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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
40 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
17.5
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
80 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
8.75
Modified dose descriptor starting point:
NOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
40 mg/m³
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
Overall assessment factor (AF):
2.5
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
80 mg/m³
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
Overall assessment factor (AF):
1.25
Dose descriptor starting point:
NOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEL

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Acute systemic effects of Cyclohexanone have been investigated in rats, mice, rabbits, monkeys and dogs after oral, dermal or intraveneous administration. After oral and occlusive dermal administration the lethal dose range appeared to be between 800 and 3000 mg/kg bw. Intraveneous infusion in dogs showed transient central nervous effects occurring at 284 mg/kg bw, depending on the plasma peak concentrations achieved (80 -320 ug/ml; Koeferl et al., 1981) and being reversible within 30 minutes. Intraveneous doses of 568 mg/kg bw were immediatedly lethal in rats (Koeferl et al., 1976). When compared with the findings of Greener et al. (1982) who showed a NOAEL of 100 mg/kg bw and day in two strains of rats after 28 intraveneous infusions the dose-effect relation appears to be quite steep. Other effects that have been noted in the course of studies with longer duration were rather unspecific and confined to high doses. Long term drinking water studies in mice and rats gave no evidence of tumors with a human relevance. On balance, the variability and uncertainty arising from a large pool of experimental data is low, no major species and strain differences have been observed and no influence of study duration. However, it is pointed out that the EU SCOEL considers the data base on mutagenicity to be further strengthened and in regard of those needs fixes the IOELV as low as 40 mg/m3.

For acute local effects from inhalation, there is an short-term EU OEL value of 20 ppm (80 mg/m3). Furthermore, a NOAEC has been described for local irritation in humans from cyclohexanone vapours (NOAEC 100 mg/m3; 25 ppm; Nelson et al., Sensory response to certain industrial solvent vapors; J.Ind.Hyg.Toxicol. 25, 282 -285; 1943; quoted also in the German MAK-documentation (Greim, H, ed. Occupational Toxicants, X, 35 -51). No irritation was reported from more recent kinetic studies in man exposed to 400 mg/m³ (Mraz et al., 1994, see chapter 7.1.1). These authors decribe certain quantitative differences in the profile of biotransformation between humans and rats; whereas rats predominantly use the reduction pathway to Cyclohexanol with subsequent glucuronidation, humans rater metabolize to 1.2- and 1.2 -Dihydroxycyclohexane. However, there is no evidence of a higher sensitivity of humans. The fact that Cyclohexanon showed acute central nerve effects in experimental animals with a steep dose-effect relation may rise a potential caveat for an increased sensitivity of children towards such effects which should be considered for general population DNELs; see below)

For the DNEL assessment of acute systemic effects (inhalation and dermal), the NOAEL (100 mg/kg/d) in the subacute rat i.v. study (Greener et al., 1982) may be employed and a similar resorption rate from skin and inhalation be assumed.

For the DNEL assessment of chronic inhalation exposure the EU IOEL (10 ppm; 40 mg/m3) is the essential data point.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
70
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
35

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/m³
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
Overall assessment factor (AF):
5
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
40 mg/m³
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
Overall assessment factor (AF):
2.5
Dose descriptor starting point:
NOAEC

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL

Local effects

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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

For the systemic DNELs concerning dermal and inhalation exposure the rationales are presented above.

Concerning oral short-term and long-term exposures, the DNELs are based upon the NOAEL (143 mg/kg bw/d) in the BASF subchronic drinking water study. The chronic drinking water studies which are also are available do not show a decrease of the NOAEL with exposure time. Furthermore, in the course of the intraveneous studies, no significant difference was seen between single administration and repeated administration; the effects observed were reversible within 30 min. Hence, the time extrapolation factor can be fixed to 1. In the light of known qualitative differences in the metabolic profiles between rodents and humans (Mraz et al., loc.cit.) a default factor of 2.5 is proposed in addition to the allometric factor of 4. (This does not necessarily mean that humans are more sensitive.) The interindividual variability towards Cyclohexanone appears to be low in the species investigated and also in human adults; however, children may be more sensitive and therefore an interspecies factor of 10 is proposed, which leads to an overall factor of 100 and oral DNELs of 1.5 mg/kg bw (acute and chronic).

For the inhalation DNELs, the calculation procedure is similar as for the workplace. The NOAEL in the 28 days infusion study 100 mg/kg bw) was used as a point of departure. Also the acute and chronic EU-IOELs (80 and 40 mg/m3) were considered as shadow dose descriptors. However, in terms of systemic toxicity a 4 -fold higher intraspecies variability was taken into account and led to a total intraspecies factor of 10. The key effect appears to be a pronounced central nerve depression to which children may be more sensitive than adults. Hence, the standards for the work place were divided by 4. For the local toxicity a 2 -fold higher intraspecies factor was considered to be sufficient.

Similarly, also the dermal DNELs for the workplace (derived from the subacute infusion study in rats with a NOAEL of 100 mg/kg/d; see above) were devided by 4.