ACETIC ANHYDRIDE CAS N°: 108-24-7, Exercises of Toxicology

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FOREWORD INTRODUCTION

ACETIC ANHYDRIDE

CAS N°: 108-24-

COVER PAGE

SIDS Initial Assessment Report for 6

th SIAM

(Paris, 9-11 June 1997)

Chemical Name: Acetic Anhydride

CAS No.: 108-24-

Sponsor Country: Canada

National SIDS Contact Point in Sponsor Country:

Mark Lewis Commercial Chemicals Evaluation Branch Environmental Protection Service Environment Canada Place Vincent Massey, 14 th^ Floor 351 St. Joseph Boulevard Hull, Quebec K1A 0H Canada

HISTORY:

The SIDS Dossier was sent for review on March 1993. At the third SIDS Initial Assessment Meeting testing approval was given for a 13-week inhalation study with extensive evaluation of the bone marrow and respiratory and reproductive tracts. The results have been incorporated into the current SIAR.

no testing ( ) testing ( )

COMMENTS:

Deadline for circulation: March 7, 1997

Date of circulation: April 25, 1997 (To all National SIDS Contact Points and the OECD Secretariat

OECD HIGH PRODUCTION VOLUME CHEMICALS PROGRAM

SIDS INITIAL ASSESSMENT REPORT

ACETIC ANHYDRIDE CAS NO. 108-24-

1. IDENTITY

Acetic Anhydride CAS No. 108-24- Synonyms: acetanhydride; acetic acid; anhydride; acetic oxide; acetyl anhydride; acetyl oxide; acetyl acetate Molecular Formula: C 4 H 6 O 3 Structural Formula: (CH 3 CO) 2 O Molecular Weight: 102. Boiling point (760 mmHg): 138.6°C (282°F) Freezing point: -73°C (-100°F) Vapor pressure: 4mm Hg at 20°C; 100 mm Hg at 36°C Odor Threshold: 0.14 ppm Flammable limits in air, percent by volume: LEL = 2.8% at 81°C; 2% at 20°C UEL = 12.4% at 129°C; 10.2% at 20°C Flash point: 52.5-53°C (closed cup); 124-130°F Autoignition Temperature: 315-331°C (629°F) Specific gravity: 1.082 - 1.083 (at 20°C) Vapor density: 3.5 (air = 1) Solubility in water: Decomposes; 2.6 wt% at 20°C Evaporation Rate: 0.46 (BuAc = 1.0) Stability: Stable in dry air

Acetic anhydride is a colorless, mobile, combustible liquid with a pungent acetic acid odor. It is primarily manufactured for captive use in production of cellulose acetate and related products, but is also marketed as a >98% purity reagent, for example, used in manufacturing pharmaceuticals. The major impurity in acetic anhydride is acetic acid. Acetic anhydride reacts violently with water to produce acetic acid and heat.

2. GENERAL INFORMATION ON EXPOSURE

2.1 General Discussion

Production capacities available for North America and Western Europe are given in Table I.

Table I. 1995 Acetic Anhydride Production Capacities (1)

Region Thousand Metric Tons

Canada 70 Mexico 87 United States 1223

Western Europe 539

Acetic anhydride is manufactured in North America by two processes. Most of the production uses the ketene - acetic acid technology, which involves thermal cracking acetic acid to ketene and the subsequent reaction of the ketene with additional acetic acid to form acetic anhydride. Methyl acetate carbonylation is a second route. Some acetic acid is produced as a co-product in the methyl acetate carbonylation process.

Acetic anhydride used as a reagent in manufacturing acetate esters, acetylation of pharmaceuticals, end-capping polyacetal homopolymers, and other reactions is consumed in the reaction step. Reactions of acetic anhydride with hydroxyl groups yield the corresponding acetate ester with coproduction of acetic acid. Acetylation of amines produce acetamides such as TAED (tetraacetylethylenediamine), which is used as a perborate bleach activator. Acetic anhydride is used to acetylate salicylic acid to aspirin and p-aminophenol to acetaminophen.

