SIDS Initial Assessment Report

for

­­SIAM 25

Helsinki, Finland; October 16-19, 2007

+-----------------------+----------------------------------------------+
| 1\. Chemical Name:    | Propionic Acid                               |
+-----------------------+----------------------------------------------+
| 2\. CAS Number:       | 79-09-4                                      |
+-----------------------+----------------------------------------------+
| **3. Sponsor          | United States of America                     |
| Country:**            |                                              |
|                       | National SIDS Contact Point in Sponsor       |
|                       | Country:                                     |
|                       |                                              |
|                       | Mr. Oscar Hernandez, Director                |
|                       |                                              |
|                       | U.S. Environmental Protection Agency         |
|                       |                                              |
|                       | Risk Assessment Division (7403 M)            |
|                       |                                              |
|                       | 1200 Pennsylvania Avenue, NW                 |
|                       |                                              |
|                       | Washington DC 20460                          |
|                       |                                              |
|                       | Phone: (202) 564-7461                        |
|                       |                                              |
|                       | E-mail: <hernandez.oscar@epa.gov>            |
+-----------------------+----------------------------------------------+
| 4\. Shared            | American Chemistry Council, Oxo Process      |
| Partnership with:     | Panel                                        |
+-----------------------+----------------------------------------------+
| 5\.                   |                                              |
| R                     |                                              |
| oles/Responsibilities |                                              |
| of the Partners:      |                                              |
+-----------------------+----------------------------------------------+
| -   Name of industry  | American Chemistry Council                   |
|     sponsor           |                                              |
|     /consortium       | Kate Schroen, Oxo Process Panel              |
|                       |                                              |
|                       | 1300 Wilson Blvd                             |
|                       |                                              |
|                       | Arlington, VA 22209                          |
|                       |                                              |
|                       | Phone: (703) 741-5612                        |
+-----------------------+----------------------------------------------+
| -   Process used      | Robust Summaries/dossiers, the SIAR, and the |
|                       | SIAP were drafted by the Oxo Process Panel's |
|                       | toxicologists. Documents were reviewed by    |
|                       | the Oxo Process Panel and the United States  |
|                       | Environmental Protection Agency.             |
+-----------------------+----------------------------------------------+
| **6. Sponsorship      |                                              |
| History**             |                                              |
+-----------------------+----------------------------------------------+
| How was the chemical  | The American Chemistry Council's Oxo Process |
| or category brought   | Panel submitted a test plan and robust       |
| into the SIDS         | summaries for this chemical to the U.S.      |
| Program?              | Environmental Protection Agency in December  |
|                       | 2001, under the International Council of     |
|                       | Chemical Associations (ICCA) Global          |
|                       | Initiative on High Production Volume (HPV)   |
|                       | Chemicals Program.                           |
+-----------------------+----------------------------------------------+
| 7\. Review Process    | Members of the Oxo Process Panel conducted a |
| Prior to the SIAM:    | comprehensive literature search. Documents   |
|                       | were prepared by the Panel and reviewed by   |
|                       | industry toxicologists prior to submission   |
|                       | to the United States Environmental           |
|                       | Protection Agency (U.S. EPA). The EPA        |
|                       | conducted reviews of submitted data and      |
|                       | offered comments to industry. The EPA        |
|                       | submitted documents to OECD for              |
|                       | consideration at SIAM 25.                    |
+-----------------------+----------------------------------------------+
| 8\. Quality check     | The quality of existing data was determined  |
| process:              | using guidance provided in the Manual for    |
|                       | Investigation of HPV Chemicals, Chapter 3:   |
|                       | Data Evaluation (OECD, 2002).                |
+-----------------------+----------------------------------------------+
| **9. Date of          |                                              |
| Submission:**         |                                              |
+-----------------------+----------------------------------------------+
| **10. Date of last    | May 2008                                     |
| Update:**             |                                              |
+-----------------------+----------------------------------------------+
| 11\. Comments:        | Data for calcium propionate (CAS No.         |
|                       | 4075-81-4) are used to satisfy the           |
|                       | developmental toxicity endpoint for          |
|                       | propionic acid. Data for calcium propionate  |
|                       | are also used to augment some environmental  |
|                       | endpoints (acute toxicity to fish,           |
|                       | invertebrates and algae). Calcium propionate |
|                       | will dissociate in water and act as a source |
|                       | of propionate ions.                          |
+-----------------------+----------------------------------------------+

Table of Contents

[**1.0** **IDENTITY** 4](#identity)

[1.1 Identification of the Substance
4](#identification-of-the-substance)

[1.2 Purity/Impurities/Additives 4](#purityimpuritiesadditives)

[1.3 Physico-Chemical Properties 4](#physico-chemical-properties)

[**2.0** **GENERAL INFORMATION ON EXPOSURE**
5](#general-information-on-exposure)

[2.1 Production Volumes and Use Patterns
5](#production-volumes-and-use-patterns)

[2.1.1 Manufacture and Consumption 5](#manufacture-and-consumption)

[2.1.2 Uses and Functions 6](#uses-and-functions)

[2.2 Environmental Exposure and Fate
7](#environmental-exposure-and-fate)

[2.2.1 Sources of Environment Exposure
7](#sources-of-environment-exposure)

[2.2.2 Photodegradation 9](#photodegradation)

[2.2.3 Environmental Stability 9](#environmental-stability)

[2.2.4 Transport Between Environmental Compartments
10](#transport-between-environmental-compartments)

[2.2.5 Biodegradation 10](#biodegradation)

[2.2.6 Bioaccumulation 11](#bioaccumulation)

[2.3 Human Exposure 11](#human-exposure)

[2.3.1 Occupational Exposure 12](#occupational-exposure)

[2.3.2 Consumer Exposure 13](#consumer-exposure)

[2.3.3 Indirect Exposure via the Environment
13](#indirect-exposure-via-the-environment)

[**3.0** **HUMAN HEALTH HAZARDS** 13](#human-health-hazards)

[3.1 Effects on Human Health 13](#effects-on-human-health)

[3.1.1 Toxicokinetics, Metabolism and Distribution
13](#toxicokinetics-metabolism-and-distribution)

[3.1.2 Acute Toxicity 14](#acute-toxicity)

[3.1.3 Irritation 16](#irritation)

[3.1.4 Sensitization 17](#sensitization)

[3.1.5 Repeated Dose Toxicity 18](#repeated-dose-toxicity)

[3.1.6 Genotoxicity 22](#genotoxicity)

[3.1.6 Carcinogenicity 24](#carcinogenicity)

[3.1.8 Reproductive/Developmental Toxicity
24](#reproductivedevelopmental-toxicity)

[**4.0** **HAZARDS TO THE ENVIRONMENT** 28](#hazards-to-the-environment)

[4.1 Aquatic Effects 28](#aquatic-effects)

[4.2 Terrestrial Effects 30](#terrestrial-effects)

[4.3 Other Environmental Effects 30](#other-environmental-effects)

[4.4 Initial Assessment for the Environment
31](#initial-assessment-for-the-environment)

[**5** **RECOMMENDATIONS** 31](#recommendations)

[**6** **REFERENCES** 32](#references)

# **1.0 IDENTITY**

## 1.1 Identification of the Substance

CAS Number: 79-09-4

IUPAC Name: Propionic acid

Molecular Formula: C~3~H~6~O~2~

Structural Formula: CH~3~-CH~2~-COOH

Molecular Weight: 74.08 g/mol

Synonyms: n-Propionic acid

> 1-Propionic acid

Methyl acetic acid

Ethyl formic acid

Ethane carboxylic acid

Methacetonic acid

Pseudoacetic acid

Carboxyethane

## 1.2 Purity/Impurities/Additives

> Purity: \>99% weight/weight
>
> Impurities: None
>
> Additives: None
>
> Remark: Propionic acid does not require the use of inhibitors or
> stabilizers.
>
> Reference: Hazardous Substance Databank (HSDB). 2005. Propionic Acid
> (CAS 79-09-4). HSDB Number 1192, complete update on 6/24/2005.

## 1.3 Physico-Chemical Properties

> **Table 1:** Summary of physico-chemical properties for Propionic Acid

  ----------------------- ------------------------ ----------------------
  **Property**            **Value**                **Reference**

  CAS Registry Number     79-09-4                  

  Physical state          transparent liquid       Budavari, 1996

  Molecular weight        74.08 g/mol              Budavari, 1996

  Melting point           -21.5 °C                 Budavari, 1996

  Boiling point           141.1 ºC                 Lide, 1996

  Relative density        0.99 at 20ºC             Budavari, 1996

  Vapor pressure          4.7 hPa at 25°C          Daubert and Danner,
                                                   1989

  Water solubility        miscible with water      Budavari, 1996

  Partition coefficient   0.33 at 25ºC             Hansch et al., 1995
  n-octanol/water (log                             
  value)                                           

  Henry's law constant    4.15 x 10^-7^            Hine and Mookerjee,
                          atm-m^3^/mol at 25 ºC    1975
                          (0.0420 Pa-m^3^/mole)    

  Dissociation constant   4.87 at 25ºC             Riddick et al., 1985
  in water (pKa)                                   

  Flashpoint              50°C (122 °F) closed cup NFPA, 2002

  Flammable range         2.9 to 12.1 volume %     NFPA, 2002

  Vapor density           2.56 (air = 1)           Sax, 1989.

  Conversion factor       1 ppm = 3.80 mg/m^3^ 1   Verschuren, 2001
                          mg/m^3^ = 0.325 ppm      

  Odor threshold          0.61 mg/m^3^ or 0.16 ppm Amoore and Hautala,
                                                   1983
  ----------------------- ------------------------ ----------------------

Propionic acid is a liquid at standard temperature and pressure, with a
boiling point of 141.1 ºC (Lide, 1996) and a melting point of -21.5ºC
(Budavari, 1996). It is slightly less dense than water with a specific
gravity of 0.99 g/cm^3^ at 20ºC (Budavari, 1996). Propionic acid is
miscible in water. Propionic acid has a reported Henry's Law constant of
4.15 x 10^-7^ atm-m^3^/mol or 0.0420 Pa-m^3^/mole (Hine and Mookerjee,
1975). It has a partition coefficient of 0.33 (Hansch et al., 1995) that
is representative of the uncharged substance. Propionic acid has a pKa
of 4.87 at 25°C (Riddick et al., 1985); at a pH of 4.87, there is an
equal amount of proprionate ions and unionized acid. As pH increases
above pH 4.87, the amount of anion will also increase. Below pH 4.87,
the amount of anion will decrease (exponentially by pH value).

The vapor density of propionic acid is approximately 2.56 times greater
than air; it has a vapor pressure of 4.7 hPa at 25ºC (Daubert and
Danner, 1989). Propionic acid has a disagreeable, sour or rancid odor
(Budavari, 1996) and a low odor threshold (Amoore and Hautala, 1983). It
has a sour and mildly cheese-like taste (Furia, 1972). Propionic acid is
a flammable liquid with a flash point of 50ºC and a flammable range of
2.9 to 12.1% by volume (NFPA, 2002).

## 1.4 Supporting Chemical Justification

Data for calcium propionate (CAS No. 4075-81-4) are used to satisfy the
developmental toxicity endpoint for propionic acid and to augment some
environmental endpoints (acute toxicity to fish, invertebrates and
algae). Calcium propionate dissociates in water to yield propionate
ions.

