortelmans, K. 1992. Salmonella mutagenicity tests: V. Results from
> the testing of 311 chemicals. Environ. Mol. Mutagen. 19 (Suppl. 21):
> 2-141.

\(b\) Test material: n-propionic acid

> Type: Salmonella/microsome bacterial mutagenicity assay (Ames test)
>
> System of Testing: Salmonella typhimurium strains TA98, TA100, TA1535,
> and TA1537
>
> Concentration: 0, 0.01, 0.03, 0.1, 0.3, 3.3, 10 ul/plate (equivalent
> to approximately 0, 0.01, 0.03, 0.1, 0.3, 3.3, 10 mg/plate)

Metabolic Activation: with and without

> Result: with metabolic activation: negative

without metabolic activation: negative

> Propionic acid was not genotoxic when tested in the
> Salmonella/mammalian microsome mutagenicity assay using tester strains
> TA 98, TA 100, TA 1535, and TA 1537. Seven concentrations of propionic
> acid were tested in the presence and absence of metabolic activation.
> There was no increase in revertants per plate at any dose level in any
> of the strains tested. A significant increase in revertants was
> observed in cultures concurrently exposed to positive controls
>
> Method: Propionic acid was tested using the standard plate
> incorporation method of the Salmonella/mammalian microsome
> mutagenicity assay using S. typhimurium tester strains TA98, TA100,
> TA1535, and TA1537. Assays were conducted in the presence and absence
> of Arochlor-induced liver S9 from male Wistar rats. Test
> concentrations of propionic acid (0, 0.01, 0.03, 0.1, 0.3, 3.3, and 10
> ul/plate) were prepared using distilled water as the solvent. Two
> independent experiments were performed; each dose was tested in
> triplicate without activation and with rat liver S-9. Concurrent
> positive and solvent controls were run with each trial. As a positive
> control, 2-aminoanthracene(1 ug/plate) was tested on all strains in
> the presence of rat S-9. As positive controls in tests without S-9,
> 2-nitrofluorene (1 ug/plate) was tested on TA98, sodium azide (1
> ug/plate) was tested on TA100 and TA1535, and 9-aminoacridine (10
> ug/plate) was tested on TA1537.
>
> Year: 1987
>
> GLP: no data
>
> Test substance: propionic acid, purity 99%
>
> Reliability: score = 2, valid with restriction; toxic dose not
> documented
>
> Reference: Basler A., von der Hude, W. and Scheutwinkel, M. 1987.
> Screening of food additive propionic acid for genotoxic properties.
> Fd. Chem. Toxic. 25: 287-290.

\(c\) Type: Salmonella/microsome bacterial mutagenicity assay (Ames
test)

> System of Testing: Salmonella typhimurium strains TA98, TA100, TA1535,
> TA1537, and TA1538
>
> Concentration: 0. 0.02375%, 0.04750%, 0.0950%

Metabolic Activation: with and without

> Result: with metabolic activation: negative

without metabolic activation: negative

> Method: Propionic acid was tested as a coded chemical using both the
> standard plate incorporation assay and the pre-incubation modification
> of the Salmonella/mammalian microsome mutagenicity assay using S.
> typhimurium tester strains TA98, TA100, TA1535, TA1537, and TA1538. In
> the plate tests, approximately 10E8 cells of a log phase culture were
> added to test tubes containing 2.0 ml of molten agar supplemented with
> biotin and trace histidine. For non-activation tests, three dose
> levels of propionic acid were added to appropriate tubes and poured
> over the surface of selective agar plates. In activation tests, 0.5 ml
> of a 9000 x g tissue supernatant and required cofactors was added to
> tubes, which were then mixed and the contents poured over the surface
> of minimal agar. Plates were incubated for 48-72 hours at 37 degrees C
> and then scored. In the pre-incubation modification of the assay,
> tests were conducted in 24-well tissue culture plates. Log phase
> bacteria were grown in complete media, then washed and resuspended in
> 0.9% saline to a density of 1 x 10E10 cells/ml. Cells plus appropriate
> volumes of the test chemical were added to each well to give a final
> volume of 1.5 ml. Cells were treated at 37 degrees C for 1 hr. After
> treatment, plates were set on ice; aliquots of cells were removed,
> diluted in saline, and plated on minimal selective medium. Plates were
> scored after incubation for 48 hr at 37 degrees C. Tests were
> performed in duplicate, in the presence and absence of metabolic
> activation. Metabolic activation was provided by S-9 preparations from
> liver, lung, and testes derived from male ICR mice, male Sprague
> Dawley rats, and male rhesus (M. mulatta) monkeys. Test concentrations
> of propionic acid (0, 0.0950%, 0.04750%, and 0.02375%) were prepared
> using 0.067 M phosphate buffer, pH 7.4 as the solvent. Concurrent
> positive and solvent controls were run with each trial. In tests
> conducted in the absence of metabolic activation (S-9), the positive
> control was methylnitrosoguanidine (2 ug/plate) for TA 100 and TA1535;
> Quinacrine mustard (20 ug/plate) for TA1537; 2-nitrofluorene (100
> ug/plate) for TA 98 and TA 1538. For tests conducted in the presence
> of S-9, positive controls (all at 100 ug/plate) were 2-aminoanthracene
> for TA100 and TA1535; 2-acetylaminofluorene for TA98 and TA1538; and
> 8-aminoquinoline for TA1537.,
>
> Year: 1976
>
> GLP: no
>
> Test substance: propionic acid, provided as a coded chemical by U.S.
> Food and Drug Administration (FDA 75-62)
>
> Remark: There was no evidence of mutagenic activity when propionic
> acid was tested in multiple tester strains of S. typhimurium in the
> Salmonella/mammalian microsome mutagenicity assay. Tests were
> performed in the presence and absence of metabolic activation from the
> lung, liver and testes from mice, rats and monkeys. Appropriate
> responses were obtained with negative and positive controls.
>
> Reliability: score = 2, valid with restriction: purity of test
> material not specified
>
> Reference: Litton Bionetics, Inc. 1976. Mutagenic Evaluation of
> Compound FDA 75-62, Propionic Acid, FCC. NTIS PB-266897, 29 p.

[]{.mark}

\(d\) Test material n-propionic acid

> Type: error prone DNA repair (SOS repair) in bacteria
>
> System of Testing: SOS-Chromotest with *E. coli* PQ37
>
> Concentration: 0, 0.3, 1.0, 3.3, 10. 33.3 mM (equivalent to 0, 22.2,
> 74.1, 222.3, 741, and 2223 ug/ml)

Metabolic Activation: with and without

> Result: The SOS chromotest was conducted on bacterial strain E. coli
> PQ37; five concentrations of propionic acid were tested, both in the
> presence and absence of S-9 from male Wistar rats and male Syrian
> hamsters. Alkaline phosphatase activity, as an indicator of toxicity,
> decreased with increasing concentrations of propionic acid. There was
> a slight increase in the SOS induction factor; however, there was no
> corresponding increase in alkaline phosphatase activity. Propionic
> acid was therefore considered to have elicited a negative response.
>
> Method: The SOS chromotest was performed using the bacterial strain E.
> coli PQ37. The test was conducted in two series of tubes containing 10
> ul of the test substance and 250 ul bacterial suspension. Cells and
> test substance were incubated in the presence and absence of S9
> prepared from Arochlor 1254 pretreated male Wistar rats and male
> Syrian hamsters. Propionic acid was tested at 0, 0.3, 1.0, 3.3, 10,
> and 33.3 mM (equivalent to 0, 22.2, 74.1, 222.3, 741, and 2223 ug/ml).
> After an incubation interval of 2 hr, beta-galactosidase and alkaline
> phosphatase levels were measured using colorimetric assays. The SOS
> induction factor represents the ratio of the optical density of
> beta-galactosidase to alkaline phosphatase. A ratio of 1.0 was
> assigned to the solvent control. A result is considered positive if
> the SOS induction factor exceeds the solvent control by 0.5 and there
> is an increase in beta-galactosidase activity. All results were
> validated in independent assays; 4-nitroquinoline-N-oxide (1uM) and
> benzo\[a\]pyrene (30uM) were included as positive controls.
>
> Year: 1988
>
> GLP: no data
>
> Test substance: n-propionic acid, purity 99%
>
> Reliability: score = 2, valid with restriction, toxic dose not
> documented
>
> Reference: von der Hude, W., Behm, C., Gurtler, R. and Basler, A.
> 1988. Evaluation of the SOS chromotest. Mutat. Res. 203: 81-94.