Most of the acetic anhydride production is consumed in manufacturing cellulose acetate esters. Cellulose acetate esters include cellulose diacetate, cellulose triacetate and mixed esters (propionates, butyrates). In the manufacture of cellulose acetate, one acetyl group from each acetic anhydride molecule reacts with the cellulose and the other acetyl group is converted to acetic acid which can be recycled back to make more acetic anhydride or be used to produce other acetic acid derivatives. Shredded pure alpha cellulose is typically soaked in aqueous acetic acid before the treated pulp is acetylated with a 60-40 mixture of acetic acid and acetic anhydride using a dilute sulfuric acid catalyst. Cellulose acetate fibers are recovered as tow or as filament yarn. Filters are made from a blend of tow and plasticizer. Cellulose acetate filament yarns are used in apparel and home furnishings. Cellulose triacetate is used in photographic film and pressure sensitive tapes. U.S. consumption of acetic anhydride in 1993, for example, was distributed in major end uses as follows in Table 2. This is generally representative of consumption in North America

Table 2. U.S. Consumption of Acetic Anhydride (Percentages) (1)

Cellulose Acetate Esters Filter Tow

Filament Yarn

Flake Export

Miscellaneous Aspirin Acetaminophen Other

Acetic anhydride reacts with water forming acetic acid and, therefore, can be used as a dehydration reagent.

2.2. Production releases

Celanese Canada, Edmonton (this plant produces both acetic anhydride and cellulose acetate)

Emissions Total (Annual Emission Estimate) Storage 7 tons Fugitive 4 tons Amount released per day 30 kg/day (Assumes plant operates 365 days/year)

3.1.1 General Discussion

In natural bodies of water, acetic anhydride hydrolyses according to a first-order reaction to acetic acid. On the basis of experimentally determined rate constants (2), one can calculate half-lives, t1/2, of 4.4 min. (at 25°C) and 8.1 min. (at 15°C).

This hydrolytic degradation to acetic acid also occurs in the atmosphere. On the basis of an experimentally determined rate constant, for the degradation of acetic acid through reaction with photochemically formed OH-radicals in the atmosphere a half-life of 22 days has been calculated (3). However, on account of its high solubility, acetic acid will be rapidly washed out of the atmosphere.

In the static Zahn-Wellens test of biodegradability, acetic acid is degraded to more than 95% within 5 days (4). In the respirometer test (22 - 24 hours in modified MITI test) acetic acid is degraded to 99% (5).

For acetic anhydride an n-octanol/water partition coefficient, log Pow, of -0.27 has been calculated, while for acetic acid a log Pow of -0.17 has been experimentally determined (6,7). Neither value gives any indication of a potential for bioaccumulation.

3.1.2 Predicted Environmental Concentration

Given the volume of acetic anhydride released to the atmosphere annually the steady state concentrations using Mackay fugacity model ChemCan IV for the region of northern Alberta can be estimated. Releases to this 378 000 km^2 area result in 2.4 x 10-15^ mg/m^3 in air, 2.33 x 10 -9^ μg/g in soil, 1.8 x 10 -11^ g/m^3 in water, and 1.9 x 10 -14^ g/m^3 in sediment assuming a residence time in air of 2.42 days and 75.1 days in water for this region. Overall reaction persistence is estimated at 0. hrs. The concentration for water can be used as a PEC in the calculation (i.e. PEC = 1.7 x 10- mg/L).

As previously noted, the by-product of acetic anhydride is acetic acid. It is quickly biodegraded and does not bioaccumulate (log Pow = -0.17). It is less toxic in comparable aquatic species than acetic anhydride and in its neutralized form (acetate) it plays an important role in the metabolism of all species.

3.2 Effects on the Environment (6,7)

The results of various laboratory tests with aquatic organisms, in which the toxic threshold concentrations for acetic anhydride were found to be about half those for acetic acid, suggest an initial toxic effect, so long as not all of the substance has hydrolyzed to acetic acid (during the first few minutes).