# **2.0 GENERAL INFORMATION ON EXPOSURE**

## 2.1 Production Volumes and Use Patterns

### 2.1.1 Manufacture and Consumption

Propionic acid is manufactured in a continuous oxidation process by
passing air as the oxygen source through liquid propionaldehyde. The
crude reaction product exits the reactor and is stripped of unreacted
propionaldehyde and impurities by passing through a series of
distillation columns to produce refined propionic acid that has a purity
of 99.5% by weight. The major impurity in the final product is acetic
acid (maximum concentration less than 0.3% by weight). Still bottoms
from each distillation are recycled. Scrubbers are used at each step to
prevent release of fugitive emissions. Scrubber condensates are
collected and redistilled and the organics collected are used as fuel or
sold as solvents. Annual consumption of propionic acid in the United
States was about 91 thousand metric tons in 2003; the pattern of use for
propionic acid is available for 1997 (Table 2; Bizzari et al., 1999). In
2003, approximately 115 thousand metric tons were produced in the United
States, and 124 thousand metric tons were produced in Western Europe;
annual production in Japan is reported to be 3 thousand metric tons
(Chemical Economics Handbook, 2003).

### 

### 2.1.2 Uses and Functions

In the United States, propionic acid has a variety of uses. It is an
intermediate used to manufacture several products, ranging from the
manufacture of feed and corn preservatives, cellulose propionate
plastics and other plasticizers, herbicides, and pharmaceuticals, and in
the manufacture of coatings and inks. It can also be used directly as a
food additive and the preservation of animal feed.

In the United States, consumption of propionic acid is for use as a
chemical intermediate for the production of propionate salts which are
used as feed and corn preservatives. In the herbicide market, propionic
acid is used as a chemical intermediate for the manufacture of Dalapon,
Erbon, and Propanil (Johnson and Esker, 1999, HSDB, 2001). Calcium and
sodium propionate are used as bacterial and mold inhibitors to prevent
spoilage in dry baked goods such as bread products and tortillas. Both
salts are also used in cheese preservation (Johnson and Esker, 1999;
Furia, 1980; Kirk-Othmer, 1993). Propionic acid is also used directly as
a grain preservative (HSDB, 2005).

Propionic acid is used for preservation of animal feed, wet corn and
silage. For 75% of this application, propionic acid is converted to
propionate salts, since this salt form is less corrosive to machinery
and is easier to handle. In feed and corn preservation applications,
either propionate or propionic acid (both in liquid form) are added
either directly or on an absorbent (such as vermiculite) to the feed to
prevent mold (Johnson and Esker, 1999, Farm Chemicals Handbook, 1999).

> **Table 2:** Consumption of Propionic Acid\*

+---------------------------------------+-------------------+----------+
| 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      |
+---------------------------------------+-------------------+----------+

\* % of total consumption in 1997; data from Bizzari et al., 1999

Propionic acid is used as an additive to control fungi and bacteria in
drinking water for livestock and poultry (USEPA, 1991). In the United
States, propionic acid and its salts, when used as a feed, grain, or
silage preservative, are regulated under the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA). Under FIFRA, each product using
propionic acid as the active ingredient must be separately registered
for use. Propionic acid is listed as a substance exempted from
requirement of a tolerance when used in accordance with good
agricultural practices as an ingredient in pesticide formulations
applied to growing crops or raw agricultural commodities after harvest
\[40 CFR 180.1001(c)\].

Propionic acid is also used as a chemical intermediate for the
production of cellulose propionate plastics and other plasticizers, and
as an intermediate for herbicides and pharmaceuticals. Cellulose acetate
propionate (CAP) is produced by reaction of propionic acid and acetic
acid or their anhydrides with cellulose. CAP is used in the production
of plastics, such as for toothbrush and other brush handles (Johnson and
Esker, 1999, Budavari, 1996). Propionic acid is also used to manufacture
polymer intermediates and pharmaceutical intermediates. Additional
smaller uses include the manufacture of propionic anhydride, methyl
propionate, and chlorinated derivatives (Johnson and Esker, 1999, HSDB,
2005).

Other minor uses include the manufacture of flexographic inks and
surface coatings (Bizzari et al., 1999). Additional relatively minor
uses reported for propionic acid have been reported to be as an additive
in electroplating (Sittig, 1985) and paints (Kirk-Othmer, 1983; NLM,
2007).

Consumption patterns in Europe and Japan are similar to those of the
USA, with the largest use as a feed and corn preservative.

Propionic acid also occurs naturally in foods, and together with other
short-chain fatty acids, is ubiquitous in the gastrointestinal tract of
humans and other mammals as end products of microbial digestion
(Harrison, 1992; Mellon et al., 2000).

Propionic acid is found naturally in humans as a normal intermediary
metabolite that represents up to 4% of the normal total plasma fatty
acids (Clayton and Clayton, 1994). In humans, propionic acid is formed
as a metabolite from the breakdown of the amino acids isoleucine,
valine, methionine, and threonine (Mellon et al., 2000). It is formed as
a terminal 3-carbon fragment in the oxidation of fatty acids, and from
the oxidation of the side chain of cholesterol (WHO, 1974a).

## 2.2 Environmental Exposure and Fate

### 2.2.1 Sources of Environment Exposure

# 

Propionic acid is manufactured within enclosed synthesis equipment using
scrubbers and other emission controls; the product is transported to
storage and shipping containers using fixed, in-place piping connected
directly to the container to minimize releases to the environment.
Process wastes are collected for recycling, treatment in biodegradation
facilities, or incineration on site. Propionic acid is shipped in bulk
in tank railcars or trucks. Smaller quantities are transported in drums.
Propionic acid may be released to the environment during transfer,
transportation, storage and disposal activities. Any spillage during
loading or handling would be recovered according to facility
regulations, and prevented from entering sewers or waterways. Emissions
of propionic acid during manufacture are not anticipated to be large,
since manufacturing equipment is enclosed and scrubbers are used to
prevent releases during the continuous synthesis process.

Aqueous waste streams may be treated in biodegradation facilities. In
the United States, propionic acid is designated as a hazardous substance
under Section 311 (b)(2)(A) of the Federal Pollution Control Act and is
further regulated by the Clean Water Act Amendments of 1977 and 1978.
The major source of environmental release is during application as a
preservative. The most likely environmental medium for propionic acid
emissions is water and soil.

In the U.S., neutralized acids are more likely to be encountered in many
water bodies than unbuffered acids in situations other than spills
because effluents discharged to publicly-owned sewage/wastewater
treatment works are required to be non-corrosive (e.g., no pH \< 5.0) to
protect the microbes in wastewater treatment plants \[40 CFR 403.5\].

Monitoring data for propionic acid suggests that the environmental
concentrations of propionic acid occur both naturally and artificially.
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 and
Winchester, 1989). 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, New Mexico. At Langmuir, New Mexico,
propionic acid was detected during the winter of 1995 at \<1 ppb
(Gaffney et. al., 1997).

The average and maximum propionic acid concentrations for the ambient
air over the Netherlands in 1980 were reported to be 0.15 and 2.0 ppb
(Guichert and Schulting, 1985). Propionic acid was detected in the
ambient air of Los Angeles, California from July to September 1984 at
concentrations ranging from 0.019 to 0.305 ppb (Kawamura et. al., 1985).
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 et al,
1989). This suggests that propionic acid is produced by photooxidation
of anthropogenic compounds during long-range transport.

Propionic acid has been detected in rain and snow precipitation at low
concentrations. For example, levels have been found to range from 0.3
µmol (75 cm ppt) to 0.8 µmol (94 cm ppt) (Chapman et al., 1986).
Propionic acid was detected in groundwater samples near a coal
gasification site near Hoe Creek in northeastern Wyoming (Stuermer et
al, 1982). It has been detected in ground-waters contaminated with
leachates from municipal and industrial landfills and hazardous waste
sites (Albaiges et al, 1986; Burrows and Rowe, 1975; Lema et al, 1988).
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, 1988). Wood preserving chemicals at
Pensacola, FL were 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., 1985).

The Ohio and Little Miami Rivers and Tanners Creek, Ohio water contained
propionic acid at concentrations ranging from 0.1 to 0.8 µg/l (Murtaugh
et al, 1965). Water samples from Lake Kizaki, Japan on Oct 28, 1977
contained propionic acid at concentrations ranging from undetected
levels to 90 µg/l (Hama and Handa, 1981).

The use of propionic anhydride as a chemical intermediate in nonpolar
solvents produces some propionic acid in the waste stream but the amount
is expected to be small.

### 2.2.2 Photodegradation 

The photochemical removal of propionic acid from the troposphere occurs
by reaction with hydroxyl radicals. This reaction is the rate-limiting
step governing the overall residence time of propionic acid in air.
Using the EPA‑developed model AOPWIN (version 1.91), secondary rate
constants for hydroxyl-radical mediated atmospheric photo-oxidation for
propionic acid were calculated to be 1.16 to 1.39 x 10^-12^
cm^3^/molecule-sec. Using a global average tropospheric hydroxyl radical
concentration of 1.5 x10^6^ OH molecules/cm^3^, and assuming 12 hours of
sunlight per day, pseudo first-order half-lives of 7.7 to 9.2 days were
calculated for propionic acid (Atkinson, 1989; AOPWIN, 2000). Another
estimated half life is 11 days (Bidleman, 1988; Atkinson, 1994). Upon
contact with water vapor in the atmosphere, propionic acid is
anticipated to ionize primarily to the dissociated form due to its pKa
of 4.9. However, dissociation depends on the amount of water vapor in
the air.

### 2.2.3 Environmental Stability

[Stability in Water]{.underline}

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 4.9 (Riddick et al, 1985), propionic
acid and the propionate ion are anticipated to exist in varying
proportions that are pH dependent. The ionized form will predominate at
neutral pH .

######## Stability in Soil

Volatilization of propionic acid is not expected from moist soil
surfaces based on its Henry's Law constant of 0.0420 Pa-m^3^/mole at
25ºC (Hine and Mookerjee, 1975). Upon release, propionic acid is
expected to volatilize from dry soil surfaces, based on a vapor pressure
of 4.7 hPa (Daubert and Danner, 1989).

The sorption characteristic of propionic acid is anticipated to be
dependent on organic content of the soil as well as pH and electrolyte
concentration. Under alkaline conditions (pH \>6.87), propionic acid is
anticipated to exist as the propionate ion which is not expected to
volatilize from moist soil or adsorb to soil as strongly as the acid
(Swann et al., 1983). The estimated K~oc~ value for propionic acid is
1.21, based on a log K~ow~ of 0.33 (Hansch et al., 1995); this value
suggests that propionic will display very high mobility in soil (Swann
et al., 1983). Monitoring data has demonstrated that propionic acid can
migrate into ground water (Burrows and Rowe, 1975; Lema et al, 1988;
Goerlitz et al, 1985).

### 

### 2.2.4 Transport Between Environmental Compartments

Fugacity modeling (Level III) was conducted for propionic acid using
EPISuite v3.12. Input parameters for propionic acid included molecular
weight 74.08 g/mol, melting point --21.5°C, water solubility 1,000,000
mg/L (miscible in water), vapor pressure 4.7 hPa, log Kow 0.33 at 25ºC,
and Henry\'s law constant of 0.0420 Pa-m^3^/mol. Half-lives in air,
water, soil and sediment were calculated by the model to be 210, 208,
416, and 1870 hours, respectively. Assuming equal and continuous diffuse
releases to air, surface water and soil, the resulting relative
distribution of propionic acid was 5.5% to air, 37.4% to water, 56.5% to
soil, and \<0.1% to sediment. 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.

In air, the vapor pressure of propionic acid of 4.7 hPa (3.53 mm Hg) at
25°C and its miscibility in water suggest that the acid will exist
solely as a vapor, as indicated in a model of gas/particle partitioning
of semi-volatile organic materials in the atmosphere (Daubert and
Danner, 1989). Airborne vapor is subject to photo-oxidation..

Because propionic acid is miscible in water, have a vapor pressure of
4.7 hPa, has a Henry's law constant of 0.0420 Pa-m^3^/mol at 25ºC, and a
molecular weight of 74.08 g/mol, it is not expected to volatilize
readily from surface waters. Volatilization is also not likely at
neutral pH because the acid exists mainly as the propionate anion. This
is shown by the estimated volatilization half-lives of 61.07 days and
1.83 years from a model river and lake, respectively (Lyman et al.,
199).

