Acetic anhydride

Endpoint summary

Description of key information

Although no modern skin or eye animal studies have been conducted, the weight of evidence indicates that the liquid material is likely to be a severe skin irritant, whilst the vapour is irritant to the eyes and respiratory tract. In humans severe irritation of the eyes and respiratory tract resulted from exposure to the vapour/aerosol and the liquid is corrosive to skin.
If data are available that indicates that the mechanism of toxicity was corrosivity, the substance shall also be labelled as ‘corrosive to the respiratory tract'.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion

Endpoint conclusion:

no study available

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

July 12 1995 to Feb 7 1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant, guideline study, available as unpublished report. No restrictions, fully adequate for assessment.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: OECD 413

GLP compliance:

yes (incl. QA statement)

Species:

rat

Strain:

other: CD (Sprague Dawley)

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd, Manston Rd, Margate, Kent, UK.
- Age at study initiation: 7-8 wks at randomisation
- Weight at study initiation: 227g (males), 184 g (females)
- Age at start of exposures: 10-11 wks
- Housing: 5/cage (same sex) in suspended stainless steel cages with wire mesh front, back and floor and stainless steel sheet sides.
- Diet (e.g. ad libitum): SDS Rat & Mouse no. 1 SQC modified maintenance diet, Special Diet Services, Witham, Essex, UK.
- Water (e.g. ad libitum): Tap water provided in ploypropylene bottles
- Acclimation period: 4 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23 ºC
- Humidity (%): 40-65 %
- Air changes (per hr): No details. Cages for each test group kept in separate ventilated cabinets.
- Photoperiod (hrs dark / hrs light): 12/12 (0730-1930)

IN-LIFE DATES: From: 12 July 1995 To: 7 February 1996

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

1, 5, 20 ppm Target concentration
0.98, 4.96, 20.0 ppm Analytical concentration
1.23, 6.5, 26.3 ppm Nominal concentration

Duration of treatment / exposure:

6 hrs/day, 5 days/week for 13 weeks

Observation period (in vivo):

13 weeks treatment; 13 weeks post-exposure

Number of animals or in vitro replicates:

15/sex/group (including 5/sex/group for withdrawal period)

Irritation parameter:

other: Ocular changes were described as part of the clinical observations.

Time point:

other: At least once daily.

Remarks on result:

other: score not provided

Irritation parameter:

other: Ophthalmic examination by indirect ophthalmoscope.

Time point:

other: All animals pre-study, all main study animals in week 13, all withdrawal animals in week 26.

Remarks on result:

other: Prior to examination, pupils were dilated using 0.5% Mydriacyl.

Irritation parameter:

cornea opacity score

Remarks:

Not measured

Time point:

24/48/72 h

Remarks on result:

not measured/tested

Irritation parameter:

iris score

Remarks:

Not measured

Time point:

24/48/72 h

Remarks on result:

not measured/tested

Irritation parameter:

conjunctivae score

Remarks:

Not measured

Time point:

24/48/72 h

Remarks on result:

not measured/tested

Irritation parameter:

chemosis score

Remarks:

Not measured

Time point:

24/48/72 h

Remarks on result:

not measured/tested

Partially closed eyes were observed during the first two expsoures in high dose animals.

During week 13, corneal changes were evident in a number of animals in the intermediate and high doses groups and comprised corneal lack-lustre and corneal opacities (bi-lateral in less than half of the cases). There were no treatment related findings in week 26.

Interpretation of results:

irritating

Remarks:

Migrated information Criteria used for interpretation of results: other: Clinical signs and ophthalmoscopy

Conclusions:

In the presence of acetic anhydride vapour, reversible ocular irritation with mild corneal effects were reported.

Executive summary:

Following whole-body inhalation exposure to 0, 1, 5 or 20 ppm acetic anhydride for 6hr/day for 13 weeks, signs of eye irritation were seen in 20 ppm animals during the first two exposures only.