For protozoa the toxic threshold concentration for acetic anhydride is between 30 and 735 mg/l (8,9,10):

Chilomonas paramaecium , 48-hour Toxic Threshold Concentration = 395 mg/l (cell multiplication inhibition test)

Entosiphon sulcatum , 72-hour Toxic Threshold Concentration (5% Effect Concentration =EC 5 ) = 30 mg/l

(cell multiplication inhibition test)

Uronema parduzci , Toxic Threshold Concentration = 735 mg/l (limited details; test duration not specified)

The toxic threshold concentration for bacteria (source: domestic wastewater treatment plant), as determined in the 24-hour fermentation-tube test, was ≥ 2,500 mg/l. The endpoint was inhibition of respiration and the parameter measured was oxygen consumption (11,4). In the cell proliferation inhibition test (16 hrs.) with Pseudomonas putida a toxic threshold concentration (3% Effect Concentration = EC 3 ) of 1,150 mg/l was found (12).

In the cell multiplication inhibition test (8 days), the following toxic threshold concentrations (EC 3 ) were determined:

Microcystis aeruginosa (cyanobacteria): 18 mg/l (13) Scenedesmus quadricauda (green algae): 3,400 mg/l (14)

In a 5-day study with Chlorella pyrenoidosa (algae) using chlorophyll reduction as the endpoint, 16.6% to 96.6% reduction was noted compared to the controls over the concentration range 50 mg/l to 400 mg/l (15).

For Daphnia magna the following effective concentrations for immobilization were determined (16):

test medium not neutralized

neutralized to protect against pH lowering by released acetic acid 24-hour EC 0 = 47 mg/l; 1370mg/l 24 hour EC 50 = 55 mg/l; 3200mg/l 24-hour EC 100 = 68 mg/l; 5900mg/l

With respect to fish toxicity, the following lethal concentrations were determined for the golden orfe ( Leuciscus idus ) (17):

48-hour LC 0 = 216 and 252 mg/l 48-hour LC 50 = 265 and 279 mg/l 48-hour LC 100 = 324 mg/l

3.3 Initial Assessment for the Environment

To determine the PNEC, the chronic lowest effect level of 18 mg/L is taken and divided by 2 to obtain an estimated NOEC of 9 mg/L based on guidance from the OECD SIDS Manual (June 1997). Applying a safety factor of 100 (because chronic NOECs are not available for the other trophic levels) provides a PNEC of 0.09 mg/L. Because chronic NOECs are not available for Daphnia or fish a comparison must be made between the PNEC derived from the lowest acute value. The lowest acute effect level is for Daphnia at 55 mg/L. Applying a safety factor of 500 because chronic data is available for algae and the substance is not persistent gives a PNEC of 0. mg/L which is slightly higher than the PNEC derived from chronic data. Therefore, using the PEC derived from the fugacity model the ratio would be as follows:

did not mention any consumer applications or markets for acetic anhydride. Based on this recent input, there is no indication that its use is in general practice internationally in the consumer industry.

Note:Though there was reference to the possible use of acetic anhydride in shoe leather cleaner and in insecticide in Germany, though requested from the German representative (Dr. Hertel, Director, BGVV) by the CEFIC Acetyls Sector Technical Committee Chairman (Mr. Steve Williams), information was not provided for reasons of confidentiality.

4.2 Effects on Human Health

The initial data gaps identified during dossier preparation were: subchronic toxicity, reproductive toxicity and in vivo mutagenicity. Based on the physical/chemical properties of acetic anhydride, its metabolite (acetic acid) plus data from a subchronic inhalation/reproductive toxicity range- finding study, the testing program discussed next was presented at the February, 1995 SIAM Meeting in Williamsburg, Virginia and approved. A 90-day subchronic inhalation study in male and female rats with an additional 90-day recovery phase to assess reversibility provided the foundation for the program. Also included was a comprehensive, microscopic assessment of the reproductive organs plus standard cytogenetic analysis of the bone marrow. Results are described next in the pertinent sections.

a) Single exposure

Acetic anhydride is corrosive to the skin, eyes and mucous membranes. Acute toxicity values are listed below (6,7,18):

Oral LD 50 : 1.8 g/kg (rats); Dermal LD 50 : 4.0 g/kg (rabbits); Inhalation LC 50 : approximately 400 ppm (1680 mg/m3; rats, 6 hrs., vapor)

No skin sensitization studies of acceptable quality are available. In a 1940 study using intracutaneous injection, a response claimed to be indicative of sensitization reaction was reported for guinea pigs receiving a 25% solution in olive oil. Given the corrosive nature of acetic anhydride, coupled with animal welfare considerations, further testing would be difficult to justify (19).