Propionic acid released onto soil will be subject to biodegradation but
will also exhibit high mobility. The estimated K~oc~ for propionic acid
of 1.201 along with the log octanol/water partition coefficient of 0.33
suggest that propionic acid will partition readily into soil, sediment,
or biota. Similarly, propionic acid in these media would tend to move to
water or ground-water if available.

### 2.2.5 Biodegradation

Propionic acid was evaluated for aerobic biodegradability using a
standard manometric technique (Warburg Respirometer). The 30-day
biochemical oxygen demand (BOD) test was conducted using combined
non-adapted domestic sewage as the inoculum. Biodegradation of propionic
acid measured after 5, 10, and 30 days was 71, 73, and 74% of the
theoretical oxygen demand (ThOD), respectively (Dias and Alexander,
1971). Malaney and Gerhold (1969) used the Warburg Respirometer
technique to assess the aerobic biodegradation of propionic acid over a
24-hour interval. Propionic acid (500 mg/L) was added to activated
sludge solids. Biodegradation after 6, 12, and 24 hours was 18.6, 30.8,
and 40.4% of the theoretical oxygen demand (ThOD), respectively.

The anerobic biodegradation of propionic acid was evaluated in an
acetate-enriched culture originated from domestic sewage sludge.
Propionic acid was added to Hungate serum bottles at a concentration of
500 to 1000 mg/L. There was 100% biodegradation after 20 days. In a
long-term anerobic acclimation study using a concentration of 10,000
mg/L, it was determined that after a lag time of 48 hours, the removal
rate for propionic acid was 100 mg/L/day (Chou et al., 1978). These
results demonstrate that propionic acid is readily biodegraded under
aerobic and anerobic conditions.

> **Table 3:** Biotic Degradation of Propionic Acid

+-----------+-------------------+------------------------+------------+
| **Type**  | **Results^1^**    | **Method**             | **R        |
|           |                   |                        | eference** |
+-----------+-------------------+------------------------+------------+
| Aerobic   | BOD~5\ days~ =    | Warburg Respirometer   | Dias and   |
|           | 71% ThOD          |                        | Alexander, |
|           |                   | freshwater, aerobic,   | 1971       |
|           | BOD~10\ days~ =   | domestic sewage seed   |            |
|           | 73% ThOD          |                        |            |
|           | BOD~30\ days~ =   |                        |            |
|           | 74% ThOD          |                        |            |
+-----------+-------------------+------------------------+------------+
| Aerobic   | BOD~6\ hours~ =   | APHA Standard Methods, | Malaney    |
|           | 18.6% ThOD        | 1971.                  | and        |
|           |                   |                        | Gerhold,   |
|           | BOD~12\ hours~ =  | seawater               | 1969       |
|           | 30.8% ThOD        | microorganisms,        |            |
|           | BOD~24\ hours~ =  | non-adapted            |            |
|           | 40.4% ThOD        |                        |            |
+-----------+-------------------+------------------------+------------+
| Anerobic  | BOD~20\ days~ =   | Hungate serum bottle   | Chou,      |
|           | 100% ThOD removal | technique (methane     | Speece,    |
|           | rate 100 mg/L/day | fermentation)          | and        |
|           |                   |                        | Siddiqui,  |
|           |                   |                        | 1978       |
+-----------+-------------------+------------------------+------------+

1: BOD = Biochemical Oxygen Demand; ThOD = Theoretical Oxygen Demand

### 2.2.6 Bioaccumulation

Using a calculated n-octanol/water partitioning coefficient (Log K~ow~)
value of 0.33 at 25ºC (Hansch et al., 1995), a bio-concentration factor
(BCF) of 3.16 has been calculated for propionic acid (BCFWIN, v. 2.15).
The equation used was Log BCF = 0.77 Log Kow -- 0.70. Based on this
value, it is anticipated that propionic acid would display a low
bioaccumulation potential (Meylan and Howard, 1997).

## 2.3 Human Exposure 

Propionic acid occurs naturally in foods, and together with other
short-chain fatty acids, is ubiquitous in the gastrointestinal tract of
humans and other mammals as end-products of microbial digestion
(Harrison, 1992). Propionic acid is found naturally in humans as a
normal intermediary metabolite that represents up to 4% of the normal
total plasma fatty acids (Clayton and Clayton, 1994). In humans,
propionic acid is formed as a metabolite from the breakdown of a variety
of amino acids including isoleucine, valine, methionine, and threonine
(Mellon et al., 2000). It is formed as a terminal 3-carbon fragment in
the oxidation of fatty acids, and from the oxidation of the side chain
of cholesterol (WHO, 1974a).

In a 1973 evaluation by the Joint FAO/WHO Expert Committee on Food
Additives which was re-affirmed in 1997, the acceptable daily intake
(ADI) of propionic acid and its sodium and calcium salts was designated
as "not limited." A similar conclusion was reached by the USEPA (2003)
when it proposed to establish an exemption from the requirement of a
tolerance limit for residues of propionic acid and its sodium salts.

General population exposure occurs via ingestion of foods containing
propionic acid either naturally or when used as a food preservative or
additive. Indirect exposures via the environment (air, water, soil) are
possible. However, possible exposures from these sources are anticipated
to be small because of the breakdown of propionic acid in the
environment.

### 2.3.1 Occupational Exposure

Propionic acid is a corrosive, flammable material with a flash point of
50ºC (122 ºF); it has a sour, disagreeable odor and a low odor
threshold. Propionic acid is manufactured in a continuous process using
enclosed equipment. In the United States, worker exposure is expected to
be minimal, since manufacture and use activities are typically conducted
in closed systems using engineering controls.

Minimal exposure may occur during maintenance, tank car loading and drum
filling, and quality control sampling. Occupational exposure is likely
to occur to a greater extent during application of propionic acid as a
food and feed preservative, especially when applied to growing crops or
crops after harvest. The recommended occupational exposure limit for
propionic acid is 10 ppm or 30 mg/m^3^ (ACGIH, 2005). These are guidance
values only and not regulatory in nature.

> **Table 4: Exposure Limits\* for Propionic Acid**

  ------------------------- --------------------------- ------------------
  **Type**                  **Exposure Limit**          **Reference**

  8-hour TWA (USA)          10 ppm (30 mg/m^3^)         ACGIH, 2005

  NIOSH REL (USA)           10 ppm (30 mg/m^3^)         ACGIH, 2005

  NIOSH-STEL (USA)          15 ppm (45 mg/m^3^)         ACGIH, 2005

  MAK (Germany)             10 ppm (31 mg/m^3^          ACGIH, 2005
  ------------------------- --------------------------- ------------------

> \*TWA: 8-hr Time Weighted Average
>
> STEL: 15-min Short Term Exposure Limit
>
> REL: 10-hr Recommended Exposure Level
>
> MAK: Maximum Concentration

In comprehensive guidance to workers who use or make flavoring agents,
both the Flavor and Extract Manufacturers Association of the United
States and NIOSH have issued information to workers about methods to
limit inhalation exposure to flavoring agents (FEMA, 2004; NIOSH, 2003).
Although propionic acid is listed as a flavoring agent in both
documents, occupational exposures to propionic acid are expected to be
limited in the United States and other countries that have established
occupational exposure limits for this material. Occupational exposure
limits for propionic acid are presented above in Table 4 (ACGIH, 2005).

Detailed information regarding ventilation and safety equipment used
where propionic acid is produced or utilized is not readily available.
However, based on flammable and corrosive properties of propionic acid,
as well as warnings, handling, and ventilation precautions contained in
the material safety data sheet (MSDS), it is anticipated that vapor
concentrations will be maintained at a level lower than the occupational
exposure limit and that recommended personal protective clothing to
prevent skin and eye contact (NIOSH, 2005) will be used at locations
where over-exposures may occur. Information on recommended methods to
limit inhalation exposure to propionic acid are also available (NIOSH,
2003).

### 2.3.2 Consumer Exposure

In addition to endogenous exposure to propionic acid, consumer exposure
to propionic acid may result from ingestion of foods that contain
propionic acid as a feed and grain preservative, or from the use of
propionate salts which are also employed as preservatives. Propionic
acid is used in the manufacture of artificial flavoring agents (Furia
and Bellanca, 1975, HSDB, 2005). In the United States, propionic acid is
a material generally regarded as safe (GRAS) by the Food and Drug
Administration (FDA) for direct addition to human food when used as an
anti-microbial agent or as a flavoring agent (21 CFR 184.1081).

Propionic acid is also used as an industrial intermediate to produce CAP
plastics, herbicides, polymers, pharmaceuticals, perfume bases, and
propionic anhydride. In these cases, potential consumer exposure is
minimal since propionic acid is not added to the final product.

Propionic acid occurs naturally in a variety of foods. Consumer exposure
may also occur from ingestion of foods that contain propionic acid.
Propionic acid occurs naturally in dairy products in small amounts
(Budavari, 1996) and occurs naturally in Swiss cheese at levels as high
as 1% (Furia, 1980). It has been isolated from boiled beef and dry cured
ham (Furia and Bellanca, 1975). Propionic acid has been qualitatively
detected as a volatile component of baked potatoes (Coleman et al.,
1981), cooked meats (Shibamoto et al., 1981), Dalieb fruit (Harper et
al., 1986), fruit brandies and dessert wines (Sponholz et al., 1989)
strawberries (Dirinck et al., 1984) and popcorn (Buttery et al., 1997).

[]{.mark}

### 2.3.3 Indirect Exposure via the Environment

Monitoring data for propionic acid suggests that the environmental
concentrations of propionic acid occur both naturally and artificially.
The use of propionic acid as a feed preservative, and its use to control
fungi in drinking water for livestock and poultry may result in its
release into the environment. It is also released into the environment
through the use of coal-derived shale oil liquid fuels, and during
disposal of coal liquefaction and gasification and wood preserving
chemical by-products. Textile mills, sewage treatment facilities,
municipal and industrial landfills, and gasoline and diesel fuelled
engines may release propionic acid into the environment.

# **3.0 HUMAN HEALTH HAZARDS**

Data from calcium propionate studies have been included in this section.
Calcium propionate dissociates in water and acts as a source of
propionate anions. Data from calcium propionate are useful when
assessing the hazards associated with the systemic toxicity of propionic
acid exposure. Calcium propionate is used as a surrogate compound for
the developmental toxicity endpoint.

## 3.1 Effects on Human Health

[]{.mark}

### 3.1.1 Toxicokinetics, Metabolism and Distribution 

Propionic acid is found naturally in humans as a normal intermediary
metabolite that represents up to 4% of the normal total plasma fatty
acids (Clayton and Clayton, 1994). In humans, propionic acid is formed
as a metabolite from the breakdown of the amino acids isoleucine,
valine, methionine, and threonine (Mellon et al., 2000). It is formed as
a terminal 3-carbon fragment in the oxidation of fatty acids, and from
the oxidation of the side chain of cholesterol (WHO, 1974a).

Propionic acid administered to rats has appeared in glycogen, glucose,
lipids, amino acids, and proteins. The route of metabolism involves
interaction with co-enzyme A, carboxylation to form
methylmalonyl-coenzyme A, and conversion to succinic acid which then
enters the citric acid cycle (WHO, 1974a; Clayton and Clayton, 1994). No
data are available on the toxicokinetics of of propionic acid.

Human (Schmutte et al., 1998; Rudell et al., 1983) and rat (Poet et al.,
2004) studies have demonstrated that short-chain saturated alcohols are
rapidly absorbed and metabolized to aldehydes which are then oxidized to
their respective acids.