Corneal lesions were observed in most animals exposed to 20 ppm and in a few exposed to 5 ppm after 13 weeks of exposure. These findings were consistent with exposure to an irritant or mildly corrosive atmosphere and were not observed histologically. There were no treatment related changes after 13 weeks of withdrawal.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Acetic anhydride (1 mole) is rapidly and extensively hydrolysed to acetic acid (2 moles) in an exothermic reaction. Acetic acid is classified as an irritant at concentrations between 10% w/w and less than 25% w/w. Concentrated acetic acid (100%) is classified as corrosive. It would be anticipated that acetic anhydride, at sufficiently high concentrations, will also be a severe irritant at sites of first contact.

Skin irritation

Non-human data

In an early rabbit study, briefly reported by modern standards, low-grade skin irritation was reported 24 hours after application of acetic anhydride (Smyth et al, 1951). As current test regulations demand the administration of higher amounts of substance and a longer observation period, it appears that this result does not accurately reflect the irritation potential of acetic anhydride to skin, within the context of current regulatory standards.

Human data

First and second degree burns of the skin were reported for 2 workers who had come into contact with a liquid mixture of acetic acid and acetic anhydride (Capellini & Sartorelli, 1967) and for a fatal accident reported by Sinclair et al. (1994).

Eye irritation

Non-human data

In an early, briefly reported, rabbit study, diluted acetic anhydride liquid was reported to induce eye irritation scored as a value of 9, on a scale from 1 to 10 (Smyth et al., 1951). Although, by modern standards, deficiencies exist in the reporting of this study, nevertheless the results indicate a clear potential for severe eye irritation for acetic anhydride.

Acetic anhydride vapour has also been reported to cause eye irritation (HRC, 1994 & 1996). Lachrymation and closed/half closed eyes were reported for animals exposed for the first time to the vapour. At the end of the second (13 week) study, low-grade corneal opacities were reported in approximately half the animals. At the end of a further 13-week recovery period, the ocular opacities had resolved.

Taken together the information indicates that acetic anhydride, in liquid of vapour forms, can cause eye irritation in both species tested, rats and rabbits.

Human data

An early document reviewed accidental exposure of workers to acetic anhydride and indicated that the substance has the potential to cause severe eye irritation in humans (McLaughlin, 1946).

Respiratory irritation

Non-human data

Single (HRC, 1994) and multiple (HRC, 1994 & 1996) inhalation exposures of rats to acetic anhydride have reported respiratory tract irritation.

Human data

An accidental release of a mixture of acetic anhydride and acetic acid to 18 workers resulted in all 18 complaining of eye and upper respiratory tract irritation (Capellini & Sartorelli, 1967). Corneal abrasions were reported in 12/18 and necrosis of nasal epithelium in most of the exposed workers. First and second degree burns of the skin were reported for 2 who had come into contact with the liquid mixture. Within 25 days all injuries were reported to have resolved. The exact nature/concentration of the atmosphere to which the workers were exposed is not known and it remains unclear to what extent these effects are due to acetic anhydride

Justification for selection of skin irritation / corrosion endpoint:
According to Annex VII Column Adaptation this study is not required since acetic anhydride is rapidly and extensively hydrolysed to acetic acid. Acetic acid is classified as corrosive.

Justification for selection of eye irritation endpoint:
Key study.

Effects on skin irritation/corrosion: corrosive

Effects on eye irritation: highly irritating

Effects on respiratory irritation: highly irritating

Justification for classification or non-classification

Severe irritation of the eyes and respiratory tract may result from exposure to the vapour/aerosol and the liquid is corrosive to skin.

Under CLP acetic anhydride warrants classification as skin corr. Category 1B, H314, “Causes severe skin burns and eye damage”.

For substances and mixtures in addition to classification for inhalation toxicity, if data are available that indicate that the mechanism of toxicity is corrosivity EUH071 — Corrosive to the respiratory tract is required.