Acute overexposure in humans has been observed to cause severe eye, skin and respiratory tract irritation (6,7). The potential for occupational asthma may be raised when a chemical is an anhydride irritating to the respiratory system. The IUCLID document (6) lists two reports of human irritation from inhalation exposure to acetic anhydride; one in 1967 and one in 1992. In the event this or other information indicates sufficient need, comprehensive analyses with modern techniques would have be employed to further explore this area. However, this is beyond the scope of the SIDS/SIAR process.

b) Repeated exposure

One early study (20) using the inhalation route in animals was poorly reported and of uncertain validity. Insufficient detail was available from this report to draw reliable conclusions about the effects of repeated inhalation exposure to acetic anhydride. Therefore, new inhalation studies were conducted.

Acetic anhydride is highly irritating and readily hydrolyzes to acetic acid. Therefore, local toxicity at site of contact is observed, but not systemic toxicity. This is demonstrated by the following inhalation studies.

In a two-week inhalation study (18), respiratory tract irritation was reported in rats exposed for 6 hrs./day, 5 days per week (or less) to 25, 100 or 400 ppm acetic anhydride vapor. Mortality (40%) was observed in the 400 ppm group after the first 6-hr. exposure period and additional exposures were not conducted in this group.

In a 13-week inhalation study (21), rats were exposed for 6 hrs./day, 5 days/week to 1, 5 or 20 ppm acetic anhydride vapor. Each group contained 15 male and 15 female animals. The study was conducted under OECD and U.S. EPA TSCA GLPs. Clinical observations of eye and respiratory tract irritation and reduced body weights were observed primarily at 20 ppm. Microscopic examination of tissues revealed signs of irritation of minimal severity in the respiratory tract (nasal passages; larynx; trachea) in most animals at the 5 ppm level. At 20 ppm, all animals showed minimal to moderate respiratory tract irritation (nasal passages; larynx; trachea; lungs). The changes seen were predominantly localized inflammatory lesions with subsequent areas of epithelial hyperplasia and/or squamous metaplasia. Since the respiratory system is the target, further details from the microscopic examination of these tissues are given next for the 5 ppm (intermediate dosage) and 20 ppm (high dosage) groups.

Nasal lesions were primarily located in the anterior portion of the nose and comprised varying, predominantly minimal, degrees of hyperplasia of the respiratory epithelium, frequently with increased goblet cell prominence. Inflammation was associated with the respiratory epithelium and also the presence of granular eosinophilic inclusions within the respiratory epithelium, possibly representative of globule leucocytes. In the transitional epithelium lining anterior portions of the nasal turbinates, hyperplasia, squamous metaplasia and inflammation, occasionally with areas of erosion, were seen together with the presence of granular eosinophilic inclusions which may represent the presence of globule leucocytes. These latter inclusions were more evident in animals from the intermediate dosage group than in those from the high dosage group where transitional epithelial squamous metaplasia was more prominent. In general olfactory epithelium was unaffected by the acetic anhydride inhalation. Various amounts of exudative inflammatory cell accumulation, predominantly minimal in degree, were seen in the nasal passages of high dosage group animals and of a single male intermediate group animal.

In the larynx, inflammatory infiltration, squamous metaplasia of the ventral epithelium and hyperplasia of the epithelium covering the arytenoid processes, frequently with varying degrees of erosion or ulceration, were seen in the majority of animals from the high dosage group as well as occasional animals from the intermediate dosage group. In general these changes were of minimal to moderate severity. In the trachea, epithelial hyperplasia was seen at various sites, including at the carina, in the majority of animals from the high dosage group and in a proportion of intermediate dosage group animals. Also seen were epithelial squamous metaplasia at the carina, eosinophilic epithelial inclusions and inflammatory infiltration of the lamina propria. These changes were predominantly of a minimal degree of severity. Finally in the lungs, changes included the presence of occasional perivascular inflammatory cells, increased prominence of bronchus-associated lymphoid tissue (BALT), small foci of fibrosis in the walls of the alveolar ducts and increased prominence of alveolar macrophages. Changes were predominantly of minimal severity.