### 3.1.2 Acute Toxicity

Acute inhalation, dermal, and oral studies on propionic acid are
discussed below and are summarized in Table 5.

[Studies in Animals]{.underline}

*Inhalation*

There was no mortality among a group of 6 rats exposed to a nominal
concentration of 36 ppm (0.14 mg/L) propionic acid vapor for 8 hours
(Union Carbide, 1957, Smyth et al., 1962). Although there was no
mortality, animals displayed signs of nasal, ocular, and skin
irritation.

In a later study, groups of male and female rats (10 per sex) were
exposed for one hour to saturated vapor/aerosol atmospheres of 2.7 or
19.7 mg/L propionic acid. One rat (1/20) died after exposure to 19.7
mg/L. Necropsy of this animal revealed congested lungs, pulmonary edema
and partial atelectasis, with intestines filled with gas. No other
mortality was observed. Clinical signs in all high dose animals during
exposure included slightly reduced respiration frequency, gasping,
narrowed eyelids, salivation, nasal secretion, and slight corneal
opacity. Signs observed in the low dose animals included narrowed
eyelids. 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. Necropsy of animals that were sacrificed at
the end of the 14-day observation interval revealed multiple petechia in
the lung in 4 of the surviving19 animals in the high dose group (BASF,
1979).

####### Dermal

Groups of four male rabbits were exposed for a single 24-hour interval
to propionic acid applied full strength under occluded conditions to the
clipped intact skin. Doses applied were 0.3125 or 0.625 ml/kg bw.
Mortality was 3/4 for the group receiving 0.625 ml/kg, with all deaths
occurring on the day of dosing.There were no deaths among animals that
received 0.3125 ml/kg. The dermal LD~50~ value for propionic acid was
determined to be 0.50 ml/kg or 490 mg/kg bw in male rabbits. Necropsy of
animals dying on study revealed hemorrhage of the lungs and intestines,
mottled livers and congested kidneys. Covered application of propionic
acid to the intact skin for 24 hours also resulted in necrosis at the
site of application (Union Carbide, 1957; Smyth et al, 1962).

Groups female Harlan-Wistar rats (120-180g) received increasing doses of
propionic acid, applied undiluted to intact (non-abraded) skin under
occluded conditions for 4 hours. The number of doses applied and the
concentration of each dose were not provided. 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 (Union Carbide, 1974b).

####### Oral

The oral toxicity of propionic acid was evaluated in groups of five male
non-fasted rats; the test material was administered as a 10% aqueous
solution at doses of 0, 2, 4, or 8, ml/kg (0, 1987, 3973, or 7947 mg/kg
bw) by oral gavage. The LD~50~ for the 10% solution of propionic acid in
male rats was determined to be 4.29 ml/kg bw (4,260 mg/kg bw); for
undiluted propionic acid, the LD~50~ is estimated to be 426 mg/kg bw.
Necropsy of animals that died revealed hemorrhagic and congested lungs
and gastrointestinal tracts, and "burned" surfaces of kidney, liver,
spleen and adrenal gland where contact was made with the
gastrointestinal tract (Union Carbide, 1957; Smyth et al, 1962).

A later study investigated the toxicity of undiluted propionic acid in
non-fasted female rats. The dose range tested and the number of rats per
group was not reported. The LD~50~ for female rats was 351 mg/kg bw
(Union Carbide, 1974b).

Groups of male and female rats (5 per sex per group) received 2000,
2500, 3200, 4000, 5000, or 6400 ml/kg bw propionic acid (equivalent
doses: 1986, 2483, 3178, 3972, 4965, and 6355 mg/kg bw) by oral
intubation. 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. The LD50 was determined to be 3490 ml/kg bw (3470 mg/kg bw) for
both sexes; it is not known if animals were fasted prior to
adminstration of the test material. Clinical signs included squatting
posture, agitation or apathy, dyspnea, cyanosis, and ruffled fur.
Necropsy of animals that died on study revealed large amount of liquid
in the abdomen and discoloration around the snout (BASF AG, 1969).

[**Table 5: Summary of Acute Toxicity Studies for Propionic
Acid**]{.mark}

+-----+----+-----------+-------+-----------+--------+---------------+
| S   | S  | Route     | Ty    | Value     | Sc     | Reference     |
| pec | ex |           | pe^1^ |           | ore^2^ |               |
| ies |    |           |       |           |        |               |
+-----+----+-----------+-------+-----------+--------+---------------+
| []{ | N  | I         | LC~0~ | 0.14 mg/L | 2      | Union Carbide |
| .ma | S^ | nhalation |       |           |        | Corp., 1957   |
| rk} | 3^ | of        |       | (36 ppm)  |        |               |
|     |    | saturated |       |           |        | Smyth et al., |
| Rat |    | vapor     |       |           |        | 1962          |
|     |    |           |       |           |        |               |
|     |    | 8 hours   |       |           |        |               |
+-----+----+-----------+-------+-----------+--------+---------------+
| []{ | M  | I         | L     | \>19.7    | 2      | BASF AG, 1979 |
| .ma | /F | nhalation | C~50~ | mg/L      |        |               |
| rk} |    | of        |       |           |        |               |
|     |    | saturated |       |           |        |               |
| Rat |    | vapo      |       |           |        |               |
|     |    | r/aerosol |       |           |        |               |
|     |    |           |       |           |        |               |
|     |    | 1 hour    |       |           |        |               |
+-----+----+-----------+-------+-----------+--------+---------------+
| []{ | M  | Dermal    | L     | 490 mg/kg | 2      | Union Carbide |
| .ma |    |           | D~50~ | bw        |        | Corp., 1957   |
| rk} |    | 24 hours  |       |           |        |               |
|     |    |           |       |           |        | Smyth et al., |
| Rab |    |           |       |           |        | 1962          |
| bit |    |           |       |           |        |               |
+-----+----+-----------+-------+-----------+--------+---------------+
| []{ | F  | Dermal    | L     | 1669      | 2      | Union Carbide |
| .ma |    |           | D~50~ | mg/kg bw  |        | Corp, 1974b   |
| rk} |    | 4 hours   |       |           |        |               |
|     |    |           |       |           |        |               |
| Rat |    |           |       |           |        |               |
+-----+----+-----------+-------+-----------+--------+---------------+
| Rat | M  | Oral      | L     | 426 mg/kg | 2      | Union Carbide |
|     |    |           | D~50~ | bw        |        | Corp., 1957   |
|     |    |           |       |           |        |               |
|     |    |           |       |           |        | Smyth et al., |
|     |    |           |       |           |        | 1962          |
+-----+----+-----------+-------+-----------+--------+---------------+
| Rat | F  | Oral      | L     | 351 mg/kg | 2      | Union Carbide |
|     |    |           | D~50~ | bw        |        | Corp., 1974b  |
+-----+----+-----------+-------+-----------+--------+---------------+
| Rat | M  | Oral      | L     | 3470      | 2      | BASF AG, 1969 |
|     | /F |           | D~50~ | mg/kg bw  |        |               |
+-----+----+-----------+-------+-----------+--------+---------------+

1: LD = Lethal Dose; LC = Lethal Concentration

2: Reliability Score

3: NS = Not Specified

######## Conclusion

Although there was only one death among rats exposed to a saturated
vapor/aerosol atmosphere (19.7 mg/L), there were significant signs of
respiratory, skin and eye irritation. The dermal LD~50~ for a 24-hr
exposure was 490 mg/kg bw. The range of oral LD~50~ values that have
been estimated for rats is between 351 and 3470 mg/kg bw; the reason for
the variation in these values may be due to the age, body weights, or
prandial state of the test animals.

### 

### 3.1.3 Irritation 

######## Skin Irritation

*Studies in Animals*

Application of 0.01 ml (10 mg) undiluted propionic acid to the uncovered
clipped skin of male rabbits for 24 hours produced necrosis 24 hours
after application (Smyth et al., 1962; Union Carbide Corp., 1957).
Uncovered application of a 10% aqueous solution of propionic acid to the
skin of rabbits for 24 hours produced moderate to marked erythema (grade
6 on a Draize scale of 10; Smyth et al., 1962).

A volume of 0.5 ml (500 mg) of undiluted propionic acid was administered
to the skin of 5 guinea pigs. Skin reaction was observed and recorded at
2, 24, and 48 hrs. At 2 hours after administration, slight to moderate
edema, moderate to severe erythema, and necrosis were observed. After 24
hr, the application site was necrotic with erythema around the
periphery. At 48 hrs, 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 (Eastman Kodak, 1974).

These data indicate that propionic acid is a corrosive material and may
produce severe skin irritation.

######## Eye Irritation

######## 

*Studies in Animals*

######## 

Instillation of a small volume (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 of propionic acid caused less severe
burns. Among rabbits treated with 0.1 ml of a 1% aqueous solution of
propionic acid, 3 of 5 were unaffected, while 2 of 5 displayed minimal
corneal damage (Union Carbide Corp., 1957). Exposure to a saturated
vapor/aerosol atmosphere (19.7 mg/L) for one hour produced corneal
opacity in rats (BASF AG, 1979). These results indicate that propionic
acid can cause severe eye irritation and corneal injury. Dilute
solutions (1% or less) of propionic acid are anticipated to cause
minimal eye damage.

######## 

######## Respiratory Tract Irritation

*Studies in Animals*

Acute inhalation toxicity studies in rats have been conducted with a
saturated vapor/aerosol atmosphere of propionic acid (19.7 mg/L).
Although mortality was only 1/20 at this concentration, animals
exhibited slightly reduced respiration frequency, gasping, narrowed
eyelids, salivation, and nasal secretion during exposure (BASF AG,
1979). These results suggest that propionic acid can cause respiratory
irritation.

*Studies in Humans*

Anecdotal information indicates workers did not experience symptoms of
respiratory irritation when exposed to propionic acid at 8-hr TWA levels
below 0.25 ppm with excursions to 2.1 ppm (ACGIH, 1991).

######## Conclusion

As a liquid, undiluted propionic acid is a corrosive material and can
produce severe skin and eye irritation. Animals exposed to a saturated
vapor/aerosol atmosphere (19.7 mg/L) of propionic acid exhibited signs
of nasal and respiratory tract irritation. Propionic acid should be
considered a respiratory tract irritant.

### 3.1.4 Sensitization

#### Studies in Animals

No definitive skin sensitization studies have been conducted in animals
for propionic acid.

Studies in Humans

Occupational sensitization has not been reported among workers. There
was no sensitization response to sodium propionate in trials with human
subjects following topical use (Haseltine, 1952). A reproducible
positive pin-prick response to a 5% aqueous solution of propionic acid
was obtained in 3 of 91 patients suffering from chronic urticaria;
patients were presumed to have prior exposure with propionic acid as a
food preservative. There was no response observed among 247 normal
control (non-urticaria) subjects (Malanin, and Kalimo, 1989).

Conclusion

There are no sensitization data for animals. There is no definitive skin
sensitization studies in humans. Therefore, a conclusion as to the
sensitization of propionic anhydride cannot be made.

### Repeated Dose Toxicity 

[Studies in Animals]{.underline}

*Inhalation*

Propionic acid is a corrosive material and a respiratory irritant. There
are no other inhalation repeated-dose toxicity studies available for
propionic acid.

*Dermal*

There is one repeated-dose dermal toxicity study for propionic acid.
Groups of 10 CD-1 (ICR) BR female mice received 50 μl of propionic acid
solution dissolved in water. Solutions of 8%, 10% or 14% propionic acid
were applied daily to the shaved skin of the interscapular area 5 days
per week for 101 days. No gross skin alterations were observed in mice
in the 8% group. At higher concentrations, skin changes at the
application site including eschar, erythema, and scale or crust
formation. Histological changes, including acanthosis and fibrous
condensation of the stratum reticulare of the corium connective tissue
were observed in all treated groups, the severity of changes increasing
with increased dose. Metaplasia and hyperplasia were not reported (BASF
AG, 1990a).