\(e\) Test material: n-propionic acid

> Type: DNA damage and repair assay in bacteria
>
> System of Testing: *E. coli* WP2, WP67(uvrA-,polA-),
> CM871(uvrA-,recA-,lexA-)
>
> Concentration: 0, 1.0, 5.0, 25 ul/plate (equivalent to approximately
> 0, 1.0, 5.0, and 25 ug/plate)

Metabolic Activation: without

> Result: positive, no dose response
>
> Propionic acid was tested in the absence of metabolic activation, in a
> bacterial DNA repair assay conducted on the repair-deficient and
> repair competent strains of the bacteria E. coli. There was a non-dose
> related increase in lethality in repair-deficient strains. Propionic
> acid was therefore considered to have elicited a positive response.
>
> Method: The bacterial DNA repair test was performed using E. coli
> bacterial strains WP2, WP67 uvrA-, polA-, and CM871 uvrA-, recA- and
> lexA-. Each tester strain was streaked crosswise onto L-medium agar
> plates and the test compound was spotted on a 10 mm sterile filter
> disc in the middle of the cross. Four plates were used for each dose.
> Propionic acid was tested at 0, 1.0, 5.0, and 25 ul per 10 mm sterile
> filter disc. Water (25 ul/disc) was used as the negative/solvent
> control. Methyl methansulphoneate (2.5 and 5.0 ug/ml) and ethyl
> methanesulphonate (5.0 ug/ml) were used as positive controls.The areas
> of bacterial death were measured after a 24-hr incubation at 37 degree
> C. Differences in growth inhibition or lethality were measured in
> millimeters and reported as the ratio between repair-competent and
> repair-deficient strains of E. coli (pol+/polA-and rec+/rec-).
>
> Year: 1987
>
> GLP: no data
>
> Test substance: propionic acid, purity 99%
>
> Remark: The authors tested n-propionic acid in four *in vitro*
> genotoxicity assays (bacterial DNA repair with E.coli, SOS chromotest
> with E. coli PQ37, bacterial point mutation or Ames test, SCE test in
> V79 cells) as well as an *in vivo* micronucleus test in Chinese
> hamsters. All tests, except the bacterial DNA repair test with E.
> coli, yielded negative results. The authors suggest that propionic
> acid is not mutagenic; they conclude that genotoxic events are
> unlikely to be involved in the genesis of preneoplastic lesions
> observed in the forestomach of rats fed propionic acid in the diet.
>
> Reliability: score = 2, valid with restriction; metabolic activation
> not utilized
>
> Reference: Basler A., von der Hude, W. and Scheutwinkel, M. 1987.
> Screening of food additive propionic acid for genotoxic properties.
> Fd. Chem. Toxic. 25: 287-290.

# **B. NON‑BACTERIAL IN VITRO TEST**

(a) Preferred value and Critical Study for SIDS Endpoint (score = 2)

Test substance: n-propionic acid

> Type: Cytogenetic assay
>
> System of Testing: Sister chromatid exchange (SCE) assay in Chinese
> hamster lung fibroblast (V79) cell culture
>
> Concentration: 0, 0.3, 1.0, 3.3, 10. 33.3 mM (equivalent to 0, 22.2,
> 74.1, 222.3, 740, 2223 ug/ml, respectively)

Metabolic Activation: with and without

> Result: without metabolic activation: negative
>
> with metabolic activation: negative
>
> n-Propionic acid was not genotoxic when tested in the *in vitro* SCE
> test in V79 cells in the presence and absence of metabolic activation.
> There was no increase in the incidence of sister chromatid exchanges
> at any concentration tested, including the highest concentration, 33
> mM or 2.2 mg/ml. The positive controls elicited a significant increase
> in SCEs.
>
> Method: Chinese hamster lung fibroblast cells (V79) were plated at
> density of 5 x 10E5 cells per flask. After 18 hr, cells were exposed
> to test concentrations of propionic acid in fresh medium supplemented
> with 10% fetal calf serum and BrdU (5-bromodeoxyuridine, 10E-5 M). DCP
> (1.3-dichloropropanol) was used as the positive control. After a 24 hr
> exposure interval, colcemid (0.1 ug/ml) was added and cultures were
> incubated for an additional 4 hr. Mitotic cells were then shaken off,
> fixed onto slides, and stained. In tests with metabolic activation,
> cells were incubated with test concentrations of propionic acid and
> 0.5 ml S-9 mix derived from Arochlor 1254-induced male Wistar rats.
> NDMA (nitrosodimethyl amine, 33mM) was used as a positive control.
> After three hr, the cells were washed and incubated for 24 hr in fresh
> medium containing BrdU. Colcemid was then added, and the cells were
> incubated for an additional 4 hr. Cells were collected, fixed onto
> slides, and stained. Propionic acid was tested at 0.1, 0.3, 1.0, 3.3,
> 10.0, and 33 mM; test solutions were prepared using distilled water as
> the solvent and the negative control. A minimum of 25 metaphase
> spreads was scored at each dose level
>
> Year: 1987
>
> GLP: no data
>
> Test substance: propionic acid, purity 99%
>
> Remark: The authors tested propionic acid in four *in vitro*
> genotoxicity assays (bacterial DNA repair with E.coli, SOS chromotest
> with E. coli PQ31, bacterial point mutation or Ames test, SCE test in
> V79 cells) as well as an in vivo micronucleus test in Chinese
> hamsters. All tests (except the bacterial DNA repair test with E.
> coli) yielded negative results. The authors suggest that propionic
> acid is not mutagenic; they conclude that genotoxic events are
> unlikely to be involved in the genesis of preneoplastic lesions
> observed in the forestomach of rats fed propionic acid in the diet.
>
> Reliability: score = 2, valid with restriction; limited number of
> metaphase spreads evaluated at each dose level
>
> Reference: Basler A., von der Hude, W. and Scheutwinkel, M. 1987.
> Screening of food additive propionic acid for genotoxic properties.
> Fd. Chem. Toxic. 25: 287-290.

\(b\) Test substance: n-propionic acid

> Type: Yeast gene mutation assay
>
> System of Testing: Saccharomyces cerevisiae, strain D4
>
> Concentration: 0, 0.625%, 1.25%, 2.5% (equivalent to approximately 625
> mg/ml, 1250 mg/ml and 2500 mg/ml)

Metabolic Activation: with and without

> Result: without metabolic activation: negative
>
> with metabolic activation: negative
>
> There was no evidence of mutagenic activity when propionic acid was
> tested in S. cerevisiae tester strain D4, both in the absence and
> presence of metabolic activation. Suspension tests performed in the
> presence of metabolic activation utilized tissue homogenates and S-9
> fractions from lung, liver and testes from mice, rats and monkeys.
>
> Method: Propionic acid was tested as a coded chemical using
> Saccharomyces cerevisiae strain D4. Stationary phase yeast cultures
> were grown in complete broth, washed and resuspended in saline to
> densities of 5 x 10E9 cells/ml. Tests were conducted in 24-well tissue
> culture plates. Cells plus appropriate volume(s) of propionic acid
> were added to each well to give a final volume of 1.5 ml. Solvent
> replaced the test compound in solvent control cultures. Yeast cells
> were treated at 30 degrees C for 4 hr; plates were shaken during
> treatment. In tests that included activation, measured amounts of test
> and control chemicals plus 0.25 ml of the stock cell suspension were
> added to each S-9 fraction. Plates were incubated at 37 degrees C for
> 4 hr; plates were shaken during treatment. After treatment flasks were
> placed on ice; aliquots of cells were removed, diluted 1:10 with
> saline and plated on selected media for enumeration of gene conversion
> (Ade+ and Try+). Plates were incubated at 30 degrees C for 3-5 days
> before scoring. Tests were performed in duplicate, in the presence and
> absence of metabolic activation. Metabolic activation was provided by
> tissue homogenates and S-9 fractions from the testes, liver and lung
> were prepared from male ICR mice, male Sprague Dawley rats, and male
> rhesus (M. mulatta) monkeys. Test concentrations of propionic acid (0,
> 0.625%, 1.25%, and 2.5%) were prepared using 0.067 M phosphate buffer,
> pH 7.4, as the solvent. Concurrent positive and solvent controls were
> run with each trial.
>
> Year: 1976
>
> GLP: no
>
> Test substance: n-propionic acid provided as coded chemical by U.S.
> Food and Drug Administration (FDA 75-62)
>
> Reliability: score = 2, valid with restriction; purity of test
> substance not specified.
>
> Reference: Litton Bionetics, Inc. 1976. Mutagenic Evaluation of
> Compound FDA 75-62, Propionic Acid, FCC. NTIS PB-266897, 29 p.

# **5.6 GENETIC TOXICITY IN VIVO**

> \(a\) preferred result and Critical Study for SIDS Endpoint;
> reliability score = 2

Test substance: n-propionic acid

Type: Cytogenetic assay

System of Testing: In Vivo Mouse Micronucleus Assay

Test species/strain: hamster/Chinese (male and female)

Concentration: 0, 124 mg/kg

> Test method: Three groups of 8-12 wk old Chinese hamsters were dosed
> with a solution 2.5% propionic acid in normal saline administered by
> intraperitoneal injection as a saline solution. The volume
> administered was 5 ml/kg body weight (determined to be the maximum
> tolerated dose and equivalent to 124 mg/kg body weight). There were
> six males and six females in each group. Additional groups of hamsters
> received the vehicle (saline, 5 ml/kg) or the positive control
> (cyclophosphamide, 80 mg/kg). Hamsters treated with the positive and
> negative control were killed 24 hr after treatment. Among animals
> treated with propionic acid, five males and five females were
> sacrificed at 12, 24, or 48 hr after dose administration. Immediately
> after sacrifice the bone marrow from each animal was collected and
> spread onto slides. Slides were fixed, stained and coded. A total of
> 5000 polychromatic erythrocytes (PCEs) were scored for the presence of
> micronuclei. The incidence of micronucleated PCEs per 100 PCEs was
> determined for each treatment group. A response was considered
> positive if a statistically significant (p\</= 0.05) increase in
> micronucleated PCEs was observed in one or more doses relative to
> vehicle control values at any sampling time. The test article was
> considered negative if there was no statistically significant increase
> in micronucleated PCEs above the concurrent control at any sampling
> interval.