4.3 Initial Assessment for Human Health

4.3.1 Occupational (Workers)

The lowest NOEL, 1 ppm (4.2 mg/m3), is based on a recent subchronic study via the most relevant exposure route, inhalation. At the LOEL, 5 ppm (21mg/m3), minimal and reversible respiratory tract irritation was observed, but no systemic toxicity. In vivo genotoxicity and developmental toxicity studies did not reveal specific effects at higher concentrations (20-25 ppm).

Workplace exposure monitoring information is available from plants producing acetic anhydride and from plants using it. Exposure levels are low because procedures and equipment plus worker training programs are in place which provide protection. Therefore, acetic anhydride is considered of low potential for risk to man.

4.3.2 Other

Given its use pattern (captive intermediate, completely reacted in use) and rapid hydrolysis (half- life 4.4 min. @ 25 C in non-human study) to normal body metabolite (acetate), consumer or widespread environmental exposure are not significant scenarios for human exposure to acetic anhydride.

5. CONCLUSIONS AND RECOMMENDATIONS

5.1 Conclusions and 5.2 Recommendations

a) Environment

Acetic Anhydride is used solely as an intermediate for chemical synthesis where it is completely reacted. In the hydrosphere, acetic anhydride is rapidly hydrolyzed (half-life 4.4 min.) to acetic acid which is readily biodegradable. In the atmosphere, it is converted to acetic acid which is subject to photooxidative degradation (half-life 22 days). Toxicity to aquatic organisms is moderate ( 18 to 3400 mg/l), but it persists only for a short time due to its rapid hydrolysis to acetate/acetic acid. It has virtually no potential for bioaccumulation (log Kow = -0.27). The PEC/PNEC ratio was much less than one (1.9 x 10 -10^ ). Therefore, acetic anhydride has a low potential for exposure and is considered to be currently of low priority for further environmental work in the SIDS context.

b) Human Health

The critical effect for acetic anhydride is irritancy at the site of contact. Because of its well-known corrosive and irritating effects on the eyes, skin and respiratory tract and low odor threshold, procedures, equipment (e.g., goggles, gloves, respirators), training and engineering controls have already been in place for many years to prevent exposure. Industrial hygiene monitoring data indicates that levels of acetic anhydride are below 1 ppm 8-hr. time-weighted-average (4.2 mg/m^3 ) in facilities where acetic anhydride is produced and where the major use of acetic anhydride takes place. Acetic anhydride is used exclusively as a chemical intermediate and there is no indication that its use is in general practice in the consumer industry. It is suggested that occupational exposure limits be revisited based on the additional testing reported in this SIAR. Acetic anhydride is considered to be currently of low priority for further health-related work in the SIDS context.

Bibliography

1. CEH-Stanford Research Institute International Data Summary 603.5000 A (1996).
2. Gold (1948) : Trans Faraday Soc. 44, 506-515.
3. Atkinson et al. (1989) : Evaluated Kinetic and Photochemical Data for Atmospheric Chemistry. Supplement III IUPAC Subcommittee on Gas Kinetic Data Evaluation for Atmospheric Chemistry, J. Phys. Chem. Ref. Data 18, 881-1097.
4. Hoechst AG (1975) : (31.07.1975) cited in IUCLID (1996).
5. Placak, Ruchhoft (1947) : Public Health Reports, XVII. The utilization of organic substrates by activated sludge, Vol. 62, 697 - 716.
6. IUCLID (1996): International Uniform Chemical Information Database.
7. BUA-Stoffbericht No. 70 (1991).
8. Bringmann et al. (1980): Z. Wasser Abwasser Forsch. 13(5), 170-173.
9. Bringmann (1978) : Z. Wasser Abwasser Forsch. 11(6), 210-215.
10. Bringmann, Kuehn (1981) : Gas-Wasserfach, Wasser-Abwasser 122(7), 308-313.
11. Hoechst AG (1975) : (13.08.1975) Cited in IUCLID (1996).
12. Bringmann, Kuehn (1976) : Gas-Wasserfach, Wasser-Abwasser 117 (9), 410-413.
13. Bringmann (1975) : Gesund.-Ing. 96(9), 238-241.
14. Bringmann, Kuehn (1980) : Water Res. 14, 231-241.
15. Gloyna, Thirumurthi (1967) : Water Sewage Works 114(3), 83-88.
16. Bringmann, Kuehn (1982) : Z. Wasser Abwasser Forsch. 15(1), 1-6.
17. Juhnke, Luedemann (1978) : Z. Wasser Abwasser Forsch. 11(5), 161-164.
18. Acetic Anhydride : 2 Weeks Repeat Dose Inhalation Toxicity Study in Male and Time-Mated Female Rats. Huntingdon Report HST 400/942606 (October 13, 1994).
19. Jacobs, J.L. (1940) : Proc. Soc. exptl. Biol. Med. 43: 641.
20. Takhirov, M.T. (1969) : Gig Sanit 34(6): 122-125.
21. Acetic Anhydride : 13-week Inhalation Toxicity Study in Rats. Huntingdon Report HST 411/961219 (August 27, 1996).
22. McMahon et al. (1979) : Cancer Res. 39(3), 682-693.
23. Cameron : Short-term test program sponsored by the Division of Cancer Etiology, National Cancer Institute, Y85 [CCRIS, 1991].
24. Mortelmans et al. (1986) : Environ. Mutagen. 8 (Suppl. 7), 1-119.
25. Cameron, T.P. (1985) : Mouse Lymphoma Mutagenesis Assay with #83634 Acetic Anhydride (ML-NII #142). Unpublished study was sponsored by NCI.
26. Food and Drug Research Laboratories Report, Teratologic Evaluation of FDA 71-78, apple cider vinegar (acetic acid) in rats, mice and rabbits, 1974. Sponsored by the U.S. FDA.