*Oral*

In studies conducted in a manner similar to OECD guideline studies,
repeated-dose toxicity was evaluated in a 100-day study in dogs and in a
91-day study in rats. In both studies, no systemic toxicity was seen,
and only point-of-contact effects were observed, including chronic
irritation with associated inflammation and proliferative repair
responses. Additional feeding studies in rats range from 28 days to
lifetime exposure. However, these studies focused only on
point-of-contact effects in the forestomach and the outcome of the
studies varied with the consistency of the diet (pelleted vs. powdered).

The dog feeding study is considered to be the definitive study for the
investigation of the repeated dose toxicity of propionic acid.

Propionic acid was fed in the diet to male and female Beagle dogs for
approximately 100 days. Groups of dogs (8 of each sex) received a 0,
0.3, 1.0, or 3.0 % propionic acid in the diet. After the administration
interval, eight high dose and control animals (4 of each sex) were
maintained for an additional 6-week recovery interval. During the
administration interval, there was no mortality and dogs did not display
clinical signs of toxicity. Based upon food consumption, the mean daily
dose administered to high dose male dogs ranged between 2,491 and 1,848
mg/kg. For high dose females, the mean daily dose administered ranged
between 2,209 and 1,832 mg/kg.

Dogs from the high-dose group displayed a decrease in appetite, which
was attributed to the unpleasant taste of the test material; the
decrease in food consumption did not significantly affect body weights
or body weight gains. There were no significant changes in hematology,
urinalysis, or clinical chemistry parameters that could be attributed to
the test material. Necropsy of dogs after the administration interval
revealed no gross lesions. Examination of tissues revealed no lesions
except point-of-contact diffuse epithelial hyperplasia of the mucosa of
the esophagus in three dogs in the high dose group. At the end of the
recovery interval, the incidence of lesions of the esophagus were the
same in control and high dose animals. The incidence of focal epithelial
hyperplasia in lower dose animals was comparable to controls. Based on
the presence of diffuse epithelial hyperplasia in the esophagus, the
LOAEL for this study is 3% propionic acid in the diet or 1,848 mg/kg bw
for male dogs, and 1,832 mg/kg bw for female dogs. The NOAEL for this
study is 1% propionic acid in the diet, or 660 and 696 mg/kg bw for male
and female Beagle dogs, respectively (BASF, 1988).

Groups of male and female Sprague Dawley rats were offered a daily diet
containing 0, 6200, 12500, 25000, or 50000 ppm propionic acid (0, 0.62%,
1.25%, 2.5%, or 5% of the diet). Each group consisted of 20 animals per
sex per dose and an additional 10 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 and
tissues collected for histological examination. Ten rats from the
control, low dose (0.62%), and high dose (5% propionic acid) groups were
assigned to post-exposure recovery groups and fed the control diet for 6
weeks. During the administration interval, there was no mortality and no
clinical signs of toxicity. Food consumption was slightly reduced in
males in the high dose (5%) group and by the end of the study, mean body
weights in this group were reduced by 6% relative to controls. There
were no significant changes in haematology or clinical chemistry
parameters that could be attributed to the test material. There were no
differences in absolute organ weights in treated groups relative to
controls. Relative kidney weights were decreased in high dose males
(12%). In high dose females, there was an increase in the relative
weights of the heart (5%) and liver (9%). Examination of tissues
revealed no lesions except point-of-contact changes of the mucosa of the
forestomach in rats in the 5% treatment group, these changes included
acanthosis, hyperkeratosis, and proliferation of the epitheium. The
changes observed in the forestomach were not observed in the
post-exposure recovery group, and there were no differences in relative
or absolute organ weights. (BASF AG, 1971). Based on these results, the
NOAEL for this study is 2.5% propionic acid in the diet.

There are other repeated-dose toxicity studies in rats in which
propionic acid is administered in the diet. Propionic acid is
incorporated into the food, which is then presented in a powdered or
pelleted form. The primary focus of these studies is the site-of-contact
effect of propionic acid on the forestomach epithelial mucosa and in
these studies other tissues were not examined. Hyperplastic changes and
papillomatous growths in the forestomach can occur, although the
incidence and severity of such changes varies with dose and diet
consistency. The data indicate that these point-of-contact effects are
the result of chronic irritation and the associated
inflammation/repair/proliferative responses that can produce a
non-genotoxic tumorigenic effect. It should be noted that neoplastic
lesions in response to oral administration of propionic acid have not
been reported. Histopathological changes were observed only in the
forestomach.

Groups of male rats were fed a control diet or a
*[pelleted]{.underline}* diet containing 4% propionic acid (assumed to
be about 2,700 mg/kg bw/day based on data from other studies) for 24
weeks. Macroscopic and histopathological examination of the stomach
revealed no adverse effects (Bueld and Netter, 1993). The same authors
fed groups of male rats a control diet, or a *[powdered]{.underline}*
diet containing 4% propionic acid (assumed to be 2,700 mg/kg bw/day
based on data from other studies). After 12 weeks, these rats displayed
severe hyperplastic changes in the forestomach but not in the glandular
stomach. The consistency of the diet (pelleted vs. powdered) had a
direct effect on the incidence of lesions observed.

Groups of male rats were fed 0, 0.4, or 4% propionic acid in ground rat
feed for 20 weeks or their lifetime. Among animals fed 0.4% propionic
acid (approximately 270 mg/kg bw/day), there were no gross changes
visible in the forestomach, however hyperplasia and hyperkeratosis were
observed histologically. No changes were detected in the mucosa of the
glandular stomach. Among rats fed a diet containing 4% propionic acid
(approximately 2,700 mg/kg bw/day), forestomach epithelial changes such
as hyperplasia and hyperkeratosis were noted at 20 weeks, and
hyperplasia with ulceration, dyskeratosis, and papillomatous elevations
(one with unspecified "carcinomatous" changes) were noted after lifetime
exposure. Erosive changes were also seen in the glandular stomach,
although no accompanying histopathological changes were observed (Griem,
1985).

In an attempt to determine when forestomach effects are induced by
propionic acid, groups of rats were fed 4% propionic acid (approximately
2,700 mg/kg bw/day) in powdered diet. Rats were sacrificed and stomachs
examined and prepared for autoradiography on feeding day 9, 15, 21, and
27. Rats fed propionic acid for 27 days displayed thickening of the
mucosa with acanthosis, and hyperkeratosis along the lesser curvature of
the forestomach. Changes in the mucosa were accompanied by edema and
infiltration of eosinophils and lymphocytes. A two-fold increase in
radiolabel index (with methyl ^3^H thymidine) was observed only in the
midregion of the forestomach epithelium and did not become apparent
until day 27 (Rodrigues et al, 1986). Using the same protocol, Harrison
and coworkers (1991) detected early proliferative changes in rats after
only 7 days. These investigators also reported histological changes in
the epithelium of the forestomach in rats, mice and hamsters fed 4%
propionic acid in a powdered diet for 7 days.

[Conclusion]{.underline}

Repeated-dose oral toxicity studies in Beagle dogs and rats demonstrate
only point-of-contact effects and no systemic toxicity (Table 6). There
were no clinical signs of toxicity, no mortality, and no evidence of
systemic toxicity in male and female Beagle dogs fed propionic acid in
the diet for 100 days. Diffuse hyperplasia of the mucosa of the
esophagus was observed in three high-dose animals immediately after the
end of the administration interval, but not after a 6-week recovery
interval. No other lesions were observed. Hyperplasia and hyperkeratosis
of the mucosa of the forestomach was observed in rats fed propionic
acid. The changes observed upon feeding of high dose of propionic acid
are the result of chronic irritation and inflammation and the associated
hyperplastic proliferative repair response.

Because humans do not have a forestomach, it is not known whether
effects similar to those observed in the rat forestomach would occur in
humans. The rat forestomach is a storage organ and food may be held in
contact with the epithelium for many hours.

**Table 6: Repeated-dose Oral Toxicity Studies for Propionic Acid**

+---------+------------+---------+-----------------+-----+----------+
| **Sp    | **Dose     | *       | **Lesions       | **S | **Ref    |
| ecies** | Levels**   | *Route/ | Observed**      | cor | erence** |
|         |            | Dur     |                 | e^1 |          |
|         |            | ation** |                 | ^** |          |
+---------+------------+---------+-----------------+-----+----------+
| Beagle  | 0, 0.3,    | In      | No evidence of  | 1   | BASF,    |
| dog     | 1.0, 3.0%  | gestion | systemic        |     | 1988     |
| (M/F)   | in the     | up to   | toxicity. Point |     |          |
|         | diet       | 106     | of contact      |     |          |
|         |            | days    | effect noted as |     |          |
|         | 0, 196,    | 42-day  | hyperplasia of  |     |          |
|         | 660, 1848  | r       | the esophageal  |     |          |
|         | mg/kg bw   | ecovery | mucosa NOAEL =  |     |          |
|         | in males;  | i       | 1% in diet or   |     |          |
|         | 0, 210,    | nterval | 660 mg/kg bw    |     |          |
|         | 696,1832   |         | (M) 696 mg/kg   |     |          |
|         | mg/kg bw   |         | bw (F)          |     |          |
|         | in females |         |                 |     |          |
+---------+------------+---------+-----------------+-----+----------+
| Rat     | 0, 0.62%,  | In      | No evidence of  | 2   | BASF AG, |
| (M/F)   | 1.25%,     | gestion | systemic        |     | 1971     |
|         | 2.5%, or   | for 91  | toxicity.       |     |          |
|         | 5% in diet | days    | P               |     |          |
|         |            | 42-day  | oint-of-contact |     |          |
|         |            | r       | changes in      |     |          |
|         |            | ecovery | forestomach     |     |          |
|         |            | i       | NOAEL = 2.5% in |     |          |
|         |            | nterval | diet            |     |          |
+---------+------------+---------+-----------------+-----+----------+
| **      |            |         |                 |     |          |
| Feeding |            |         |                 |     |          |
| Studies |            |         |                 |     |          |
| for     |            |         |                 |     |          |
| S       |            |         |                 |     |          |
| ite-of- |            |         |                 |     |          |
| Contact |            |         |                 |     |          |
| Effects |            |         |                 |     |          |
| in the  |            |         |                 |     |          |
| Rat     |            |         |                 |     |          |
| Forest  |            |         |                 |     |          |
| omach** |            |         |                 |     |          |
+---------+------------+---------+-----------------+-----+----------+
| Rat (M) | 0, 4% in   | In      | None, no        | 2   | Bueld    |
|         | pelleted   | gestion | mortality       |     | and      |
|         | diet \[no  | 24      |                 |     | Netter,  |
|         | data on    | weeks   |                 |     | 1993     |
|         | food       |         |                 |     |          |
|         | co         |         |                 |     |          |
|         | nsumption; |         |                 |     |          |
|         | see text\] |         |                 |     |          |
+---------+------------+---------+-----------------+-----+----------+
| Rat (M) | 0, 4% in   | In      | Ulceration with | 2   | Bueld    |
|         | powdered   | gestion | marginal        |     | and      |
|         | diet \[no  | 12      | hyperplasia in  |     | Netter,  |
|         | data on    | weeks   | forestomach; no |     | 1993     |
|         | food       |         | changes to      |     |          |
|         | co         |         | glandular       |     |          |
|         | nsumption; |         | stomach         |     |          |
|         | see text\] |         |                 |     |          |
+---------+------------+---------+-----------------+-----+----------+
| Rat (M) | 0, 0.4,    | In      | 4% in diet      | 2   | Griem,   |
|         | 4.0% in    | gestion | (approximately  |     | W., 1985 |
|         | ground     | 20      | 2700 mg/kg      |     |          |
|         | (non       | weeks   | bw/day): At 20  |     |          |
|         | -pelleted) | or      | weeks,          |     |          |
|         | diet       | l       | hyperplasia and |     |          |
|         |            | ifetime | hyperkeratosis  |     |          |
|         | \[no data  |         | of forestomach  |     |          |
|         | on food    |         | mucosa. After   |     |          |
|         | co         |         | lifetime        |     |          |
|         | nsumption; |         | exposure:       |     |          |
|         | see text\] |         | ulceration,     |     |          |
|         |            |         | hyperplasia,    |     |          |
|         |            |         | hyperkeratosis, |     |          |
|         |            |         | papillomatous   |     |          |
|         |            |         | elevations in   |     |          |
|         |            |         | forestomach     |     |          |
+---------+------------+---------+-----------------+-----+----------+
| Rat (M) | 0, 4% in   | In      | 4% in diet      | 2   | R        |
|         | powdered   | gestion | (approximately  |     | odrigues |
|         | diet       | up to   | 2700 mg/kg      |     | et al.,  |
|         | (app       | 27 days | bw/day):        |     | 1986     |
|         | roximately |         | Thickening of   |     |          |
|         | 2,700      |         | forestomach     |     |          |
|         | mg/kg bw/  |         | mucosa with     |     |          |
|         | day)       |         | inflammatory    |     |          |
|         |            |         | infiltrates,    |     |          |
|         |            |         | acanthosis, and |     |          |
|         |            |         | hyperkeratosis  |     |          |
+---------+------------+---------+-----------------+-----+----------+