GLP no data

Test substance: n-propionic acid, purity 99%

> Test results: Propionic acid was not genotoxic when was tested in vivo
> in a Chinese hamster micronucleus assay at a maximum tolerated dose of
> doses 124 mg/kg (5 ml/kg of a 2.5% propionic acid solution in normal
> saline). Four hamsters died within a few hours of injection. Ten
> hamsters (5 male and 5 female) were sacrificed at 12, 24, and 48 hr
> after treatment. A total of 5000 PCEs were scored for each sacrifice
> interval. The number of micronucleated polychromatic erythrocytes
> (PCEs) per 100 PCEs in propionic acid-treated groups was not
> significantly increased relative to vehicle controls in either male or
> female hamsters, regardless of collection time. The positive control,
> cyclophosphamide, induced a significant increase in micronucleated
> PCEs relative to the vehicle control in both male and female hamsters.

Lowest dose

producing toxicity: 124 mg/kg by intraperitoneal injection

Effect on Mitotic Index

or P/N Ratio: None

Genotoxic effects: negative

> Comments: The authors tested propionic acid in four in vitro
> genotoxicity assays (bacterial DNA repair with E.coli, SOS chromotest
> with E. coli PQ31, bacterial point mutation or Ames test, SCE test in
> V79 cells) as well as a micronucleus test in Chinese hamsters. All
> tests, except the bacterial DNA repair test with E. coli yielded
> negative results. The authors suggest that propionic acid is not
> mutagenic; they conclude that genotoxic events are unlikely to be
> involved in the genesis of preneoplastic lesions observed in the
> forestomach of rats fed propionic acid in the diet. (See also USEPA
> report: Mavournin, K.H. et al. 1990. The in vivo micronucleus assay in
> mammalian bone marrow and peripheral blood. A report of the US
> Environmental Protection Agency Gene-Tox Program. Mutat. Res. 239:
> 29-80.).
>
> Reliability: score = 2, valid with restriction; single dose level
> tested
>
> Reference: Basler A., von der Hude, W. and Scheutwinkel, M. 1987.
> Screening of food additive propionic acid for genotoxic properties.
> Fd. Chem. Toxic. 25: 287-290.

# **5.7 CARCINOGENICITY**

\(a\) Critical Study for SIDS Endpoint

> Test material: n-propionic acid
>
> Species: rat

Strain: Wistar

> Sex: male

Route of Admin: oral (feed)

Exposure Period: 20 weeks or lifetime

Freq. of Treatment: daily

Post Exposure

> Observation Period: none
>
> Doses: 0, 0.4, or 4%
>
> Control Group: yes
>
> NOEL:
>
> LOEL:
>
> Method: Groups of male Wistar rats received 0, 0.4% or 4.0% propionic
> acid mixed in ground rat feed. There were 30 rats in each group; the
> feeding regimen was initiated when rats were 3 weeks old. After 20
> weeks, 10 rats from each group were sacrificed. The remaining animals
> were maintained on their respective diets and observed until death.
> Animals sacrificed and dying on study were subject to necropsy. Organs
> (stomach, intestine, esophagus, liver, kidneys, spleen, heart, lungs,
> adrenals, pancreas, thyroid, and brain) were fixed in 5% formalin,
> then prepared for histopathological examination.
>
> Remark: Food consumption for individual animals was not measured,
> however, approximate average consumption for animals fed 0.4 and 4.0%
> propionic acid was estimated at 270 and 2700 mg/kg bw/day.
>
> Year: 1985

GLP: no data

> Test substance: n-propionic acid, purity not specified.
>
> Results: No changes were grossly visible in the stomach of animals
> that received feed with 0.4% propionic acid and sacrificed at 20
> weeks; the limiting ridge, however, was slightly swollen in all
> animals. Hyperplasia and hyperkeratosis was observed histologically.
> Similar changes were observed among moribund rats in this group that
> were sacrificed by 2 yr; however there were no changes in the mucosa
> of the glandular stomach.
>
> Among rats fed a ground diet of rat feed containing 4% propionic acid
> and sacrificed at 20 weeks, 6 of 10 displayed elevations in the
> forestomach mucosa in the area of limiting ridge. Histological
> examination of these areas revealed marked squamous hyperplasia of the
> epidermis with incipient ulceration and hyperplasia of the mucosal
> papillae. Hyperkeratosis and hyperplasia were observed in the
> forestomach mucosa of the remaining animals. Animals that died on
> study or were sacrificed by 2 yr displayed hyperplasia with ulceration
> and/or dyskeratosis, and papillomatous elevations. One papilloma with
> carcinomatous changes was also observed. The limiting ridge exhibited
> extensive hyperplastic changes in all animals in the 4% group. Erosive
> changes were also detected in the glandular region of the stomach.
> Control animals did not exhibit any pathological changes of the
> stomach or forestomach mucosa.
>
> Remark: Animals fed 4% propionic acid in a ground (non-pelleted) diet
> for their lifetime exhibited pre-neoplastic changes in the
> forestomach. It has been suggested that these effects are caused by
> the acidity and irritancy of the acid which produce persistent and
> prolonged cell damage and subsequent reparative proliferation
> (Harrison, P.T.C., 1992. Propionic acid and the phenomenon of rodent
> forestomach tumorigenesis: A review. Fd. Chem. Toxicol. 30: 333-340).
>
> Reliability: score = 2, valid with restriction; test substance
> concentration in feed not verified, only forestomach effects were
> evaluated, results of histologic evaluation of other organs not
> reported.
>
> Reference: Griem, W. 1985. Tumorigenic effect of propionic acid on the
> forestomach mucosa in rats in feeding experiments.
> Bundesgesundheitsgblatt 28: 322-327.

# **5.8 TOXICITY TO REPRODUCTION**

\(a\) Critical Study for SIDS Endpoint

> Test material: n-propionic acid
>
> Species: dog

Strain: Beagle

> Sex: male and female

Route of Admin: oral (in feed)

Exposure Period: 3 months (90 days)

Freq. of Treatment: daily

Post Exposure

> Observation Period: 6 weeks
>
> Doses: 0, 3000, 10,000 or 30,000 ppm in diet
>
> Control Group: yes
>
> NOAEL: 10,000 ppm (1.0% in diet)
>
> LOAEL: 30,000 ppm (3 % in diet)
>
> Method: Laboratory bred Beagle dogs (male and female, 4-8 months old)
> were house singly in separate indoor kennels (floor area 1.5 m^2^)
> with constant access to an outdoor kennel (floor area 4.5 m^2^) during
> both adaptation and administration intervals. Body weights were
> determined weekly and food consumption was measured daily beginning 7
> days prior to initiation of the study. Dogs were offered a daily food
> ration of 700 g; this ration consisted of 350 g pulverized food
> pellets mixed into a paste in each individual food dish by the
> addition of 350 g water (controls), or 350 g of the appropriate
> propionic acid aqueous solution.
>
> Groups of Beagle dogs were assigned to 4 different test groups and fed
> a diet containing 0, 0.3, 1.0, or 3.0% n-propionic acid. Groups of 16
> dogs (8 males and 8 females) received the control or the high dose (3%
> propionic acid) diet, while groups of 8 dogs (4 males and 4 females)
> received 0.3% and 1.0% propionic acid in the diet. Dogs received the
> test diet for approximately 3 months (106 days for males, 99 days for
> females) when they were sacrificed and subject to necropsy. Four males
> and four females from the control and high dose (3% propionic acid)
> were assigned to the recovery groups and fed the control diet for 6
> weeks.
>
> Purity and stability of the test material were analyzed at the start
> of the study, after 10 weeks, and at the end of the administration and
> recovery intervals. The concentration of the test material for each
> test concentration was analyzed in duplicate at the start of the
> study, after about 6 weeks, and at the end of the administration
> interval. The stability of the test material in the food was evaluated
> prior to initiation of the study.
>
> During the administration interval, dogs were offered food once per
> day in late morning; left over diet was removed the following day and
> the amount subtracted from the initial amount. During the recovery
> interval, dogs were offered food once per day mid-day for a period of
> two hours; left-over food was removed and weighed.
>
> All dogs were weighed once per week before eating. Animals were
> observed daily and examined at least once per day for clinical signs
> of toxicity. Before initiation and at the end of the administration
> interval of the study, an ophthalmological examinations were conducted
> on control and high (3% propionic acid) animals. Samples were
> collected for hematological, urinalysis, and clinical chemistry
> evaluations prior to initiation and then again during the
> administration and recovery intervals.
>
> All animals were sacrificed under anesthesia by exsanguinations from
> the cervical and brachial vessels. Animals were necropsied and all
> gross lesions recorded. The following organs were removed and weighed:
> liver, kidneys, adrenal glands, thyroid (including parathyroid)
> glands, testes and ovaries. All major organs and tissues, as well as
> the sternum with marrow, mesenteric and axillary lymph nodes, salivary
> glands, and peripheral nerve (ischiadicus) were prepared for
> histological examination.
>
> [Statistical evaluation]{.underline}: The statistical evaluation of
> variables included calculation of mean and standard deviations.
> Comparison of change was carried out using a Kruskal & Wallis test or
> a Mann-Whitney U test for the comparison of several dose groups with a
> control group. The minimum level of significance was determined to be
> p [\<]{.underline} 0.05.
>
> The Kruskal-Wallis one-way analysis of variance by ranks. *in*:
> Siegel, S. 1956. Nonparametric Statistics for the Behavior Sciences.
> London: McGraw Hill Book Company. P. 184-194.
>
> The Mann-Whitney U Test. *in*: Siegel, S. 1956. Nonparametric
> Statistics for the Behavior Sciences. London: McGraw Hill Book
> Company. P. 116-127.
>
> Results: Based on food consumption, the mean daily dose administered
> to high dose (3% propionic acid in diet) males ranged between 2491
> mg/kg bw at the start of the study, to 1848 mg/kg bw at the end of the
> administration interval. For high dose females, the mean daily dose
> ranged between 2209 and 1832 mg/kg bw at the start and end of the
> study, respectively. The mean daily dose administered to mid-dose (1%
> propionic acid in diet) males ranged from 835 to 660 mg/kg bw;
> mid-dose females received mean daily doses between 844 and 696 mg/kg
> bw. The mean daily dose for low-dose males was between 249 and 196
> mg/kg; for females 252 and 210 mg/kg bw.
>
> There were no deaths and during the administration and recovery
> intervals, dogs did not display any clinical signs of toxicity. Four
> females in the high dose group displayed a marked and prolonged lack
> of appetite, while an additional 2 females and 4 males in the high
> dose group displayed a slight reduction in appetite. This decrease in
> food consumption was attributed to the presence of the test material.
> The decrease in food consumption did not significantly affect body
> weight gain. There were no differences in body weights or body weight
> gains between groups during the 3-month administration interval and
> the 6-week recovery interval.
>
> There were no significant changes in hematology or urinalysis
> parameters. An approximately 30% decrease in alkaline phosphatase
> activity in high dose dogs was determined to be an artifact caused by
> interference with the detection method produced by the propionyl
> Coenzyme A, a metabolite of propionic acid.
>
> Necropsy of dogs at the end of the administration interval revealed no
> gross lesions. There were no significant changes in the relative or
> absolute weight of the testes or ovaries in test group animals
> relative to controls, and there were no histologic changes in the male
> or female reproductive organs in animals fed propionic acid in the
> diet for 90 days.

