Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
84 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
DNEL derivation method:
other: MAK Value
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

DNEL long-term Inhalation:

In an inhalative study on rats the NOAEL for developmental toxicity for acetyl acetone was set to 53 ml/m3. At the next highest concentration of 202 ml/m3significantly reduced fetal body weights were recognized only in three percent of the individuals. Clear fetotoxic effects and unequivocal maternal toxicity appeared at 398 ml/m3. The NOEL for developmental toxicity with 53 ml/m3is below of the NOAEL for systemic toxicity of 101 ml/m3from an inhalative 14 week study on rats. The next highest concentration of 307 ml/m3showed slight changes in body weight of the females, hematology, biochemistry and urinalysis. In a recovery group these effects were no longer determinable at 307 ml/m3. At a concentration of 650 ml/m3 mortality and broad neuropathological damages were observed. The NOAEL for developmental toxicity therefore is the most sensitive endpoint. The MAK value is therefore set to be 20 ml/m3.

For the clear fetotoxicity at 398 ml/m3in the above mentioned study a secondary developmental toxic effect is considered based on the unspecific effects and the broad maternal toxicity. For the marginal fetotoxicity at 202 mg/m3a causality with the maternal toxicity can not clearly been derived. Based on the very slight severity of the effects of the unspecific fetal toxicity at 202 mg/m3and the NOAEL at 53 ml/m3no teratogenic effect has to be reckoned with.

Acetyl acetone produces braud systemic effects at dermal exposition at a concentration of 1000 mg/kg bw/day in a 9 days study. It is unclear in which amount the skin damage increased the dermal penetration in this case. Compared to the inhalation route similar exposition concentrations generate similarly severe effects. Therefore a relevant dermal uptake has to be considered. The substance has a relatively low dermal LD50. The effects occur fast after contact whereas the irritating effects are only slight. Therefore skin penetration can not be increased by irritation. Following the models of Guy and Potts (1993) as well as Wilschut et al. (1995) and taking into account a skin area of 2000 cm2256 or 415 mg will absorbed from a saturated aqueous solution within one hour. With a MAK value of 20 ml/m3(84 mg/m3) 840 mg of the substance will be taken up via inhalation within one day. The calculated dermally absorbed amount is nearly half the amount that is inhaled if the MAK value is observed.

Carcinogenicity or long-term studies are not available for acetyl acetone. Acetyl acetone shows a slight genotoxic potential in vitro. The micronucleus assay on peripheral erythrocytes of the mouse is clearly positive after ip application and indicated a clastogenic potential of the substance in vivo. Nevertheless this potential has not been observed after inhalative exposition. The dominant lethal assay shows that toxic effects are present in germ cells whereas no mutagenic effects arise. Therefore acetyl acetone is not classified into the catregories of germ cell mutagenes or cancerogenes [MAK value justification, 2007].

This value is also supported by the German OEL (ARW) of 30 ml/m3(126 mg/m3) issued by the Committee on Hazardous Substances (AGS) in March 2008.

DNEL long-term dermal:

If the respiratory rate (8 hour) of a worker is assumed to be 10 m3/person with a body weight of 70 kg the corrected NOAEL(dermal) is therefore: = 84 mg/m3* 10 m3/70 kg =12 mg/kg bw/day (8 hour day)

The following assessment factors were applied to the corrected NOAEL:

Assessment factor for route-to-route extrapolation (systemic): 1 (the repeated inhalation and dermal studies suggest similar effects, such as those on the brain, irrespective of route of exposure. Therefore it is proposed that no assessment factor by applied in this case.)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

The typical pattern of worker exposure to acetylacetone is low levels of exposure on a repeated basis. Short-term high exposures are considered unlikely given the high levels of control in place at sites producing and using the substance. DNELs for long-term exposure are therefore adequate to protect against short-term exposures and no separate short-term DNELs are calculated.

No oral exposure will occur during normal handling and use therefore DNELs via the oral route are not calculated.

 

Repeated-dose toxicity – local effects – dermal route:

No suitable quantitative data are available.

 

Repeated-dose toxicity – local effects – inhalation route:

No additional assessment factors are applied to the MAK. Therefore the DNEL (local effects – inhalation) =20 ppm (84 mg/m3).

Repeated-dose toxicity – systemic effects – dermal route - worker:

The DNEL for systemic effects via the dermal route is determined on the basis of route-to route extrapolation from the inhalation MAK as follows:

MAK = 20 ppm (84 mg/m3)

If the respiratory rate (8 hour) of a worker is assumed to be 10 m3/person with a body weight of 70 kg the corrected NOAEL (dermal) is therefore: = 85 mg/m3* 10 m3/70 kg =12mg/kg bw/day (8 hour day).

The following assessment factors were applied to the corrected NOAEL:

Assessment factor for route-to-route extrapolation (systemic): 1 (the repeated dermal and inhalation studies suggest similar effects, such as those on the brain, irrespective of route of exposure. Therefore it is proposed that no assessment factor by applied in this case.)

The overall DNEL (repeated-dose, dermal, worker) is therefore =12 mg/kg bw/day.

Repeated-dose toxicity – systemic effects – inhalation route – worker:

No assessment factors have been applied to the MAK.

The overall DNEL (repeated-dose – systemic – inhalation - worker) is therefore 20 ppm (84 mg/m3) .

 

Repeated-dose toxicity – systemic effects – oral route - general population:

This DNEL is calculated using the MAK as follows:

MAK = 20 ppm (84 mg/m3)

It is assumed that the OEL applies to workers with a respiratory volume of 10 m3/person over an 8 hour period. This equates to a total intake of 84 mg/m3*10m3/day= 840 mg/day

Therefore the equivalent exposure limit for general population with 20 m3/person respiratory volume over 24 hours is: 840 mg/day/20 m3/day =42 mg/m3. If the respiratory rate (24 hour) of the general population is assumed to be 20 m3/person with a body weight of 60 kg the corrected NOAEL(oral) is therefore: = 42 mg/m3*20 m3/60 kg =14 mg/kg bw/day.

The following assessment factors were applied to the corrected NOAEL:

Assessment factor for route-to-route extrapolation (systemic): 1 (the repeated oral and inhalation studies suggest similar effects, suchas those on the brain, irrespective of route of exposure. Therefore it is proposed that no assessment factor by applied in this case.)

However, since the assessment for general population includes potentially sensitive populations, it is considered appropriate to apply an additional assessment factor for intraspecies differences.

Assessment factor for intraspecies differences (systemic): 2 (difference in default assessment factors for workers and the general population)

The overall DNEL (repeated-dose, oral, general population) is therefore = 14 mg/kg bw/day / 2 = 7mg/kg bw/day.

Repeated-dose toxicity – systemic effects – inhalation route – worker:

No assessment factors have been applied to the MAK.

The overall DNEL (repeated-dose – systemic – inhalation - worker) is therefore 20 ppm (84 mg/m3).