reaction products of acetic anhydride and adipic acid

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Non GLP, published in peer reviewed literature, animal experimental study. Minor restrictions in design and/or reporting but otherwise adequate for assessment. Read-across justification: The available toxicological data for the target and source substances is outlined in the data matrix (Annex I). The toxicological properties of the target substance are related mainly to acetic acid/acetate since the anhydride components of the substance are hydrolytically unstable. When the target substance comes in contact with water or moisture a complete hydrolysis will take place to form no other hydrolysis products than acetic acid/acetate and adipic acid. Thus, the use of data from acetic acid and adipic acid is justified to evaluate toxicological properties of the target substance. Furthermore, data from acetic anhydride is used in the assessment. Experimental data obtained with the source substances indicate that the substances has low oral (LD50 > 1780 – 3310 mg/kg bw) and inhalation (LC50 1680 - 7700 mg/m3) acute toxicity. Furthermore, the acetic acid and acetic anhydride are irritating to skin at concentration < 25% and corrosive to skin at ≥ 25%. Acetic anhydride and acetic acid are not tested for sensitisation due corrosive properties; adipic acid did not show any evidence of sensitising in an animal study. The source substances did not show positive response in genetic toxicity studies available. Repeated toxicity studies via oral route conducted for acetic acid showed NOAEL values ≥ 210 mg kg bw/day and via inhalation route for acetic anhydride 4.2 mg/m3.. Reproduction toxicity studies conducted for acetic acid did not show any adverse effects on reproduction at the highest concentration tested (1600 mg/kg bw/day).

Data source

Reference

Reference Type:

publication

Title:

Sensory irritation of acetic acid, hydrogen peroxide and peroxyacetic acid and their mixture in mice

Author:

Gagnaire F, Marignac B, Hecht G & Hery M

Year:

2001

Bibliographic source:

Ann. Occup. Hyg. Vol 46, No. 1, pp97-102

Materials and methods

Test guideline

Qualifier:

no guideline followed

Deviations:

not applicable

Principles of method if other than guideline:

Sensory respiratory irritation was assessed in mice during acute exposure to acetic acid, by recording respiratory rate using whole-body plethysmography. The concentration responsible for a 50% decrease in respiratory rate (RD50) is used to compare irritant potentials of chemicals and to establish acceptable levels of exposure.

GLP compliance:

not specified

Test type:

other: sensory irritation test

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Acetic acid

EC Number:

200-580-7

EC Name:

Acetic acid

Cas Number:

64-19-7

Molecular formula:

C2H4O2

IUPAC Name:

acetic acid

Details on test material:

- Name of test material (as cited in study report): Acetic acid
- Physical state: liquid
- Analytical purity: 100%
- Other: supplied by Prolabo, Fontenay sous Bois, France

Test animals

Species:

mouse

Strain:

other: OF1

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: IFFA Credo, Domaine des Oncins, Saint-Germain-sur-l'Arbresle, France
- Weight at study initiation: 20-25 g
- Housing: 10 per cage in polycarbonate cages (37.5 cm long x 21.6 cm wide x 14.7 cm tall) with hardwood chipping bedding
- Diet: available ad libitum, except during exposure. Supplied by UAR-Alimentation, Villemoisson, Epinay-sur-Orge, France, (sterilised by irradiation)
- Water: filtered tap water available ad libitum except during exposure
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22°C
- Humidity: 50-60%
- Air changes (per hr): not reported
- Photoperiod: 12 hrs dark / 12 hrs light, (light cycle 07:00 - 19:00)

IN-LIFE DATES: From: To: not reported

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

nose/head only

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: inhalation chamber equipped with 4 plethysmographs
- Exposure chamber volume: 2.5L
- Method of holding animals in test chamber: mice restrained in body plethysmographs, with head enclosed in inhalation chamber
- Source and rate of air: not reported
- Method of conditioning air: not reported
- System of generating vapour: acetic acid vapours generated using a peristaltic pump to feed a vaporisation chamber
- Treatment of exhaust air: not reported
- Temperature, humidity, pressure in air chamber: not reported

TEST ATMOSPHERE
- Brief description of analytical method used: Not reported (described in accompanying paper Hecht & Hery, 2002)

Analytical verification of test atmosphere concentrations:

yes

Remarks:

data not reported

Duration of exposure:

60 min

Concentrations:

57, 100, 212 and 389 ppm, equivalent to 140, 246, 522 and 957 mg/m3

No. of animals per sex per dose:

8

Control animals:

no

Details on study design:

The mice were restrained in body plethysmographs while their heads were enclosed in the inhalation chamber. The breathing frequency was monitored with a pressure transducer before and during the 60 min exposure period, and throughout the recovery period. For each concentration, a time-effect curve was plotted and the maximum decrease in respiratory rate occurring during the exposure period was recorded. The exposure concentration-response relationship was used to calculate the linear regression equation, the RD50 and the corresponding 95% confidence intervals.

Statistics:

Differences in the respiratory rate before and during exposure to acetic acid were analysed statistically using Student's t-test for paired data. The concentration-response curves were analysed by least-squares linear regression and the RD50 values calculated with their 95% confidence limits.

Results and discussion

Effect levels

Sex:

male

Dose descriptor:

other: RD50

Effect level:

227 ppm

95% CL:

198 - 269

Exp. duration:

60 min

Remarks on result:

other: 558 mg/m3

Other findings:

The onset of the response (a characteristic "break" in respiration, causing an elongation in the period from the end of inspiration until the start of expiration) was rapid and was close to maximal within the first 2 minutes of exposure to each concentration. For each concentration, the response was characteristic of sensory irritation and there was no trace of pulmonary irritation (ie a characteristic pause at the end of expiration). Recovery was rapid after exposure and, after 15 minutes recovery, the respiratory rate had reached 86-98% of that prior to exposure.
The concentration responsible for a 50% decrease in respiratory rate (RD50) was calculated to be 227 ppm (558 mg/m3) - see Table 1.

Any other information on results incl. tables

 Table 1 - Acetic Acid – range of exposure concentrations, linear equation and RD₅₀value with confidence intervals

Range of exposure concentrations (ppm)	Linear Regression Equation	Correlation coefficient (no. of concentrations studied)	RD50(ppm)	95% confidence interval (ppm)
57-389	Y= 18.89 ln(x)–52.5	0.977 (7)	227	198-269

Applicant's summary and conclusion

Interpretation of results:

sligthly toxic

Remarks:

Migrated information Criteria used for interpretation of results: OECD GHS

Conclusions:

Acetic acid possesses sensory irritant properties.

Executive summary:

The expiratory bradypnoea indicative of upper airway irritation in mice was evaluated during a 60 min period of oronasal exposure to acetic acid. The airborne concentration resulting in a 50% decrease in the respiratory rate of mice ( RD50) was calculated as 227 ppm (558 mg/m3) for acetic acid.