Reliability: score = 1, valid without restriction; GLP study

> Reference: BASF. 1988. Study of the toxicity of propionic acid in
> Beagle dogs. Administration in the diet over 3 months and a 6-week
> recovery period. Project No. 31D0473/8590. Study conducted by the
> Department of Toxicology of BASF Aktiengesellschaft, 6700
> Ludwigshafen/Rhein, FRG. Report dated July 8, 1988.

\(b\) Critical Study for SIDS Endpoint

> Species: rat

Strain: Sprague-Dawley

> Sex: male and female

Route of Admin: oral (in feed)

Exposure Period: 3 months (91 days)

Freq. of Treatment: daily

Post Exposure

> Observation Period: 6 weeks (42 days)
>
> Doses: 0, 6200, 12500, 25000, and 50000 ppm in diet (equivalent to 0,
> 0.62, 1.25, 2.5, and 5%)
>
> Control Group: yes
>
> NOAEL: 6200 ppm (0.62% in diet)
>
> LOAEL: 12500 ppm 1.25 % in diet)
>
> Method: Groups of male(135-136 g) and female (128-129 g) Sprague
>
> Dawley rats were offered a daily food ration containing 0, 6200,
> 12500, 25000, or 50000 ppm propionic acid (0, 0.62, 1.25, 2.5, and
> 5%). The method of food preparation is not described, and it is not
> clear if the concentration of the test material in the food was
> measured. Each group consisted of 20 animals per sex per dose and an
> additional 10 post-exposure animals were included in the control,
> 0.62, and 5% groups. Rats received the test diet for approximately 3
> months (91 days) when they were sacrificed and subject to necropsy.
> Ten rats from the control, low dose (0.62%), and high dose (5%
> propionic acid) were assigned to the post-exposure recovery groups and
> fed the control diet for 6 weeks.
>
> Clinical observations and food consumption were monitored daily. Rats
> were weighed weekly. Hematological examinations were performed with 10
> animals per dose per sex on day 19-21 and day 75-78. Urinalysis was
> performed on day 14-17 and day 70-73. At the end of the study, weights
> of liver, kidneys and heart were determined. Organs examined at
> necropsy (macroscopic and histological) included tissues from the CNS,
> heart, lung, thyroid, liver, kidneys, adrenals, spleen, pancreas,
> stomach, intestine, urinary bladder, testes/ovaries and intestine
> lymph nodes.

Test substance: n-propionic acid, technical grade (purity not specified)

> Results: There was no mortality among control or treated rats:
>
> [Body weight]{.underline}: Males showed a dose-dependent reduced
> weight gain with a clear reduction in the 5% treatment after day 7-14,
> resulting in a reduced body weight at the end of the study by 6%,
> whereas the body weight/ body weight gain in females was not affected
> or slightly decreased. Animals of all treatments showed comparable
> body weight gain in the post exposure period; however, the differences
> in body weights remained.
>
> [Food consumption]{.underline}: comparable to the control, but
> slightly reduced in males of the 5% treatment. Animals of all
> treatments showed comparable food consumption in the post exposure
> period. Although food consumption was monitored, the mean dose
> received (mg/kg bw) for each group is not available.
>
> [Clinical signs]{.underline}: no clinical signs in any animal of the
> treatment groups.
>
> [Hematological findings]{.underline}: no differences to the control in
> any treatment.
>
> [Clinical biochemistry findings]{.underline}: no differences beyond
> physiological variations between the control and any treatment.
>
> Necropsy of rats at the end of the administration interval revealed no
> gross lesions. There were no significant changes in the relative or
> absolute weight of the testes or ovaries in test group animals
> relative to controls, and there were no histologic changes in the male
> or female reproductive organs in animals fed propionic acid in the
> diet for 90 days.
>
> Reliability: score = 2, valid with restrictiond; purity of test
> material and method of diet preparation not specified.
>
> Reference: BASF AG. 1971. 90-day feeding study on rts with propionic
> acid. Department of Toxicology, translation of the unpublished report
> No. XX/200, dated 30 July 1971.

# **5.9 DEVELOPMENTAL TOXICITY/TERATOGENICITY**

> \(a\) Critical Study for SIDS Endpoint
>
> Test substance: calcium propionate
>
> Remark: calcium propionate is the calcium salt of propionic acid
>
> Species: mouse
>
> Sex: females dosed
>
> Strain: CD-1
>
> Route of admin.: oral gavage
>
> Exposure period: gestation days 6-15
>
> Frequency of
>
> treatment: daily during exposure period
>
> Duration of test: On day 17, dams subject to Cesarean section
>
> Doses: 0, 3, 14, 65, 300 mg/kg bw
>
> Control Group: negative (sham) control and aspirin (150 mg/kg bw) used
> as positive control
>
> NOAEL Maternal.: 300 mg/kg bw
>
> NOAEL Devel: 300 mg/kg bw
>
> Method: other
>
> Year: 1972
>
> GLP: no
>
> Method: Virgin young female CD-1 mice were housed individually and
> mated with young adult males. The presence of a vaginal plug was used
> to indicate day 0 of gestation (GD 0). Beginning on day 6 and
> continuing through day 15 of gestation, groups of mated females
> received the the test material by oral intubation. The test material
> was provided by the U.S. Food and Drug Administration (FDA) as a coded
> test material (FDA 71-36)
>
> . The number of females mated and pregnant were as follows:
>
> Mated Pregnant
>
> Negative control 30 21
>
> Positive control 28 20
>
> 3.0 mg/kg-bw/day 26 21
>
> 14.0 mg/kg-bw/day 25 20
>
> 65 mg/kg-bw/day 30 20
>
> 300 mg/kg-bw/day 29 21
>
> Females were given free access to food and water.
>
> Body weights of dams were taken on Days 0, 6, 11, 15, and 17 of
> gestation. Dams were observed each day for food and water intake and
> other measures of appearance and behavior. On Day 17, Cesearean
> section was performed on all dams. The urogenital tract was examined
> in detail for anatomical normality.
>
> Numbers of implantation sites, resorption sties, and live and dead
> fetuses were recorded. Body weights of live pups were also recorded.
>
> All pups were examined grossly for external congenital abnormalities.
> One-third of fetuses of each litter underwent detailed visceral
> examinations; the remaining two-thirds were stained and examined for
> skeletal defects.
>
> [Statistical analyses]{.underline}: No statistical analysis was
> performed on the results obtained from this test material, which was
> the 15^th^ in a series of at least 42 compounds to be tested under the
> auspices of the U.S. Food and Drug Administration. Because of the
> inherent variability of biological data, statistical analysis was
> deferred until data for all test compounds were collected and when the
> pooling of sequential sets of control values would greatly enhance the
> statistical power of the findings. A subsequent review of the data
> (FASEB, 1979) states that calcium propionate did not exert a
> significant effect, and the number of abnormalities observed in fetal
> and skeletal tissue did not differ from the number occurring in the
> sham-treated controls. The method of statistical analysis employed was
> not described in FASEB report.
>
> Result: No clearly discernible effect on nidation or maternal or fetal
> survival was seen. The numberof abnormalities in the treated groups
> did not differ from the sham control group.
>
> Reliability: (2) valid with restrictions; non-GLP study, no
> information on statistical analyses or method used for mating (whether
> 1:1 or not); purity of test material not stated.

Reference: Food and Drug Research Laboratories, Inc. (1972). Teratologic

> evaluation of FDA 71-36 (calcium propionate) in mice, rats, hamsters,
> and rabbits. Report prepared under DHEW contract no. FDA 71-260. NTIS
> No: PB-221 778.
>
> Federation of American Societies for Experimental Biology (FASEB).
> 1979. Evaluation of the health aspects of propionic acid, calcium
> propionate, sodium propionate, dilauryl propionate, and
> thiodipropionic acid as food ingredients. Report prepared for the U.S.
> Food and Drug Administration. NTIS No. PB80104599.

