Acetic anhydride

Toxicity to reproduction

Administrative data

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

study technically not feasible

Justification for data waiving:

other:

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING

Non-human data
Three prenatal developmental toxicity studies by oral administration of the read-across substance, acetic acid, showed no effects on maternal rats and rabbits at doses up to 1600 mg/kg/day and in mice up to 345 mg/kg/day. A 90-day inhalation toxicity study in rats with acetic anhydride at dose levels of 1, 5 and 20 ppm (equivalent to 4.18, 20.9 and 83.5 mg/m3) showed significant local toxicity to the respiratory tract and also to the eyes (corneal lesions) as a consequence of whole-body exposure to the treated atmospheres. The respiratory effects comprised inflammatory lesions in the respiratory tract with areas of hyperplasia and/or squamous metaplasia. Associated with this localised inflammatory response was an increased severity of medullary plasmacytosis in the cervical lymph nodes. However, there were no indications of systemic toxicity caused by inhalatory acetic anhydride at these exposure levels in rats, including no effects on the male and female reproductive tract.
Within an aqueous environment acetic anhydride is rapidly hydrolysed to acetic acid. Developmental toxicity data are available for apple cider vinegar (containing 5% acetic acid). As acetic anhydride is rapidly and extensively transformed in vivo to acetic acid, it is reasonable to consider systemic exposure to the two substances comparable and systemic toxicity endpoints, such as reproduction and development, would be similar in animals exposed to either substance. In contrast, local toxicity effects of the two chemicals are likely to depend upon the molecular structure of the parent substance and its metabolic/chemical fate within the micro-environment of the site of first contact.

Human data
No relevant human information is available.

Conclusions
The waiving of the conduct of an extended one-generation reproductive toxicity study in rats with acetic anhydride is made on the basis that:
1. The significant local toxicity resulting from treatment with either acetic acid or acetic anhydride by oral or inhalation administration, due to the irritant nature of both substances, would significantly limit the maximum dose levels that could be achieved with either substance in vivo. Consequently, it would be unlikely that sufficient systemic exposure could be achieved by either route of administration in order to assess this reproductive endpoint.
2. Acetic anhydride is considered corrosive because of its significantly irritant capability and the fact that acetic acid is itself classified as corrosive. Consequently, there would be considerable ethical concerns around the dosing of such substances in vivo, particularly at the expected high doses levels needed to achieve sufficient systemic exposure.

Summary
The regulatory 90-day inhalation toxicity study in rats with acetic anhydride showed no effects on the male or female reproductive tract at a dose level up to 20 ppm (83.5 mg/m3). In support of the lack of potential reproductive effects are the regulatory developmental toxicity studies by the oral route in the rat, mouse and rabbit (Morgareidge 1974), which have been read across from acetic acid. These studies on acetic acid showed an absence of effect on reproduction and pregnancy in females at doses up to 1600 mg/kg/day in rats and rabbits and 345 mg/kg/day in mice.
Therefore, taking a comparative line through the rat studies, a NOAEL of 1600 mg/kg/day for acetic acid on maternal and developmental toxicity by the oral route can be converted into a NOAEL by the inhalation route which can be compared to the inhalation 90-day study with acetic anhydride:
The NOAEL of 1600 mg/kg/day relates to the test material in the form of cider vinegar which is 5% acetic acid. Therefore, the NOAEL in terms of acetic acid is 80 mg/kg/day. Each molecule of acetic anhydride would, on hydrolysis, produce 2 molecules of acetic acid. So in terms of anhydride, this NOAEL is approximately 40 mg/kg/day. This oral dose can be modified to an inhalatory dose over a 24-hour period in rats by using the standard respiratory volume for rats for 24 hours exposure of 1.15 m3/kg/day: 34.7 mg/m3
This value corresponds with the inhalatory dose levels on the 90-day toxicity study with acetic anhydride of 4.18 mg/m3 (1 ppm), 20.9 mg/m3 (5 ppm) and 83.5 mg/m3 (20 ppm) (HRC 1996). In this study, there was no evidence of systemic toxicity, although there were significant adverse local effects on the respiratory tract at 5 and 20 ppm.
In order to assess the potential for a substance to affect reproduction, it is essential that systemic absorption is achieved. Whilst toxicokinetic assessment has not been included in any of the studies used in this assessment, it is clear from the available toxicity profile of acetic anhydride that, despite the rapid hydrolysis of acetic anhydride (1 mole) to acetic acid (2 moles), sufficiently high systemic exposure, either via the oral or inhalation routes of administration, could not be achieved because of the limitations imposed by severe local reactions. The read across substance, acetic acid (100%), is classified as corrosive but is normally tested in the form of cider vinegar which has an acetic acid content of 5%.
Systemic exposure to acetic anhydride has not been demonstrated at repeated inhalation doses up to 417.55 mg/m3 because of the severity of localised toxicity. Therefore, very large doses of cider vinegar (5% acetic acid) would be required to achieve potential systemic exposure equivalent to a systemic exposure of acetic anhydride. it is concluded that very high doses of a corrosive substance either acetic acid (read across substance) or acetic anhydride (target substance) would need to be given to rats by either the inhalation or oral routes of administration in order to achieve systemic exposure for the assessment of potential reproductive toxicity. There would be considerable ethical concerns around the dosing of such substances in vivo as well as the difficulties that inevitable local toxicity would present in the interpretation of reproductive toxicity resulting from significant maternal stress.

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:

not specified