Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
708 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
705 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
2
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 057 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
1.5
Dose descriptor starting point:
NOAEC

Workers - Hazard via dermal route

Systemic effects

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

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Additional information - workers

Acute/short-term exposure – systemic effects

 

Diethyl ketone is not classified for acute dermal toxicity. Thus, the derivation of the respective DNEL is not required. This is in accordance with ECHA guidance on information requirements and chemical safety assessment, chapter R.8 (2008).

Diethyl ketone is also not classified for acute inhalation toxicity. However, as the inhalation of vapours of aliphatic ketones can cause reversible central nervous system depression in humans at concentrations usually exceeding the threshold for airway-irritation, diethyl ketone is classified and labelled according to Directive 67/548/EEC with R67 (vapours may cause drowsiness and dizziness) and according to Regulation 1272/2008/EC with H336 (may cause drowsiness or dizziness). There is no dose-response information available, which would allow the derivation of a DNEL. However, no neurological effects were observed in humans at concentrations causing eye and respiratory irritation. Thus, the DNEL derived for acute local effects (see below) is sufficient to prevent drowsiness and dizziness.

 

Acute/short-term exposure - local effects

 

Diethyl ketone is not classified for skin irritation, but for respiratory irritation according to Directive 67/548/EEC (R37, irritating to the respiratory system) and for eye and respiratory irritation according to Regulation 1272/2008/EC (eye damage Cat 2 / H 319, causes serious eye irritation; STOT single 3, H335, may cause respiratory irritation). In human volunteers the threshold for eye and respiratory irritation was around 700 ppm (2470 mg/m³) and 400 ppm (1410 mg/m³), respectively (Douglas and Coe, 1987). Applying an assessment factor of 1.5 to the lowest threshold of 400 ppm to compensate for methodological uncertainties regarding the study (number of volunteers unknown, inhalation of 10 breaths of 1 L gas) results in an acute DNEL for local effects of 300 ppm (1057 mg/m³). This concentration was also derived by ACGIH (2001) as TLV-STEL for occupational exposure to diethyl ketone and represents the European short-term IOEL value of the structurally very closely related methyl ethyl ketone (Directive 2000/39/EC), which confirms the validity of the established DNEL. 

 

Long-term exposure - systemic effects

 

The repeated oral dose toxicity of diethyl ketone was examined in two subsequent drinking water studies in rats (EPA/OTS, 1983). Each study consisted of only one dose group of 5 female rats treated at 1860 mg/kg bw. The main focus was on in-life parameters (mainly neurobehaviour) and histopathology in the first and second study, respectively. Even though both studies are scientifically acceptable as they provide relevant toxicological information on the repeated dose toxicity of diethyl ketone, they are not sufficient for the establishment of a DNEL.

Therefore, the 90-d inhalation toxicity study in rats with the structurally very similar methyl ethyl ketone (Cavender et al., 1983), which is reliable without restrictions, was used for DNEL derivation. A NOAEC of 5000 ppm was derived from this study.

 

Inhalation

The NOAEC of 5000 ppm is corrected taking into account the longer exposure period of workers in comparison to rats (6 h / 8 h) and light activity at work (standard 8-h respiratory volume / (worker 8-h respiratory volume = 6.7 m³ / 10 m³ ):

NOAEC(corrected) = 5000 ppm x 6/8 x 6.7/10 = 2513 ppm

For the establishment of the DNEL the following assessment factors are applied: The intraspecies assessment factor of 5 for the worker, the duration assessment factor of 2 for extrapolation from sub-chronic to chronic and an additional factor of 1.25 for quality of database to cover any uncertainties which might be involved in the read-across approach. An assessment factor for allometric scaling is not required because the starting point is an inhalation study. An interspecies factor for remaining differences is not used as toxicokinetic data for methyl ethyl ketone did not reveal a significant difference between rat and human metabolism. Also, an additional assessment factor for dose-response is not needed.

The long-term DNEL(inhalation) for systemic effects is calculated as follows:

DNEL(long-term inhalation, systemic) = 2513 ppm / (5 x 2 x 1.25) = 201 ppm (corresponding to 708 mg/m³)

The reliability of the DNEL is confirmed by the occupational exposure limit of 200 ppm which is the TLV-TWA in the U.S. for Diethyl ketone (ACGIH, 2001) and the European long-term IOEL value for methyl ethyl ketone (Directive 2000/39/EC). 

 

Dermal exposure

In the toxicokinetic section it was concluded that absorption a comparable absorption between the inhalation and dermal route can be assumed only if the skin is occluded to prevent a significant loss of the substance by evaporation. Thus, as a worst case assumption, no difference between dermal and inhalation absorption is considered for the calculation of the dermal DNEL by route-to-route extrapolation from the inhalation DNEL:

DNEL(long-term dermal, systemic) = 708 mg/m³ x 10 m³ / 70 kg = 101 mg/kg bw/d

 

Long-term exposure - local effects

Repeated dermal exposure to diethyl ketone may cause skin dryness or cracking. There are no experimental data available allowing the derivation of a local dermal DNEL. However, the risk management measures in place (see section 11 of the IUCLID and section 9 of the CSR) are appropriate and sufficient to control the risk.

 

In human volunteers the threshold for eye and respiratory irritation was around 700 ppm (2470 mg/m³) and 400 ppm (1410 mg/m³), respectively (Douglas and Coe, 1987). Applying an assessment factor of 2 to the lowest threshold of 400 ppm to compensate for methodological uncertainties regarding the study (number of volunteers unknown, inhalation of 10 breaths of 1 L gas) and repeated exposure results in a long-term DNEL for local effects of 200 ppm (705 mg/m³). This value was also derived by ACGIH (2001) as TLV-TWA value for occupational exposure to Diethyl ketone and represents the European IOEL value of methyl ethyl ketone (Directive 2000/39/EC), confirming the validity of the established DNEL.

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

There are only industrial and professional uses of diethyl ketone. Therefore, no DNELs for the general population have to be derived.

Categories Display