\(b\) Critical Study for SIDS Endpoint

> Test substance: calcium propionate
>
> Remark: calcium propionate is the calcium salt of propionic acid
>
> Species: rat
>
> Sex: females dosed
>
> Strain: Wistar
>
> Route of admin.: oral gavage
>
> Exposure period: gestation days 6-15
>
> Frequency of
>
> treatment: daily during exposure period
>
> Duration of test: On day 20, dams subjected to Cesarean section
>
> Doses: 0, 3, 14, 65, 300 mg/kg bw
>
> Control Group: negative (sham) control and aspirin (250 mg/kg bw) used
> as positive control
>
> NOAEL Maternal.: 300 mg/kg bw
>
> NOAEL Devel: 300 mg/kg bw
>
> Method: other
>
> Year: 1972
>
> GLP: no
>
> Method: Virgin female Wistar rats were housed individually and mated
> with young adult males. The presence of a vaginal plug was used to
> indicate day 0 of gestation (GD 0). Beginning on day 6 and continuing
> through day 15 of gestation, groups of mated females received the the
> test material by oral. The test material was provided by the U.S. Food
> and Drug Administration (FDA) as a coded test material (FDA 71-36)
>
> The number of females mated and pregnant were as follows:
>
> Mated Pregnant
>
> Negative control 24 23
>
> Positive control 24 24
>
> 3.0 mg/kg-bw/day 24 22
>
> 14.0 mg/kg-bw/day 24 21
>
> 65 mg/kg-bw/day 24 23
>
> 300 mg/kg-bw/day 24 22
>
> Females were given free access to food and water.
>
> Body weights of dams were taken on Days 0, 6, 11, 15, and 20 of
> gestation. Dams were observed each day for food and water intake and
> other measures of appearance and behavior. On Day 20, Cesearean
> section was performed on all dams. The urogenital tract was examined
> in detail for anatomical normality.
>
> Numbers of implantation sites, resorption sties, and live and dead
> fetuses were recorded. Body weights of live pups were also recorded.
>
> All pups were examined grossly for external congenital abnormalities.
> One-third of fetuses of each litter underwent detailed visceral
> examinations (at 10x magnification); the remaining two-thirds were
> stained and examined for skeletal defects.
>
> [Statistical analyses]{.underline}: No statistical analysis was
> performed on results obtained from this test material, which was the
> 15^th^ in a series of at least 42 compounds to be tested under the
> auspices of the Food and Drug Administration. Because of the inherent
> variability of biological data, statistical analysis was deferred
> until data for all test compounds were collected and when the pooling
> of sequential sets of control values would greatly enhance the
> statistical power of the findings. A subsequent review of the data
> (FASEB, 1979) states that calcium propionate did not exert a
> significant effect, and the number of abnormalities observed in fetal
> and skeletal tissue did not differ from the number occurring in the
> sham-treated controls. The method of statistical analysis employed was
> not described in the FASEB report..
>
> Result: No clearly discernible effect on nidation or maternal or fetal
> survival was seen. The numberof abnormalities in the treated groups
> did not differ from the sham control group.
>
> Reliability: (2) valid with restrictions; non-GLP study, no
> information on statistical analyses or method used for mating (whether
> 1:1 or 1:2 or other method). Also purity of test material not stated.

Reference: Food and Drug Research Laboratories, Inc. (1972). Teratologic

> evaluation of FDA 71-36 (calcium propionate) in mice, rats, hamsters,
> and rabbits. Report prepared under DHEW contract no. FDA 71-260. NTIS
> No: PB-221 778.
>
> Federation of American Societies for Experimental Biology (FASEB).
> 1979. Evaluation of the health aspects of propionic acid, calcium
> propionate, sodium propionate, dilauryl propionate, and
> thiodipropionic acid as food ingredients. Report prepared for the U.S.
> Food and Drug Administration. NTIS No. PB80104599.

\(c\) Critical Study for SIDS Endpoint

> Test substance: calcium propionate
>
> Remark: calcium propionate is the calcium salt of propionic acid
>
> Species: hamsters
>
> Sex: females dosed
>
> Strain: Syrian golden, outbred
>
> Route of admin.: oral gavage
>
> Exposure period: gestation days 6-10
>
> Frequency of
>
> treatment: daily during exposure period
>
> Duration of test: On day 14, dams subjected to Cesarean section
>
> Doses: 0, 4, 19, 86, 400 mg/kg bw
>
> Control Group: negative (sham) control
>
> positive (aspirin at 250 mg/kg bw) control
>
> NOAEL Maternal.: 400 mg/kg bw
>
> NOAEL Devel: 400 mg/kg bw
>
> Method: other
>
> Year: 1972
>
> GLP: no
>
> Method: Female virgin outbred hamsters were housed individually and
> mated with mature males (1:1). The appearance of motile sperm was
> considered Day 0 of gestation. Beginning on day 6 and continuing
> through day 10 of gestation, groups of mated females received the the
> test material by oral intubation. The test material was provided by
> the U.S. Food and Drug Administration (FDA) as a coded test material
> (FDA 71-36)
>
> The number of females mated and pregnant were as follows:
>
> Mated Pregnant
>
> Negative control 22 22
>
> Positive control 22 21
>
> 4 mg/kg-bw/day 22 21
>
> 19 mg/kg-bw/day 22 22
>
> 86 mg/kg-bw/day 22 22
>
> 400 mg/kg-bw/day 22 21
>
> Females were given free access to food and water.
>
> Body weights of dams were taken on Days 0, 8, 10, and 14 of gestation.
> Dams were observed each day for food intake and other measures of
> appearance and behavior. On Day 14, Cesearean section was performed on
> all dams. The genital tract was examined in for anatomical normality.
>
> Numbers of implantation sites, resorption sties, and live and dead
> fetuses were recorded. Body weights of live fetuses were also
> recorded.
>
> All fetuses were examined grossly for external congenital
> abnormalities. One-third of the fetuses of each litter underwent
> detailed visceral examinations (at 10x magnification); the remaining
> two-thirds were stained and examined for skeletal defects.
>
> [Statistical analyses]{.underline}: No statistical analysis was
> performed on results obtained from this test material, which was the
> 15^th^ in a series of at least 42 compounds to be tested under the
> auspices of the Food and Drug Administration. Because of the inherent
> variability of biological data, statistical analysis was deferred
> until data for all test compounds were collected and when the pooling
> of sequential sets of control values would greatly enhance the
> statistical power of the findings. A subsequent review of the data
> (FASEB, 1979) states that calcium propionate did not exert a
> significant effect, and the number of abnormalities observed in fetal
> and skeletal tissue did not differ from the number occurring in the
> sham-treated controls. The method of statistical analysis employed was
> not described in the FASEB report.
>
> Result: No clearly discernible effect on nidation or maternal or fetal
> survival was seen. The numberof abnormalities in the treated groups
> did not differ from the sham control group.
>
> Remark: It should be noted that the dosing period differs from OECD
> recommendations for this species. Therefore, care must be taken in
> interpreting results.
>
> Reliability: (2) valid with restrictions; non-GLP study, no
> information on statistical analyses. Also purity of test material not
> stated. Dosing period differs from OECD guidelines for this species.

Reference: Food and Drug Research Laboratories, Inc. (1972). Teratologic

> evaluation of FDA 71-36 (calcium propionate) in mice, rats, hamsters,
> and rabbits. Report prepared under DHEW contract no. FDA 71-260. NTIS
> No: PB-221 778.
>
> Federation of American Societies for Experimental Biology (FASEB).
> 1979. Evaluation of the health aspects of propionic acid, calcium
> propionate, sodium propionate, dilauryl propionate, and
> thiodipropionic acid as food ingredients. Report prepared for the U.S.
> Food and Drug Administration. NTIS No. PB80104599.

\(d\) Critical Study for SIDS Endpoint

> Test substance: calcium propionate
>
> Remark: calcium propionate is the calcium salt of propionic acid
>
> Species: rabbit
>
> Sex: females dosed
>
> Strain: Dutch-belted
>
> Route of admin.: oral gavage
>
> Exposure period: gestation days 6-18
>
> Frequency of
>
> treatment: daily during exposure period
>
> Duration of test: On day 29, dams subjected to Cesarean section
>
> Doses: 0, 4, 19, 86, 400 mg/kg bw
>
> Control Group: negative (sham) control
>
> Positive (6-aminonicotinamide at 2.5 mg/kg bw) control (given on GD 9)
>
> NOAEL Maternal.: 400 mg/kg bw
>
> NOAEL Devel: 400 mg/kg bw
>
> Method: other
>
> Year: 1972
>
> GLP: no
>
> Method: Female Dutch-belted rabbits were given 0.4 ml of human
> chorionic gonatoropin (440 IU) in the ear and artificially inseminated
> with 0.3 ml diluted semen (approximately 20 x 10^6^ motile sperm) from
> proven buck. Females were then exposed to the control or test
> substance each day during gestation days 6-18. The number of females
> "mated" and pregnant were as follows:
>
> Mated Pregnant
>
> Negative control 17 10
>
> Positive control 15 10
>
> 4 mg/kg-bw/day 25 10
>
> 19 mg/kg-bw/day 15 10
>
> 86 mg/kg-bw/day 24 9
>
> 400 mg/kg-bw/day 20 11
>
> Females were housed individually with free access to food and water.
>
> Body weights of dams were taken on Days 0, 6, 12, 18, and 29 of
> gestation. Dams were observed each day for food intake and body
> weight, and other measures of appearance and behavior. On Day 29,
> Cesearean section was performed on all dams. The urogenital tract was
> examined in detail for anatomical normality.
>
> Numbers of corpora lutea, implantation sites, resorption sties, and
> live and dead fetuses were recorded. Body weights of live pups were
> also recorded.
>
> All fetuses were examined grossly for external congenital
> abnormalities. The live fetuses of each litter were placed in an
> incubator for 24 hours for evaluation of neonatal survival. All
> surviving pups were sacrificed and all were examined for visceral
> abnromailities (by dissection) and all were stained and examined for
> skeletal defects.
>
> [Statistical analyses]{.underline}: No analysis performed on the
> results obtained from this test material, which ws the 15^th^ in a
> series of at least 42 compounds to be tested under the auspices of the
> Food and Drug Administration. Because of the inherent variability of
> biological data, statistical analysis was deferred until data for all
> test compounds were collected and when the pooling of sequential sets
> of control values would greatly enhance the statistical power of the
> findings. A subsequent review of the data (FASEB, 1979) states that
> calcium propionate did not exert a significant effect, and the number
> of abnormalities observed in fetal and skeletal tissue did not differ
> from the number occurring in the sham-treated controls. The method of
> statistical analysis employed was not described in the FASEB report.
>
> Result: No clearly discernible effect on nidation or maternal or fetal
> survival was seen. The numberof abnormalities in the treated groups
> did not differ from the sham control group.
>
> Reliability: (2) valid with restrictions; non-GLP study, no
> information statistical analyses. Also purity of test material not
> stated.