Additional information sources (not included in SIDS).

a. CEH-Stanford Research Institute International Data Summary 603.5000 A. b. IUCLID (1996): International Uniform Chemical Information Database. c. Acetic Anhydride: 2 Weeks Repeat Dose Inhalation Toxicity Study in Male and Time-Mated Female Rats. Huntingdon Report HST 400/942606 (October 13, 1994). d. Acetic Anhydride: 13-week Inhalation Toxicity Study in Rats. Huntingdon Report HST 411/961219 (August 27, 1996). e. BUA-Stoffbericht No. 70 (1991).

Attachment 1

Health:

Because of the irritating and unstable nature of acetic anhydride, a conventional testing approach is not recommended. Since acetic anhydride readily hydrolyzes to acetic acid in water (half-life about 3 minutes), systemic toxicity is unlikely and emphasis will be placed on toxicity at the site of contact for the most relevant route of potential human exposure. Because a repeated inhalation exposure study of acceptable quality is not available, a 90-day vapor inhalation study in the rat via OECD guidelines is recommended. Emphasis will be placed on effects in the upper respiratory tract and subsequent reversibility.

Appropriate studies on reproductive and developmental toxicity are not available for acetic anhydride. A teratology study conducted with an acetic acid solution was negative. This result combined with a careful evaluation of the gonads in the proposed 90-day inhalation study is considered to provide sufficient information.

Results from gene mutation studies in vitro with acetic anhydride have been negative except for one equivocal response. Studies assessing chromosomal aberrations are not available. An in vitro chromosomal aberration study is not recommended because the published literature indicates that acidic materials lower culture medium pH resulting in artifacts. Cytogenetic evaluation of bone marrow from animals in the 90-day inhalation study will be conducted.

Because of the corrosive nature of acetic anhydride and the minimal potential for prolonged exposure, the need for testing should be evaluated in light of animal welfare concerns before proceeding.

Environmental:

Acceptable acute studies are available for fish, invertebrates and algae. Since acetic anhydride hydrolyzes quickly to a well-studied material of low toxicity (acetic acid/acetate) additional studies to assess ecotoxicity, environmental fate and biodegradation are not recommended.