1: Reliability score

### 3.1.6 Genotoxicity

Data on gene mutations, chromosomal aberrations, and other genotoxicity
endpoints are summarized below and in Tables 8 and 9. Appropriate
responses were obtained with concurrent positive and negative controls
in these studies.

*In Vitro* *Studies -- Gene Mutations Assays*

Propionic acid was tested in two replicate assays as a coded chemical in
the *Salmonella typhimurium* mutagenicity assay using the pre-incubation
method and tester strains TA98, TA100, TA102, TA104, TA1535, TA1537, and
TA1538. In each replicate assay, propionic acid was tested in triplicate
at doses of 0, 100, 333, 1000, 3333, and 10,000 µg/plate in the presence
and absence of Arochlor-induced liver S-9 mix from Sprague Dawley rats
and Syrian hamsters. Toxicity was determined by a thinning of the
background lawn, and/or a reduction in the number of colonies per plate.
Propionic acid was not mutagenic when tested to a maximum dose of 10,000
µg/plate, both in the presence and absence of metabolic activation
(Zeiger et al., 1992).

Propionic acid was not mutagenic to bacteria in the *Salmonella
typhimurium* mutagenicity assay using both the standard plate
incorporation and pre-incubation assay protocols, both in the presence
and absence of metabolic activation (Litton Bionetics, 1976; Basler et
al, 1987).

In a yeast gene mutation assay, there was no evidence of mutagenic
activity when propionic acid was tested in *Saccharomyces cerevisiae*
(strain D4) yeast cells at concentrations up to 2.5% (v/v) or 2,500
mg/ml, both in the presence and absence of metabolic activation (Litton
Bionetics, 1976).

*In Vitro -- Other Assays*

####### Propionic acid was negative when tested in the SOS-Chromotest with Escherichia coli PQ37 (von der Hude et al., 1988). Propionic acid was tested in the absence of metabolic activation in multiple strains of E. coli (WP2, WP67 uvrA-), PolA-, CM871 uvrA-, recA-, and lexA-) in a bacterial DNA damage and repair assay. A non-dose related increase in lethality was observed in repair-deficient strains of E.coli relative to repair proficient strains; propionic acid was therefore considered to have elicited a positive response in this assay (Basler et al, 1987).

In non-bacterial *in vitro* genetic toxicity tests, propionic acid
elicited negative results in a Sister Chromatid Exchange (SCE)
cytogenetic assay in Chinese hamster lung fibroblast (V79) cells (Basler
et al, 1987) when tested in the presence and absence of metabolic
activation.

####### 

####### In Vivo Studies -- Chromosomal Aberrations

Propionic acid was tested in an in vivo micronucleus assay in male and
female Chinese hamsters at the maximum tolerated dose of 124 mg/kg bw
administered as a 2.5% solution by intraperitoneal injection. Four
hamsters died within a few hours of dosing. Among remaining animals
treated with propionic acid, 5 males and 5 females were sacrificed after
12, 24, or 48 hours after dosing and bone marrow collected and evaluated
for the presence of micronucleated polychromatic erythrocytes. There was
no increase in the incidence of micronuclei in male or female hamsters
treated with propionic acid as compared to concurrent controls (Basler
et al, 1987).

**Table 8**: **Summary of** **Gene Mutations and Chromosomal Aberrations
Studies**

  ---------------- ---------------------- ------------------- ---------------- ---------------- -------------- ---------------
  **Test           **Assay**              **Concentration**   **Metabolic      **Results**      **Score^1^**   **Reference**
  substance**                                                 Activation**                                     

  ***Gene                                                                                                      
  Mutations (In                                                                                                
  Vitro)***                                                                                                    

  Propionic Acid   Ames Assay/pre-        0, 100, 333, 1000,  Rat and hamster  Negative with    1              Zeiger et al.,
                   incubation protocol    3333, 10,000        liver S-9        and without                     1992
                   *S. tyhimurium* tester ug/plate                             metabolic                       
                   strains TA98, 100,                                          activation                      
                   102, 104, 1535, 1537,                                                                       
                   1538                                                                                        

  Propionic Acid   Ames Assay/plate       0, 100, 333, 1000,  Rat liver S-9    Negative with    2              Basler et al.,
                   incorporation assay    3333, 10,000                         and without                     1987
                   *S. tyhimurium* tester ug/plate                             metabolic                       
                   strains TA98, 100,                                          activation                      
                   1535, 1537                                                                                  

  Propionic Acid   Ames Assay/standard    0, 0.02375%,        Rat, mouse,      Negative with    2              Litton
                   plate and pre-         0.04750%, and       monkey S-9 and   and without                     Bionetics, Inc.
                   incubation protocols   0.0950% equivalent  tissue           metabolic                       1976
                   *S. tyhimurium* tester to 0, 273, 475, and homogenatefrom   activation                      
                   strains TA98, 100,     950 ug/ml           testes, liver,                                   
                   1535, 1537, 1538                           lung                                             

  Propionic Acid   Gene mutation assay in 0, 0.625%, 1.25%    Rat, mouse,      Negative with    2              Litton
                   yeast cell             and 2.5% (v/v)      monkey S-9 and   and without                     Bionetics, Inc.
                   *Schisosaccharomyces   equivalent to 0,    tissue           metabolic                       1976
                   pombe* tester strain   625, and 2500 mg/ml homogenatefrom   activation                      
                   D4                                         testes, liver,                                   
                                                              lung                                             

  ***Chromosomal                                                                                               
  Aberrations                                                                                                  
  Assays (In                                                                                                   
  Vivo)***                                                                                                     

  Propionic Acid   Micronucleus assay in  0, 124 mg/kg        Test conducted   Negative at 12,  2              Basler et al.,
                   Chinese hamsters       administered by IP  in male and      24, and 48 hr                   1987
                                          injection           female Chinese   after                           
                                                              hamsters         administration                  
  ---------------- ---------------------- ------------------- ---------------- ---------------- -------------- ---------------

1: Reliability score

**Table 9**: **Summary of** **Other In Vitro Genotoxicity Studies**

  ------------- -------------------- ------------------- --------- -------------- ------------------ -------------- ---------------
  **Test        **Assay**            **Concentration**             **Metabolic    **Results**        **Score^1^**   **Reference**
  Substance**                                                      Activation**                                     

  Propionic     SOS Chromotest       0, 0.3, 1.0, 3.3,   Rat and                  Negative with and  2              von der Hude et
  Acid          (Error prone DNA     10, and 33 mM       hamster                  without metabolic                 al., 1988.
                repair or SOS        equivalent to 0,    liver S-9                activation                        
                repair) in *E. coli* 22.2, 74, 222, 740,                                                            
                tester strain PQ37   and 2222 ug/ml                                                                 

  Propionic     DNA damage and       0, 1.0, 5.0, 25               None           Positive; non-dose 2              Basler et al.,
  Acid          repair assay in *E   ug/plate                                     related increase                  1987
                coli* WP2, WP67                                                   in lethality in                   
                (uvrA-,polA-), CM87                                               repair-deficient                  
                (uvrA-,recA-lexA-)                                                strains                           

  Propionic     Sister Chromatid     0, 0.3, 1.0, 3.3,             Rat liver S-9  Negative with and  2              Basler et al.,
  Acid          Exchange (SCE) Assay 10, and 33 mM                                without metabolic                 1987
                in Chinese hamster   equivalent to 0,                             activation                        
                V79 cells            22.2, 74, 222, 740,                                                            
                                     and 2222 ug/ml                                                                 
  ------------- -------------------- ------------------- --------- -------------- ------------------ -------------- ---------------

1: Reliability score

[Conclusion]{.underline}

*In vitro* genotoxicity testing of propionic acid has resulted in
uniformly negative results when tested in the presence of metabolic
activation. In one DNA damage and repair assay, propionic acid displayed
a non-dose specific positive result in the absence of metabolic
activation. An *in vivo* micronucleus test in Chinese hamsters was also
negative. There appears to be no potential for induction of gene
mutations or chromosomal aberrations by propionic acid.

### 3.1.7 Carcinogenicity

####### Studies in Animals

Groups of male rats were fed 0, 0.4, or 4% propionic acid in ground rat
feed for 20 weeks or their lifetime. Among animals fed 0.4% propionic
acid (approximately 270 mg/kg bw/day), there were no gross changes
visible in the forestomach, although hyperplasia and hyperkeratosis were
observed histologically. No changes were detected in the mucosa of the
glandular stomach. Among rats fed a diet containing 4% propionic acid
(approximately 2700 mg/kg bw/day), forestomach epithelial changes such
as hyperplasia and hyperkeratosis were noted at 20 weeks; hyperplasia
with ulceration, dyskeratosis, and papillomatous elevations (one with
uncharacterized "carcinomatous changes") were noted after lifetime
exposure (Griem, 1985). Cancer of the forestomach was not observed. No
other organs were examined.

Conclusion

Based on a lifetime oral ingestion study in rats, propionic acid is not
predicted to have carcinogenic potential at the point-of-contact
(forestomach). The changes observed upon feeding of high doses of
propionic acid are the result of chronic irritation and inflammation and
the associated hyperplastic proliferative repair response.

### 3.1.8 Reproductive/Developmental Toxicity

[Studies in Animals]{.underline}

There are no reproductive/developmental toxicity studies, and no
fertility data are available for propionic acid. Data are available for
propionic acid from repeated-dose feeding studies in dogs (100 days) and
rats (91 days) that examined the testes and ovaries of the animals.
Details of toxicity to other organs are described under Section 3.1.5,
Repeated-Dose Toxicity Similarly, there are no developmental toxicity
studies available for propionic acid and therefore data for calcium
propionate in four species are presented.

*Effects on Fertility/Reproductive Organs*

Propionic acid was fed in the diet to male and female Beagle dogs for
approximately 100 days. Groups of dogs (8 of each sex) received a 0,
0.3, 1.0, or 3.0% propionic acid in the diet. Based upon food
consumption, the mean daily dose administered to high dose male dogs was
2,491 mg/kg bw at the start of the study, and 1848 mg/kg bw at the end
of the study. For high-dose females, the mean daily dose administered
ranged between 2,209 and 1,832 mg/kg bw at the start and end of the
study, respectively. There were no effects observed on male or female
reproductive organs (testes and ovaries) (BASF, 1988). The NOAEL for
this study for systemic/reproductive organ effects is 3% propionic acid
in the diet or 1,848 mg/kg bw for male dogs, and 1,832 mg/kg bw for
female dogs.

