Acetic anhydride

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.2 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Modified dose descriptor starting point:

NOAEC

Value:

4.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

Inhalation route is directly applicable.

AF for dose response relationship:

1

Justification:

ECETOC/ECHA default – clear NOAEC

AF for differences in duration of exposure:

1

Justification:

Local effect, no need for adjustment for duration

AF for interspecies differences (allometric scaling):

1

Justification:

ECETOC/ECHA default for inhalation route. No factor for allometric scaling is needed as local irritation effect, independent of basal metabolic rate.

AF for other interspecies differences:

1

Justification:

Humans are not considered more sensitive than rats and an overall AF of 1 is considered appropriate

AF for intraspecies differences:

1

Justification:

Reduced factor of 1 since the critical effect is a direct, local effect not influenced by toxicokinetics (due to physico-chemical properties of the substance).

AF for the quality of the whole database:

1

Justification:

ECETOC/ECHA default; GLP-compliant guideline study

AF for remaining uncertainties:

1

Justification:

Local effect with clear NOAEC, no need for adjustment

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Most sensitive endpoint:

irritation (respiratory tract)

Route of original study:

By inhalation

DNEL related information

Justification:

L

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.2 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: ECHA - substance specific AFs

Overall assessment factor (AF):

1

Dose descriptor:

NOAEC

AF for dose response relationship:

1

Justification:

ECETOC/ECHA default – clear NOAEC

AF for differences in duration of exposure:

1

Justification:

Local effect, no need for adjustment for duration

AF for interspecies differences (allometric scaling):

1

Justification:

ECETOC/ECHA default for inhalation route. No factor for allometric scaling is needed as local irritation effect, independent of basal metabolic rate.

AF for other interspecies differences:

1

Justification:

Humans are not considered more sensitive than rats and an overall AF of 1 is considered appropriate.

AF for intraspecies differences:

1

Justification:

Reduced factor of 1 since the critical effect is a direct, local effect not influenced by toxicokinetics (due to physico-chemical properties of the substance).

AF for the quality of the whole database:

1

Justification:

ECETOC/ECHA default; GLP-compliant guideline study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

other toxicological threshold

Value:

12.6 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Overall assessment factor (AF):

1

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

An IOELV has not been established for acetic anhydride. Although some national OELs exist, for the purposes of this submission DNEL values are derived following the principles outlined in the relevant REACH guidance (Chapter R.8: Characterisation of dose [concentration]-response for human health).

Acute toxicity

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. C&L) has been identified and there is a potential for high peak exposures. These “peaks” are normally associated with inhalation exposure, but are less common for skin contact and ingestion. Acetic anhydride does not present an acute hazard following ingestion or skin contact. It is, however, classified as harmful via inhalation exposure and therefore consideration of an acute DNEL_inhalation is required.

From the acute data available for acetic anhydride it is not possible to clearly define a threshold for irritation. However, from the 13-week study with a clear NOAEC at 1 ppm and limited histopathological findings restricted to the upper respiratory tract (nasal passages and larynx) at 5 ppm, the true threshold for irritation effects is between the two. In the same study significant recovery from irritation effects was reported in animals exposed to acetic anhydride for 13 weeks and then allowed a 13-week period without exposure.

In summary, it is proposed that 3 ppm would be protective for short term exposure (based on local effects):

DNEL_{acute (inhalation)} = 3 ppm (12.6 mg/m³)

Irritation

Acetic anhydride is classified as corrosive hence appropriate RMM and OCs should be employed. 

For inhalation exposure, the acute DNEL_{acute (inhalation)} of 3 ppm is proposed for acetic anhydride and is considered to be protection for acute, local irritation effects.

DNEL_{acute (local)} = 3 ppm (12.6 mg/m³)

Long-term systemic effects

Dermal

Acetic anhydride is classified as corrosive hence appropriate RMM and OCs should be employed. No DNEL_{l-t dermal} is therefore appropriate.

Inhalation

Dose descriptor 

The starting point of the NOAEC of 1 ppm (4.2 mg/m³) from the 90 day inhalation study will be used (HRC, 1996).

Considering exposure to acetic anhydride at an atmospheric concentration of 1 ppm (4.2 mg/m3), systemic exposure to acetate at this concentration is insignificant (see section 5.6.3 above). For an 8 hour day spent at light work, and assuming 100% absorption of acetic anhydride/acid for a worker would be:

Systemic dose     = 4.2 mg/m3* wRV m3/kg bw * [mw acetic anhydride / acetic acid]

= 4.2 * 0.144 * [102.09 / 60.05]

= 1.03 mg/kg bw. 

To put this intake into perspective with the known removal of acetate, it has been shown that about ~0.5 mg/kg bw acetate can be removed each minute via endogenous pathways, such as the citric acid cycle, in humans following administration of acetate in a drink (Smith et al., 2007). Daily administration of 40 mg/kg bw/day may be used as a medicinal product (Johnston & Gaas, 2006), and 30 mg/kg bw /day is estimated as average human dietary intake (Ishiwata et al., 2002), with peak excursions up to 240 mg/kg bw /day (EU DAR, 2008).

Modification of dose descriptor

No modification is necessary.

According to the REACH guidance, time scaling is not appropriate when the toxic effect is mainly driven by the exposure concentration (as for irritation). Activity has marginal influence and thus there is no need for application of the 0.67 conversion factor to account for the difference between resting and light work respiratory volumes.

DNEL_{l-t inhal}                   = 1 ppm (4.2 mg/m³)

Long-term local effects

The DNEL is derived for the critical effect of upper respiratory tract irritation and therefore the DNEL_{l-t inhalation} applies
DNEL_{l-t inhal (local)}        = 1 ppm (4.2 mg/m³)

Dermal

Acetic anhydride is classified as corrosive hence appropriate RMM and OCs should be employed. 

No information is available to characterise the repeated local effects of acetic anhydride on the skin, while route-to-route extrapolation (respiratory tract to skin) is not appropriate.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

No consumer exposure anticipated therefore no DNELs proposed