Study CAS No: 108-24- (Status of database prior to initiation of testing in 1993)

Info Avail

GLP OECD Study

Other Study

Estim. Methods

Accept- able

SIDS Testing Req’d Y/N Y/N Y/N Y/N Y/N Y/N Y/N

PHYSICAL-CHEMICAL 2.1 Melting Point Y Y N 2.2 Boiling Point Y Y N 2.3 Vapour Pressure Y Y N 2.4 Partition Coefficient N N 2.5 Water Solubility Y Y N

OTHER STUDIES RECEIVED

ENVIRONMENTAL FATE/ BIODEGRADATION 4.1.1 Aerobic biodegradability

Y Y N

4.1.3.1 Hydrolysis Y Y N 4.1.3.2 Photodegradability N N 4.3 Env. Fate/ Distribution N N 4.4 Env. Concentration N N

OTHER STUDIES RECEIVED N

ECOTOXICOLOGY 5.1 Acute Toxicity Fish Y Y N 5.2 Daphnia Y Y N 5.3 Algae Y Y N 5.6.1 Terrest. Organisms N N 5.6.2 Terrest. Plants N N 5.6.3 Avians N N 5.6.4 Avian Reproduction N N

OTHER STUDIES RECEIVED N

TOXICOLOGY 6.1 Acute Oral Y Y N Acute Dermal Y Y N Acute Inhalation Y Y N 6.2 Skin Irritation Y Y N Eye Irritation Y Y N 6.3 Skin Sensitization Y Y N 6.4 Repeated Dose Y N Y 6.5 Genetic Toxicity Gene Mutation Y Y Y N Chromosomal Aberrations

N N Y

6.7 Reproductive and Developmental Toxicity

Y Y N

OTHER STUDIES RECEIVED Y

1.6 Purity of Industrial Product

1.6.1 Degree of purity (percentage by weight/volume)

Acetic Anhydride 95.0% - 99.0% (HCC-MSDS)

1.6.2 Identity of major impurities

Acetic Acid (CAS No. 94-19-7) 4% maximum (HCC-MSDS)

1.6.3 Essential additives (stabilizing agents, inhibitors, other additives), if applicable

Not applicable.

2. Physical-Chemical Data

*2.1 Melting or Decomposition Point

-73.1 °Centigrade Method (e.g., OECD, others): GLP: YES [ ] NO [ ] Comments: Reference: CRC Handbook of Chemistry and Physics, 65th ed., Robert C. Weast, ed. 1984, CRC Press Inc., Boca Raton, Florida. p. C-

*2.2 Boiling Point (including temperature of decomposition, if relevant).

138-140.5 °C (at 760 mm Hg) 1013 hPa Method (e.g., OECD, others): GLP: YES [ ] NO [ ] Comments: Reference: IUCLID (1996)

*2.3 Vapour Pressure

7.2 hPa at 25.4 °C (calculated) Method (e.g., OECD, others): GLP: YES [ ] NO [ ] Comments: Calculations based on 1 Atmosphere = 101,325 N/m^3 1 kPa = 1000 N/m^3 Reference: IUCLID (1996)

*2.4 Partition co-efficient n-Octanol/water

log Pow = -0. Method: calculated [X]

measured [ ] GLP: YES [ ] NO [ ] Analytical Method: Comments (e.g., is the compound surface active or dissociative?): Acetic anhydride hydrolyzes quickly to acetic acid which is very water soluble (see section 4.1.3) Reference: IUCLID (1996)

*2.5 Water Solubility

120 g/l at °C (with hydrolysis) Method (e.g., OECD, others): GLP: YES [ ] NO [ ] Analytical Method: Comments (e.g., the detection limit for insoluble substances): Reference: DATENBLATT’ ALTSTOFFE’ (Data sheet on ‘Old Materials’) May 2, 1988, Hoechst AG.

2.6 Flash point (liquids)

49.4 °C closed cup [X] 65.5 °C open cup [X] Method (e.g., OECD, others including references to the standard test used): Tag open cup = ASTM D Tag closed cup = ASTM D GLP: YES [ ] NO [ ] Comments: Flash point open cup reported as 150 °F conversion C° = 5/9 (F° - 32) Reference: Closed cup: The Condensed Chemical Dictionary, 10th ed. Gessner G. Hawley ed. 1981, Van Nostrand Reinhold Company, New York, p. 6- Open cup: Hygienic Guide Series Acetic Anhydride. American Industrial Hygiene Association Journal 32:66-67 (1971)

2.7 Flammability (solid/gases)

Method (e.g., OECD, others): GLP: YES [ ] NO [ ] Test results: Comments: References:

2.8 pH in water

pH at mg/l (water) pKa Method (e.g., OECD, others): GLP: YES [ ] NO [ ]