Groups of male and female Sprague Dawley rats were offered a daily diet
containing 0, 6200, 12500, 25000, or 50000 ppm propionic acid (0, 0.62%,
1.25%, 2.5%, or 5% of the diet). Each group consisted of 20 animals per
sex per dose. Rats received the test diet for approximately 3 months (91
days) when they were sacrificed and subject to necropsy and tissues
collected for histological examination. There were no effects observed
on male or female reproductive organs (testes and ovaries) (BASF, 1971).
The NOAEL for this study for reproductive organ effects is 5% propionic
acid in the diet.

**Table 9: Summary of Reproductive Toxicity Studies with Propionic
Acid**

  ----------- ---------- ------------ -------------------- -------------- ---------------
  **Test      **Dose     **Route/     **Results**          **Score^1^**   **Reference**
  Species**   Levels**   Duration**                                       

  Beagle dog  0, 0.3,    Ingestion,   No mortality or      1              BASF, 1988
  M/F         1.0, 3% in up to 106    clinical signs of                   
              the diet   days         toxicity; no effect                 
              (0, 196,                on male/female                      
              660, 1848               reproductive organs                 
              mg/kg in                at 3% in diet or                    
              males; 0,               1848 mg/kg bw for                   
              210, 696,               males and 1,832                     
              1832 mg/kg              mg/kg bw for females                
              in                                                          
              females)                                                    

  Rat M/F     0, 0.62%,  Ingestion    No mortality or      2              BASF AG, 1971
              1.25%,     for 91 days  clinical signs of                   
              2.5%, or                toxicity; no effect                 
              5% in diet              on male/female                      
                                      reproductive organs                 
                                      at 5% in diet                       
  ----------- ---------- ------------ -------------------- -------------- ---------------

> 1: Reliability Score

*Developmental Toxicity*

There are no data available for propionic acd; data for calcium
propionate in four species (mouse, rat, hamster, and rabbit) are
presented.

Calcium propionate was fed to pregnant CD-1 mice and Wistar rats during
gestation days 6-15 at dose levels of 3, 14, 65, and 300 mg/kg-bw/day.
Pregnant rabbits and hamsters were fed calcium propionate at a doses of
0, 4, 19, 86, and 400 mg/kg-bw/day during gestation days 6-18 (rabbits)
or 6-10 (hamsters). Body weights of dams were taken at several intervals
during gestation. Dams were observed each day for food and water intake
and other measures of appearance and behavior. Dams were sacrificed on
gestation day 17 (mice), 20 (rats), 14 (hamsters), or 29 (rabbits).
Numbers of implantation sites, resorption sites, 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 the fetuses of each litter underwent detailed visceral
examinations; two-thirds were examined for skeletal defects. In all
species, there was no effect on maternal or fetal survival, or on fetal
or litter size. No increase in fetal or skeletal abnormalities was
observed (FDRL, 1972; FASEB, 1979).

**Table 10:** **Summary of Developmental Toxicity Study using Calcium
Propionate**

+---------+-----------+-----------+--------------------+-----+-------+
| **Test  | **Dose    | **Route/  | **Results**        | **S | **R   |
| subs    | Levels**  | D         |                    | cor | efere |
| tance** |           | uration** |                    | e^1 | nce** |
|         |           |           |                    | ^** |       |
+---------+-----------+-----------+--------------------+-----+-------+
| Calcium | R         | R         | In all species,    | 2   | FDRL, |
| Pro     | ats/mice: | ats/mice: | there was no       |     | 1972  |
| pionate | up to 300 | 10 days   | effect on litter   |     |       |
|         | mg/kg bw/ | during    | size or fetal      |     | F     |
|         | day       | g         | viability. No      |     | ASEB, |
|         | Rabbits:  | estation; | increase in fetal  |     | 1979  |
|         | up to 400 | Rabbits:  | or skeletal        |     |       |
|         | mg/kg     | 13 days   | abnormalities      |     |       |
|         | bw/day    | during    |                    |     |       |
|         | Hamsters: | gestation |                    |     |       |
|         | up to 400 | Hamsters: |                    |     |       |
|         | mg/kg     | 5 days    |                    |     |       |
|         | bw/day    | during    |                    |     |       |
|         | gestation | gestation |                    |     |       |
+---------+-----------+-----------+--------------------+-----+-------+

1: Reliability Score

######## Conclusion 

There are no data on fertility and limited data from two feeding studies
are available on the reproductive toxicity of propionic acid. In a study
with Beagle dogs, ingestion of high concentrations of propionic acid (up
to 3% in diet or 1848 mg/kg bw for males and 1,832 mg/kg bw for females)
for up to 106 days had no effect on male and female reproductive organ
weights and no lesions were observed upon gross or microscopic
examination of male and female reproductive organs (testes and ovaries).
There was no effect male or female reproductive organs (testes and
ovaries) in rats that ingested up to 5% propionic acid in the diet for
90 days.

In a feeding study, calcium propionate (calcium salt of propionic acid)
was fed to pregnant mice, rats, rabbits, and hamsters. There was no
effect on litter size and viability, and no increase in fetal
abnormalities in mice and rats fed calcium propionate during gestation
at doses up to 300 mg/kg-bw/day or in hamsters and rabbits fed this
compound during gestation at doses up to 400 mg/kg-bw/day.

1.  **Initial Assessment for Human Health**

There was no mortality among rats exposed for 8 hours to approximately
0.14 mg/L (a nominal value of 36 ppm) propionic acid vapor; exposed rats
exhibited signs of nasal, ocular and skin irritation. Mortality was 1/20
among rats exposed for one hour to propionic acid (19.7 mg/L) as a
vapor/aerosol atmosphere; exposed rats displayed reduced respiration
frequency, gasping, narrowed eyelids, salivation, nasal secretion, and
corneal opacity. The dermal LD~50~ in male rabbits was 490 mg/kg-bw;
necrosis of the skin was observed at the site of application. Animals
that died displayed hemorrhage of the lungs and intestines, and
congested livers and kidneys. The range of acute oral LD~50~ values
reported for propionic acid in rats is between 351 and 3470 mg/kg bw.
The reason for the variation in these values may be due to the age, body
weights, or prandial state of the test animals. Ascites, hemorrhage of
the lungs and gastrointestinal tract, and "burned" surfaces of organs in
contact with the gastrointestinal tract were observed in animals that
died.

Propionic acid is a corrosive material and causes severe skin and eye
irritation and is irritating to the respiratory tract. Signs of nasal,
ocular, and skin irritation were seen in animals exposed to propionic
acid vapor in the acute inhalation study described above. There are no
animal sensitization data for propionic acid.

In humans topically exposed to sodium propionate, there was no
sensitization response. Three of 91 human subjects with chronic
urticaria (presumed to have had prior exposure to propionic acid as a
food preservative) displayed a reproducible positive skin prick response
to a 5% solution of propionic acid; none of the 247 control
(non-urticaria) subjects displayed a positive response.

Repeated-dose data for dogs and rats are available for propionic acid
via the oral route of exposure. Male and female Beagle dogs were exposed
to 0, 0.3, 1.0, or 3.0% propionic acid (0, 196, 660, and 1,848
mg/kg-bw/day for males and 0, 210, 696, and 1,832 mg/kg-bw/day for
females in the diet for approximately 100 days. There was no mortality
and no clinical signs of toxicity. Three high-dose animals had
point-of-contact effects that included diffuse epithelial hyperplasia at
multiple levels of the esophageal mucosa. The incidence of spontaneous
lesions in the esophagus was similar in lower dose animals and controls.
The incidence of lesions of the esophagus in the high-dose animals after
a 6-week recovery interval was similar to controls. The LOAEL for this
study was 3% propionic acid in the diet (1,848 mg/kg-bw/day in male
dogs, and 1,832 mg/kg-bw/day in female dogs). The NOAEL was 1% propionic
acid in the diet (660 and 696 mg/kg bw-day for male and female dogs,
respectively).

**Male and female Sprague Dawley rats were exposed to 0, 6200, 12,500,
25,000, or 50,000 ppm propionic acid (0, 0.62%, 1.25%, 2.5%, or 5% of
the diet) for 91 days. There was no mortality. Males in the high dose
(5%) group displayed decreased appetite and body weight gain.
Examination of tissues revealed no lesions except point-of-contact
changes of the mucosa of the forestomach in the 5% treatment group. The
changes observed in the forestomach were not observed in the
post-exposure recovery groups.** Several repeated-dose dietary studies
with different forms of diet (pelleted, powdered, or ground)
administered to male rats have been conducted with propionic acid. These
studies suggest that the form of the diet may influence the types of
effects observed. In Wistar rats fed 4% test substance (approximately
2,700 mg/kg-bw/day) in a pelleted diet for 24 weeks, no effects on the
forestomach or gastric mucosa were observed.

However, when Wistar rats were fed the same amount in powdered feed for
12 weeks, severe changes in the forestomach (including crater-like
growths, marginal hyperplasia, and central ulceration) were seen. No
changes, however, were observed in the glandular stomach. In a shorter
study (9, 15, 21 or 27 days) using 4% in a powdered diet of Fischer 344
rats, histopathological changes were seen in the forestomach at 27 days,
including thickened mucosa with acanthosis and hyperkeratosis and some
infiltration of white blood cells.

Finally, a study in male rats in which propionic acid was given at 0.4%
(approximately 270 mg/kg bw/day) in ground feed for 20 and 24 weeks
resulted in a few effects in the forestomach (some hyperplasia and
hyperkeratosis). In the same study, ground feed containing 4%
(approximately 2,700 mg/kg bw/day) for 20-24 weeks produced papilloma
elevations (one with unspecified "carcinomatous" changes), marked
squamous hyperplasia of the epidermis, ulceration and hyperplasia of the
mucosa of the forestomach. The changes observed upon feeding of high
dose of propionic acid in these types of studies are the result of
chronic irritation and inflammation and the associated hyperplastic
proliferative repair response.

Propionic acid has been tested *in vitro* in bacterial reverse mutation
assays using *Salmonella typhimurium* strains TA98, 100, 102, 104, 1535,
1537, 1538 with standard plate incorporation and pre-incubation
protocols. The test substance did not result in gene mutations in either
the presence or absence of metabolic activation; it was also negative in
an *in vitro* gene mutations assay using *Schisosaccharomyces pombe*
(yeast). Propionic acid was negative in a DNA repair assay using *E.
coli* in the presence of metabolic activation, but displayed a
non-dose-related positive response in the absence of metabolic
activation. Propionic acid was also negative in an *in vivo*
micronucleus test using male and female Chinese hamsters. Based on these
results, propionic acid has shown no potential to induce gene mutations
or chromosomal aberrations.

There are no reproductive, fertility, or developmental toxicity studies
available for propionic acid. In a repeated-dose oral toxicity study,
there were no changes in the reproductive organs (testes and ovaries) of
male and female dogs fed up to 3% propionic acid (up to 1,848 and 1,832
mg/kg-bw/day in males and females, respectively) in the diet for
approximately 100 days. Similarly, there were no changes in the
reproductive organs (testes and ovaries) of male and female rats fed up
to 5% propionic acid in the diet for 91 days.

In a developmental toxicity study, calcium propionate was fed to
pregnant mice and rats during gestation days 6-15 at dose levels from 3
to 300 mg/kg-bw/day. Pregnant rabbits and hamsters were fed calcium
propionate at doses ranging from 4 to 400 mg/kg-bw/day during gestation
days 6-18 (rabbits) or gestation days 6-10 (hamsters). In all species,
there was no effect on maternal or fetal survival, or on fetal or litter
size. No increases in fetal or skeletal abnormalities were observed in
any species when compared with controls.