Reference: Food and Drug Research Laboratories, Inc. (1972). Teratologic

> evaluation of FDA 71-36 (calcium propionate) in mice, rats, hamsters,
> and rabbits. Report prepared under DHEW contract no. FDA 71-260. NTIS
> No: PB-221 778.
>
> Federation of American Societies for Experimental Biology (FASEB).
> 1979. Evaluation of the health aspects of propionic acid, calcium
> propionate, sodium propionate, dilauryl propionate, and
> thiodipropionic acid as food ingredients. Report prepared for the U.S.
> Food and Drug Administration. NTIS No. PB80104599.

# **5.10 OTHER RELEVANT INFORMATION** 

# **A. Specific toxicities** 

> \(a\) Type: In vitro developmental toxicity
>
> Species: *Xenopus laevis* (African clawed frog)
>
> Route of Admin: immersion
>
> Exposure period: 96 hours
>
> Freq of treatment: continuous
>
> Duration of test: 96 hours
>
> Doses: not specified
>
> Control group: yes
>
> Method: other: FETAX Assay
>
> Test substance: propionic acid
>
> Method: The Frog Embryo Teratogenesis Assay-Xenopus (FETAX) assay was
> used to assay the potential of propionic acid to induce developmental
> toxicity in vitro. Embryos of the South African clawed frog were
> maintained in FETAX solution and exposed for 96 hr to at least eight
> concentrations of propionic acid. Exposure groups of 25 embryos per
> concentration were maintained using a static renewal system in which
> exposure media was changed at 24-h intervals. Control embryos were
> reared in FETAX solution under identical environmental conditions.
> Developmental malformations were determined at the end of the 96-hr
> exposure interval. Data from at least three independent assays were
> pooled to calculate the 96-hr LD50 and 96-hr EC50 for malformations.
> Values were corrected for density. The developmental hazard index or
> DHI was calculated by dividing the 96 hr LC50 by the 96-hr EC50.
>
> Result: The LC50 (with 95% confidence limits) for propionic acid was
> 7455 (7243-7450) mg/l. The EC50 for malformations was 898 (780-1156)
> mg/l. The primary malformations induced were craniofacial defects,
> especially microcephaly, and abnormal gut coiling. Skeletal
> malformations were noted at near-lethal concentrations. Abnormal gut
> coiling, and skeletal and cranial defects were also noted in controls.
> The developmental hazard index or DHI was determined to be 8.2.
> Comparison of FETAX results with other carboxylic acids determined
> that there was no correlations between log Kow and pKa with the DHI.
> Among saturated acids, the highest developmental hazard was associated
> with medium length (C-5 and C-6)
>
> Remark: SAR and SMR (structure-metabolism relationship) studies
> suggest that while propionic acid displays teratogenic potential in
> vitro, it is extremely unlikely to show activity in vivo because of
> its susceptibility to β-oxidation. (DiCarlo, F.J. 1990.
> Structure-activity relationships (SAR) and structure-metabolism
> relationships (SMR) affecting the teratogenicity of carboxylic acids.
> Drug Metabolism Reviews 22: 411-449).
>
> Reference: Dawson, D.A., Schultz, R.W., and Hunter, R.S. 1996.
> Developmental toxicity of carboxylic acids to Xenopus embryos: a
> quantitative structure-activity relationship and computer-automated
> structure evaluation. Teratogen. Carcinogen. Mutagen. 16: 109-124.

#  **Toxicodynamics, toxicokinetics** 

**B.1 In vivo studies**

\(a\) Test substance: n-propanol, purity \>98%

> Species: rat

Strain: Sprague-Dawley

> Sex: male
>
> Route of Admin: intravenous
>
> Exposure Period: 15 minutes
>
> Exposure Concentration: 100 and 500 um/kg
>
> Control Group: None (biological samples taken prior to exposure)
>
> Method: Cannulated male rats (240-360 kg) were obtained with dual
>
> indwelling jugular and femoral vein cannulas (Hilltop Lab Animals,
> Inc. Scottsdale, PA). Rats (5 per dose) were infused with 100 or 500
> umole/kg ^13^C-propanol through the femoral cannula. Dose solutions
> were prepared in sterile physiologically buffered saline (PBS) at
> target volumes of 10 ml.kg body weight. Dosing solutions were
> administered using a 5 ml gas tight syringe mounted on a programmable
> syringe pump connected to the femoral cannula. The dosing syringe was
> weighed before and after dosing to quantify the volume actually
> administered. Dosing solutions were analyzed using gas chromatography
> and a mass selective detector. Blood samples were drawn from the
> jugular cannul at 0, 1,3,6,10, and 14 minutes during the 15 minute
> infusion and 1,3,5, and 10 minutes post infusion using a heparinized
> syringe. The concentration of ^13^C-propanol and ^13^ C-propionic acid
> were determined using an HP6890 Plus gas chromatograph equipped with a
> HP5973 Mass Selective Detector. Separations were achieved by capillary
> column chromatography. ^13^C-radiolabeled propanol and propionic acid
> (sodium salt) were obtained from Cambridge Isotope Laboratories; each
> radiolabeled compound had a purity of greater than 98%.
>
> Year: 2004
>
> GLP: no (conducted in spirit of GLP, but not specifically)
>
> Test substance: n-propanol
>
> Purity: \>98%
>
> Results: Rats were infused with target doses of 100 or 500 umol/kg
> ^13^C-propanol over 15 minutes. Acutal doses administered were 95-110%
> of the target dose. ^13^C labeled propionic acid was used to
> discriminate from background endogenous sources. Blood samples were
> collected from the jugular canula while the dose was infused through
> the femoral cannula. Propanol and propionic acid were detected one
> minute after onset of administraton of propanol. Blood levels began to
> drop at the end of the 15-minute infusion interval.
>
> Blood propionic acid levels in rats
>
> infused with 500 umol/kg propanol

+----------------------+-----------------------------------------------+
| Time                 | Concentration (nmol/kg)                       |
|                      |                                               |
| (min)                |                                               |
+----------------------+-----------------------------------------------+
| 1                    | 71 + 35                                       |
+----------------------+-----------------------------------------------+
| 3                    | 310 + 80                                      |
+----------------------+-----------------------------------------------+
| 6                    | 512 + 123                                     |
+----------------------+-----------------------------------------------+
| 10                   | 984 + 95                                      |
+----------------------+-----------------------------------------------+
| 14                   | 792 + 130                                     |
+----------------------+-----------------------------------------------+
| 16\*                 | 229 + 58                                      |
+----------------------+-----------------------------------------------+
| 18                   | 125 + 12                                      |
+----------------------+-----------------------------------------------+
| 20                   | 78 + 15                                       |
+----------------------+-----------------------------------------------+
| 30                   | 52\*\*                                        |
+----------------------+-----------------------------------------------+

> \*1 minute after end of 15-minute infusion interval
>
> \*\*Not detected in 4 of 5 dosed animals at 30 minutes
>
> Blood concentration response curves for propanol and propionic acid
> during the infusion interval were similar in shape, however peak blood
> concentrations of n-propanol were 30-fold greater than peak blood
> levels of propionic acid..
>
> Reliability: score = 1, valid without restriction
>
> Reference: Poet, T., Wu, H., and Corley, R.A. 2004. Phase 1 Propyl
> Family PBPK Model Development Studies: Intravenous Kinetics and In
> Vitro Metabolism in Male Sprague Dawley Rats. Unpublished report.
> Battelle Pacific Northwest National Laboratory. Center for Biological
> Monitoring and Modeling, Richland, WA. Battelle Project No. 43825.