# **4.0 HAZARDS TO THE ENVIRONMENT**

## 4.1 Aquatic Effects

######## Acute Toxicity Test Results

Acute aquatic toxicity studies are summarized below and in Table 11.

The toxicity of propionic acid to fish has been evaluated with three
freshwater species of fish. Propionic acid was evaluated using a static
test system with fathead minnows (*Pimephales promelas*) according to
Standard Methods for Examination of Water and Wastewater (APHA, 1971).
Fish were exposed to nominal concentrations of 0, 25, 50, 65, 85, and
120 mg/L; test solutions were not buffered prior to addition of fish.
The 96-hr LC~50~ (and 95% confidence interval) values were reported as
51.8 (45.9-58.5) mg/L (Waggy and Payne, 1974). Static 96-hour tests were
also conducted with bluegill sunfish *Lepomis macrochirus* and rainbow
trout *Oncorhynchus mykiss*; the 96-hr LC~50~ values for propionic acid
in these species were 85.3 mg/L and 67.1 mg/L, respectively using
unbuffered test solutions (Union Carbide, 1979).

The toxicity of propionic acid to aquatic invertebrates was evaluated
with *Daphnia magna* according to Standard Methods for Examination of
Water and Wastewater (APHA, 1971); test solutions were not buffered
prior to addition of test organisms. The static 48-hr LC~50~ was 22.7
(21.0-24.6) mg/L (Union Carbide, 1979).

One study evaluated the effect of propionic acid on the green algae
*Scenedesmus subspicatus* according to OECD Guideline 201. Test
solutions were not neutralized. Based on cell density ( biomass), the
72-hr EbC~50~ was 45.8 mg/L; the 96-hr EbC50 was 42.9 mg/L. A
stimulatory effect on growth was noted at lower test concentrations.
NOEC values based on cell density could not be determined; however, the
72- and 96-hr EbC~20~ values were determined to be 33.5 and 12.3 mg/L,
respectively (BASF AG, 1987).

**Table 11: Summary of Acute Environmental Toxicity Data for Propionic
Acid**

+-----------------+-------------+-----------+------+-----------------+
| **Test          | **LC~50~ or | **        | **Sc | **Reference**   |
| Organism**      | EC~50~**    | Duration/ | ore^ |                 |
|                 |             | E         | 1^** |                 |
|                 | **(mg/L)**  | ndpoint** |      |                 |
+-----------------+-------------+-----------+------+-----------------+
| ***Acute        |             |           |      |                 |
| toxicity -      |             |           |      |                 |
| Fish***         |             |           |      |                 |
+-----------------+-------------+-----------+------+-----------------+
| Fathead minnow  | 96-hr       | 96 hr     | 2    | Waggy and       |
|                 | LC~50~ =    | static;   |      | Payne, 1974     |
| *Pimephales     | 51.8        | mortality |      |                 |
| promelas*       |             |           |      |                 |
+-----------------+-------------+-----------+------+-----------------+
| Bluegill        | 96-hr       | 96 hr     | 2    | Union Carbide,  |
| sunfish         | LC~50~ =    | static;   |      | 1979            |
| *Lepomis        | 85.3        | mortality |      |                 |
| macrochirus*    |             |           |      |                 |
+-----------------+-------------+-----------+------+-----------------+
| Rainbow trout   | 96-hr       | 96 hr     | 2    | Union Carbide,  |
| *Oncorhynchus   | LC~50~ =    | flow      |      | 1979            |
| mykiss*         | 67.1        | thru;     |      |                 |
|                 |             | mortality |      |                 |
+-----------------+-------------+-----------+------+-----------------+
| ***Acute        |             |           |      |                 |
| toxicity -      |             |           |      |                 |
| I               |             |           |      |                 |
| nvertebrates*** |             |           |      |                 |
+-----------------+-------------+-----------+------+-----------------+
| Water flea      | 48-hr       | 48 hr     | 2    | Union Carbide,  |
|                 | EC~50~ =    | static; I |      | 1979            |
| *Daphnia magna* | 22.7        | immob     |      |                 |
|                 |             | ilization |      |                 |
+-----------------+-------------+-----------+------+-----------------+
|                 |             |           |      |                 |
+-----------------+-------------+-----------+------+-----------------+
| ***Acute        |             |           |      |                 |
| toxicity -      |             |           |      |                 |
| Algae***        |             |           |      |                 |
+-----------------+-------------+-----------+------+-----------------+
| Green algae     | 72-hr       | 96 hr     | 2    | BASF AG, 1987   |
| *Scenedesmus    | E~b~C~50~ = | static;   |      |                 |
| subspicatus*    | 45.8        | biomass   |      |                 |
|                 |             |           |      |                 |
|                 | 96-hr       |           |      |                 |
|                 | E~b~C~50~ = |           |      |                 |
|                 | 42.9        |           |      |                 |
+-----------------+-------------+-----------+------+-----------------+

1: Reliability Score

All of studies described above were conducted using unbuffered systems
and the acidity of the test material resulted in low pH test conditions.
Tests conducted with calcium propionate do not experience significant
changes in pH and are considerably less toxic than propionic acid (Table
12). Based on results obtained with calcium propionate, it is apparent
that pH changes do contribute to the overall toxicity of propionic acid
observed in unbuffered test systems.

**Table 12: Summary of Acute Environmental Toxicity Data for Calcium
Propionate**

+-----------------+-------------+-----------+------+-----------------+
| **Test          | **LC~50~ or | **        | **Sc | **Reference**   |
| Organism**      | EC~50~**    | Duration/ | ore^ |                 |
|                 |             | E         | 1^** |                 |
|                 | **(mg/L)**  | ndpoint** |      |                 |
+-----------------+-------------+-----------+------+-----------------+
| ***Acute        |             |           |      |                 |
| toxicity -      |             |           |      |                 |
| Fish***         |             |           |      |                 |
+-----------------+-------------+-----------+------+-----------------+
| Golden Orfe     | NOEC = 5000 | 96 hr     | 2    | BASF AG, 1990b  |
|                 |             | static;   |      |                 |
| *Leuciscus      | 96-hr       | mortality |      |                 |
| idus*           | LC~50~ \>   |           |      |                 |
|                 | 10,000      |           |      |                 |
+-----------------+-------------+-----------+------+-----------------+
| ***Acute        |             |           |      |                 |
| toxicity -      |             |           |      |                 |
| I               |             |           |      |                 |
| nvertebrates*** |             |           |      |                 |
+-----------------+-------------+-----------+------+-----------------+
| Water flea      | NOEC = 250  | 48 hr     | 2    | BASF AG, 1989a  |
|                 |             | static;   |      |                 |
| *Daphnia magna* | 48-hr       |           |      |                 |
|                 | EC~50~ \>   | I         |      |                 |
|                 | 500         | immob     |      |                 |
|                 |             | ilization |      |                 |
+-----------------+-------------+-----------+------+-----------------+
| ***Acute        |             |           |      |                 |
| toxicity -      |             |           |      |                 |
| Algae***        |             |           |      |                 |
+-----------------+-------------+-----------+------+-----------------+
| Green algae     | 72-hr       | 96 hr     | 2    | BASF AG, 1989b, |
| *Scenedesmus    | EbC~50~     | static;   |      | 2007            |
| subspicatus*    | \>500       | growth    |      |                 |
|                 |             | rate,     |      |                 |
|                 | 72-hr       | biomass   |      |                 |
|                 | ErC~50~     |           |      |                 |
|                 | \>500       |           |      |                 |
+-----------------+-------------+-----------+------+-----------------+

1: Reliability Score

## 4.2 Terrestrial Effects

[Acute Toxicity Test Results]{.underline}

No ecotoxicological data for propionic acid were identified for
terrestrial wildlife (*i.e*., birds and

mammals).

## 4.3 Other Environmental Effects

The effect of acids on germination of lettuce seeds of *Lactuca sativa*
was investigated using C-3 through C-8 carboxylic acids. Test solutions
of each acid were prepared and then mixed with agar to provide the
germination medium. A total of 20 seeds were sown in each replicate;
each concentration was tested in five replicates. The EC~50~ for
inhibition of lettuce seed germination for propionic acid was 1.7
[+]{.underline} 0.6 mM, or 125.8 mg/L. The pH measured at the EC~50~
concentration was 5.75 (Reynolds, 1979a,b).

The effect of aliphatic acids on second-stage juveniles of the parasitic
plant nematode, *Meloidogyne arenaria* was investigated using C-3
thorugh C-7 aliphatic acids. A series of dilutions for each acid was
prepared from 100 mM to 0.01 mM in distilled water. Four replicates were
tested at each dose, and approximately 50-100 nematodes were tested in
each replicate. 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 EC50 for dead or paralyzed nematodes for propionic acid was
reported as 37 mg/L (Djian et al., 1994).

## Initial Assessment for the Environment 

## 

Propionic acid has a melting point of -21.5ºC and a boiling point of
141ºC. It has a vapor pressure of 4.7 hPa at 25ºC, a log K~ow~ value of
0.33 at 25ºC, and is miscible with water. The propionate ion will
predominate at environmental pH values of 5 to 9.

Hydrolysis is not expected to occur due to the lack of hydrolyzable
functional groups. The photochemical removal of vapor-phase propionic
acid in the atmosphere, as mediated by hydroxyl radicals, occurs with a
calculated half-life between 7.7 and 9.2 days. Based on Level III
distribution modelling for propionic acid (assuming equal and continuous
releases to air, water and soil), it is estimated that the majority of
propionic acid released to the environment will partition into air
(5.5%), water (37.4%) and soil (56.5%) with a smaller amount (\<0.1%)
into sediment. The Fugacity modelling for the acid used the log K~ow~
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. Propionic acid is not anticipated
to volatilize readily from surface waters (calculated volatilization
half-lives for propionic acid are 61 days from a model river and 1.83
years from a model lake). With a pKa of 4.9, the form of propionic acid
in water is pH dependent. Propionic acid is readily biodegradable under
aerobic and anaerobic conditions. Propionic acid is not likely to
bioaccumulate in aquatic organisms based on its log K~ow~ value.

Acute aquatic toxicity data (fish, daphnia, and algae) are available for
propionic acid. A 96-hour static test with the fathead minnow
(*Pimephales promelas*) resulted in a 96-h LC~50~ of 51.8 mg/L. In a
static test with *Daphnia magna*, the 48-h EC~50~ was 22.7 mg/L. In a
test with green algae (*Scenedesmus subspicatus)*, the 96-hr EbC~50~ was
42.9 mg/L. In these studies, the test solution was not buffered prior to
addition of the test organisms, resulting in low pH in the test
solutions. Aqueous solutions of calcium propionate do not display
significant changes in pH and are less toxic to aquatic organisms. The
96-hr LC~50~ in fish (*Leuciscus idus*) is \>10,000 mg/L, the 48-hr
EC~50~ in *D. magna* is \>500, and the 72-hr EC~50~ (biomass and growth
rate) in algae (*S. subspicatus*) is \>500 mg/L. These results suggest
that the toxicity observed in tests with propionic acid may be related
to changes in pH.

# **5 RECOMMENDATIONS**

For human health, the chemical is a low priority for further work. The
chemical is corrosive and possesses properties indicating a hazard for
human health (skin, eye and respiratory tract irritation). These hazards
do not warrant further work as they are related to transient effects
which may become evident only at high exposure levels. They should
nevertheless be noted by chemical safety professionals and users.

For the environment, the chemical is of low priority for further work.
The chemical possesses properties indicating a hazard for the
environment (acute toxicity to aquatic organisms between 1 and 100
mg/L). However the chemical is readily biodegradable and has limited
potential for bioaccumulation.

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