\(c\) Test substance: methanol and 1-propanol

> Remark: In an effort to study the kinetics of methanol and propanol in
> humans in the absence of ethanol, human volunteers ingested methanol
> and propanol and blood was sampled every 15 minutes
>
> Species: human, sex not specified
>
> Route of Admin: oral
>
> Exposure Period: alcohol in water mixture ingested over a 15 minute
> interval
>
> Frequency: one-time exposure
>
> Duration of test: 60-112 minutes
>
> Exposure concentration: 12.5 mg/kg body weight
>
> Methods: Groups of human volunteers (5 to 7, sex not specified)
> ingested a methanol/water or propanol/water mixture with a
> concentration of 1 mg/ml/kg over a 15 minute interval. To insure
> abstinence from ethanol, a blood sample from each volunteer was taken
> prior to the beginning of the test. Solid food was consumed by the
> volunteers approximately 5 hours prior to beginning the test. At the
> end of the ingestion interval, the first blood sample was taken; among
> volunteers who drank methanol, four more samples were drawn every 15
> minutes. Among volunteers who drank propanol, 16 blood samples were
> drawn every 5 to 7 minutes using indwelling canullae. Blood samples
> were evaluated for the presence of alcohol.
>
> Results: Resorption of methanol was complete after 30 minutes; the
> distribution factor was determined to be 0.72. After reaching a peak
> concentration of approximately 9 mg/kg body weight, blood
> concentrations fell at a continuous elimination rate of approximately
> 2.2 mg/kg/hr.
>
> No detectable traces of propanol were detected in the blood of humans
> 15 minutes after the end of the ingestion interval. propanol. The
> authors propose that larger doses must be used to ensure measurable
> blood concentrations.
>
> Remark: These results demonstrate that propanol is rapidly metabolized
> in humans after ingestion. In vivo rat inhalation studies have
> demonstrated that propyl alcohol is metabolized to propionic acid.
> Propionic acid is a short chain fatty acid that is a metabolic
> intermediate normally found in cells.
>
> Reference: Schmulte, P., Bilzer, N., and Penners, B-M. 1988. On
> kinetics of congener methanol and propanol-1 in absence of ethanol.
> Blood Alcohol 25: 137-141.

\(c\) Test material: n-propyl alcohol, purity not specified

Species: human

> Strain: not applicable
>
> Sex: not available
>
> Route of Admin: oral
>
> Exposure Period 2 hours
>
> Freq. of Treatment: single
>
> Duration of Test: 11 hours
>
> Exposure Conc.: Propanol and ethanol were administered in water to
> produce a blood propanol level of 14 μmol/L at end of dosing interval.
>
> Control Group: None (biological samples taken prior to exposure)
>
> Method: In an effort to understand the elimination kinetics of
> aliphatic alcohols found in alcoholic beverages, human test subjects
> consumed propanol in a ethanol/water vehicle over a two hour time
> interval. Blood samples were collected prior to consumption, at the
> end of the two-hour consumption period, and at one, two, eight (urine
> only), and nine hours after the end of the exposure period. Each blood
> sample was homogenized, treated with β--glucuronidase, deproteinated,
> and esterified with methanol or ethanol to detect the "down-stream"
> aldehyde or acid metabolites. Blood concentration-time curves were
> constructed for propanol, propionaldehyde, and propionic acid.
>
> Year: 1983
>
> GLP: no
>
> Test substances: propyl alcohol, ethyl alcohol
>
> Purity: not specified
>
> Result: The blood concentrations of propyl alcohol and propionic acid
> were approximately 14 and 19 μmol/L at the end of the ingestion
> interval. The concentration of propionaldehyde was less than 1 μmol/L
> at all time points tested; this result demonstrates that the aldehyde
> is immediately oxidized to propionic acid. These results demonstrate
> that propionic acid is the major metabolite of propyl alcohol
> metabolism. The presence of ethanol did not significantly affect how
> propanol was metabolized. Blood levels of propanol decreased over the
> next two hours while the propionic acid levels in the blood peaked at
> 22 μg/L one hour after the end of the 2-hour ingestion interval and
> then declined thereafter.
>
> The authors diagramatically describe the metabolism of propanol to
> propionaldehyde and ending with propionic acid.
>
> Blood levels\* of propanol and metabolites in humans
>
> following propanol administration.
>
> [Sampling time (hr) Propanol Propionaldehyde Propionic
> acid]{.underline}
>
> Beginning of dosing 0 0\*\* 0
>
> End of dosing (2 hr) 14 0 19
>
> 1 hr post dosing 10 0 22
>
> 2 hr post dosing 7.5 0 13.5
>
> [9 hr post dosing 0 0 3 .]{.underline}
>
> \*mean μmol/L whole blood; values derived from graphs provided in the
> paper.
>
> \*\*blood levels less than 1 μmol/L
>
> Remark: These data demonstrate that propanol is metabolized in humans
> to propionaldehyde, which in turn is oxidized to propionic acid. Blood
> levels for propionic acid were higher than the alcohol at every
> sampling interval. The data also demonstrate the extremely transient
> nature of propionaldehyde, which is immediately converted to propionic
> acid.
>
> Reliability: score = 2, valid with restriction; purity of test
> material not specified
>
> Reference: Rudell, E. von, Bonte, W., Sprung, R., and Kuhnholz, B.
> 1983. Zur Pharmakokinetik der holheren aliphatischen Alkohole. Beitr.
> Gerichtl. Med.. 41: 211-218.

######## B2. In Vitro

# **C. Other**

\(a\) Remark: Propionic acid is normal intermediary metabolite that, in

> humans, represents up to 4% of the normal total plasma fatty acid and
> is utilized by most organs. Propionic acid is a constituent of foods,
> including dairy products, and may constitute as much as 1% of some
> cheeses. The calcium and sodium salts of propionic acid are added to
> foods as antimicrobials and preservatives. The average daily intake of
> calcium propionate and sodium propionate for persons over 2 years old
> was estimated as 45 mg and 33 mg, respectively.
>
> Reference: Clayton, G.D. and Clayton, F.E. (Eds.). 1994. Patty's
> Industrial Hygiene and Toxicology, 4^th^ Edition. Volume II, Part E:
> Aliphatic Carboxylic Acids. New York: John Wiley & Sons, Inc.

\(b\) Remark: 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 an end-product
> of the microbial digestion of carbohydrates, including sugars,
> starches, and other polysaccharides such as celluloses,
> hemicelluloses, and pectins (dietary fiber).
>
> Reference: Harrison, P.T.C. 1992. Propionic acid and the
>
> phenomenon of rodent forestomach tumorigenesis: A review. Fd. Chem.
> Toxicol. 30: 333-340.
>
> \(c\) Remark: The target of systemic effect of repeated oral exposure
> to
>
> propionic acid is the rodent forestomach, with effects ranging from
> hyperplasia to ulcers to tumors. The exact action of propionic acid on
> the forestomach is not known but may be due to its acidity and
> irritancy or because it has specific effects on normal physiological
> mechanisms, or because of a combination. Other factors such as altered
> nutritional status may also be involved. Although humans do not have a
> forestomach, the epithelium of the esophagus is histologically similar
> to that of the rodent forestomach. A fundamental difference between
> these organs, however, is contact time between the epithelium and
> food. Food is transported rapidly past the esophagus and contact time
> is minimal, whereas the rodent forestomach functions as a storage
> organ and food may be held in contact with the epithelium for hours.

Reference: Harrison, P.T.C. 1992. Propionic acid and the

> phenomenon of rodent forestomach tumorigenesis: A review. Fd. Chem.
> Toxicol. 30: 333-340.
>
> \(d\) Remark: 1-Propanol is rapidly oxidized to its corresponding
> aldehyde
>
> which is then converted to propionic acid. Propionic acid is
> conjugated with coenzyme A (CoA). Propionyl-CoA is carboxylated to
> methylmalonyl-CoA, and then trans-carboxylated to succinyl-CoA, which
> subsequently enters the tricarboxylic (Krebs) cycle to be metabolized
> to carbon dioxide and water.

Reference: Bonte, W., Rudell, E., Sprung, R., Frauenrath, C. et al.,
1981

> Experimentelle Untersuchungen zum Nachweis geringer Dosen hoherer
> aliphatischer Alkohole im Urin von Versuchsteilnehmern. Blutalkohol
> 18:399-411. *Cited in:* Comprehensive Risk Assessment Report of
> Propan-1-ol (CAS 71-23-8), 2003.
>
> Rietbrock, N. and Abshagen, U. 1971. Pharmakokinetik und Stoffwechsel
> aliphatischer Alkohole. Arzneimittelforsch 21:1309-1319. *Cited in:*
> Comprehensive Risk Assessment Report of Propan-1-ol (CAS 71-23-8),
> 2003.
>
> \(e\) Remark: Propionic acid is rapidly absorbed through the
> gastrointestinal
>
> tract and little is excreted in the urine. Three days after a dose of
> 14 C sodium propionate, 77% was found in expired air, and only 7
> percent in urine and feces. Some propionic acid is oxidized to lactic
> acid during intestinal absorption, however the majority passes to the
> liver where it is removed from the blood. Propionate is formed as the
> terminal 3-carbon fragment as propionyl co-enzyme A (CoA) in the
> oxidation of odd-numbered fatty acids. The route of metabolism of
> propionic acid involves interaction with CoA, carboxylation to form
> methylmalonyl-CoA, and subsequent conversion to succinic acid which
> enters the citric acid cycle.

References: Clayton, G.D. and Clayton, F.E. (Eds.). 1994. Patty's
Industrial

> Hygiene and Toxicology, 4^th^ Edition. Volume II, Part E: Aliphatic
> Carboxylic Acids. New York: John Wiley & Sons, Inc.
>
> WHO (World Health Organization). 1974 WHO Food Additive Series, Number
> 5: Toxicological Evaluation of Some Food Additives Including
> Anticaking Agents, Antimicrobials, Antioxidants, Emulsifiers, and
> Thickening Agents. WHO, Geneva.
>
> \(f\) Remark: Propionyl CoA is formed during catabolism of amino acids
>
> (isoleucine, valine, methionine, and threonine); it is also
>
> formed by ß oxidation of fatty acids containing anodd-number of
> carbons. Propionyl CoA is also derived from anaerobic bacterial
> fermentation of carbohydrates in the colon. The maximum contribution
> of catabolism of propiogenic amino acids to total propionate
> production has been assessed to be between 5% and 66%, with bacterial
> fermentation accounting for a large proportion of the remainder. In
> vitro bacterial fermentation studies have demonstrated that that the
> administration of the antibiotic metronidazole can significantly
> reduce the production of short chain fatty acids, including propionic
> acid. Administration of metronidazole in vivo resulted in a 50%
> decrease in propionic acid in the plasma within 24 hours, and plasma
> propionate levels were reduced 27% relative to pre-treatment levels.
>
> Reference: Mellon, S.G., Deshpande, S.A., Mathers, J.C., and Bartlett,
> K. 2000. Effect of oral antibiotics on intestinal production of
> propionic acid. Arch. Dis. Child. 82: 169-172.
>
> \(g\) Remark: Evidence was provided for the oxidation of propionate in
> animal tissues via (1) conversion to propionyl coenzyme A, (2)
> ATP-dependent carboxylation to methylmalonyl coenzyme A, and (3)
> conversion of the carbon skeleton of methyl malonate to succinate,
> which is further oxidized by the citric acid cycle. Conversion of
> methyl malonate to succinate takes place by a relatively direct route.
> Experiments using pig hearts and rat liver mitochondria and further
> analysis of compounds were specifically described and a discussion of
> other related experiments was presented.
>
> Reference: Flavin, M. and S. Ochoa. Metabolism of propionic acid in
> animal tissues. I. Enzymatic conversion of propionate to succinate.
> Journal of Biological Chemistry. 229: 965-979.

# **5.11 EXPERIENCE WITH HUMAN EXPOSURE**

> \(a\) Remark: An adult male receiving daily doses 6000 mg sodium
>
> propionate displayed no adverse effects. Urine pH was slightly
> alkaline.
>
> Reliability: score = 2, valid with restriction, data from handbook or
> collectionof data.
>
> Reference: WHO (World Health Organization). 1974 WHO Food Additive
> Series, Number 5: Toxicological Evaluation of Some Food Additives
> Including Anticaking Agents, Antimicrobials, Antioxidants,
> Emulsifiers, and Thickening Agents. WHO, Geneva.

\(b\) Remark: Minimal irritation was evident when a 1.0 M solution

> (approximately 7.4%) of propionic acid was applied under occlusion for
> 24 hours per day on ten consecutive days.
>
> Reliability: score = 4, not assignable, data from secondary source
>
> Reference: Stillman, M.A., Maibach, H.I., and Shalita, A.R. 1975.
> Relative irritancy of free fatty acids of different chain length.
> Contact Dermatis 1: 65-69. *Cited in:* BIBRA Toxicity Profile for
> Propionic Acid and Its Common Salts, dated June 1986. BIBRA
> Information Services, Surrey, England.

\(c\) Remark: There was no sensitization response to sodium

> propionate following topical use, or after 'extensive' trials
> (conditions not detailed).
>
> A 10% sodium propionate solution at pH 7.2 caused slight, transient
> stinging in the nose.
>
> A 20% solution of sodium propionate at pH 7-8.5 did not cause skin
> irritation (conditions not detailed).
>
> Reliability: score = 4, not assignable, data from secondary source
>
> Reference: Haseltine, W.W. 1952. J. Pharm. Pharmac. 4: 120. *Cited
> in:* BIBRA Toxicity Profile for Propionic Acid and Its Common Salts,
> dated June 1986. BIBRA Information Services, Surrey, England.

(d) Remark: In a study of urticarial reactions, 8 subjects of a group of
    91

> patients suffering from chronic or recurrent urticaria or recurrent
> angioedema produced positive a skin-prick reaction in response to a 5%
> aqueous solution of propionic acid. Upon re-testing, only 3 subjects
> with a history of chronic uticaria or recurrent angioedema displayed a
> reproducible positive reaction. None of the 247 normal (non-uticaria)
> human control subjects displayed a response to propionic acid..
>
> Subjects were examined in the Department of Dermatology of Turku
> University Central Hospital in Finland between June 1983 and October
> 1986. Patients were presumed to have prior exposure to propionic acid
> because of its use as a food preservative. During the initial visit,
> each prospective subject was encouraged to follow an additive-free
> diet. Histamine chloride (3 mg/ml) and physiological saline were used
> as positive and negative controls, respectively. The volume of test
> and control agents administered in the skin prick test was not
> specified. Tests were read after 15 minutes.
>
> Reliability: score = 2, valid with restriction, meets generally
> acceptable scientific standards
>
> Reference: Malanin, G. and Kalimo, K. 1989. The results of skin
> testing with food additives and the effect of an elimination diet in
> chronic and recurrent urticaria and recurrent angioedema. Clin. Exper.
> Allergy 19: 539-543.
>
> \(e\) Remark: Acute propionic acid exposures in workers have resulted
> mild skin burns, mild eye redness, and one case of mild cough and
> asthma-like response. No irritation was noted with 8- hr TWA levels
> below 0.25 ppm and with excursions to 2.1 ppm.
>
> Reliability: score = 2, valid with restriction, data from handbook or
> collection of data
>
> Reference: American Conference Governmental Industrial Hygienists
> (ACGIH). 1991. Documentation of Threshold Limit Values and Biological
> Exposure Indices, 6^th^ Edition. Cincinnati, OH: ACGIH.
>
> \(f\) Remark: A 10% solution of sodium propionate (pH 7.2) applied to
> the
>
> eye produced slight, transient stinging. Solutions of up to 15% sodium
> propionate have been used to treat eye infections.
>
> Reliability: score = 4, not assignable, data from secondary source
>
> Reference: Haseltine, W.W. 1952. A note on sodium propionate. J.
> Pharm. Pharmac. 4: 120. *Cited in:* British Industrial Biological
> Research Association (BIBRA).
>
> 1986\. Toxicity Profile for Propionic Acid and Its Common Salts, dated
> June 1986. BIBRA Information Services, Surrey, England.
>
> \(g\) Remark: Cases of elevated levels of propionic acid in the blood
>
> (propionic acidemia) reported in humans have been associated with rare
> disorders of lipid and amino acid catablism. Propionic acidemia in
> humans produces metabolic abnormalities and toxic encephalopathy
> resembling Reye Syndrome. Clinic signs and symptoms include tachypnea,
> vomiting, lethargy, irritability, shock, coma and death. In most
> cases, presentation occurs in infancy with onset of symptoms, and
> morbidity is high. Severe ketoacidosis with pH values as low as 6.80
> can occur and produce circulatory shock, hypoxia and brain damage.
> Repetitive episodes causes neurotoxicity with neuronal cell death
> leading to mental retardation. Death can occur at any time from an
> acute episode.
>
> Reliability: score = 2, valid with restriction, data from handbook or
> collection of data

**Reference:** Roth, K.S. 2006. Propionic Acidemia (Propionyl CoA
Carboxylase Deficiency). eMedicine from WebMD. Last updated on February
3, 2006. available at [www.emedicine.com](http://www.emedicine.com/).

# **6.0 REFERENCES** 

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Ambrose, D. et al. 1981. Thermodynamic properties of organic oxygen
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[]{.mark}

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Amoore, J.E. and Hautala, E. 1983. Odor as an aid to chemical safety:
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Atkinson, R. 1989. Kinetics and Mechanism of the Gas-Phase Reactions of
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Barton, H.A. et al. 2000. Family approach for estimating reference
concentrations/doses for

series of related organic chemicals. Toxicol. Sci. 54: 251-261.

BASF AG. 1969. Report on the acute per oral toxicity of propionic acid
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Toxicology, translation of the unpublished report No. XIX/264, dated 27
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BASF AG. 1971. 90-day feeding study on rts with propionic acid.
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of the unpublished report No. XX/200, dated 30 July 1971.

BASF AG (sponsor of INBIFO study). 1979. Determination of the acute
inhalation toxicity LC50 of propionic acid as vapour on male and female
rats. BASF AG translation of the unpublished report BASF No. 77/523,
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BASF AG. 1987. Algal Growth Inhibition Test. Project report 1103/87.
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BASF. 1988. Study of the toxicity of propionic acid in Beagle dogs.
Administration in the diet over 3 months and a 6-week recovery period.
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of Calcium propionate on water flea Daphnia magna Straus. Department of
Ecology, unpublished data, report No. 1/1540/2/88, 16 Mar 1989.

BASF AG. 1989b. Luprosil salt (Calciumpropionate). Algal growth
inhibition test. Department of

Ecology, unpublished data, report No. 2/1540/88, 25 Sep 1989.

BASF AG. 1990b. Study of the dermal effects of propionic acid after a
3-month epicutaneous application

in female mice. Department of Toxicology, translation of the unpublished
report No. 39C0473/85127,

dated 19 Nov. 1990.

BASF AG. 1990a. Luprosil salt (Calcium propionate). Acute toxicity to
fish, Golden orfe (Leuciscus idus L., golden variety). Department of
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BASF AG. 2007. Department for Product Safety, recalculation of EbC50 and
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