Reaction mass of ethanol and propan-2-ol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

500 mg/m³

DNEL related information

Overall assessment factor (AF):

1

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:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 900 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Dose descriptor starting point:

NOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

343 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

24

Modified dose descriptor starting point:

NOAEL

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:

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

Additional information - workers

DNEL inhalation based on isopropanol:

Long-term DNELs:

IOEL/OEL

There is no IOEL value for IPA. A German MAK was available and deemed suitable for derivation of the DNEL.

Reference: Deutsche Forschungsgemeinschaft List of MAK and BAT Values 2007 Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area Report No. 43

Translated data:

In animal experiments testing subchronic exposures of at least 500 ml/m³ nasal incrustations were observed in male rats. Since there were no microscopic changes, the toxicological relevance of these results is doubtful. The renal changes also observed in male rats exposed to these concentrations are species- and sex-specific effects. When exposing the animals to 1,500 ml/m³ of 2-propanol, only female mice presented a higher relative liver weight. After chronic exposure of male rats to at least 500 ml/m³, the testicle weights and interstitial cytoadenomas of the testicles were found to be slightly increased. In mice inhaling these concentrations the relative testicle weights were reduced, whereas the absolute and relative liver weights were increased. However, this did not always apply to both sexes. The histological results of these organs were not contributory. For the present, it is difficult to state the human relevance of the partially minimal or sex-specific findings in rats and mice exposed to 500 ml/m³.

'MAK Values and Pregnancy' (examinations on rats, 1989): that inhalation of 400 ml/m³ of 2-propanol presumably does not have any embryotoxic effect has been confirmed by further examinations on another species. 

 

The MAK value of 2-propanol is provisionally lowered to 200 ml/m³ (=500 mg/m³). Since there are only few and partially only conditionally convincing results concerning the irritant effect of 2-propanol in man and animal, any irritant effect is considered unlikely at this concentration.

Starting Dose for DNEL calculation:

500 mg/m³(based on occupational exposure of 8 hours/day, 5 days/week)

Modified dose for DNEL Calculation

Worker – Inhalation = 500 mg/m³(no adjustment required)

Worker – Dermal =500 mg/m³x 10 m³/d/70 kg = 71 mg/kg/d; 71 mg/kg/d x 100%/8% (Absorption correction – see absorption data below) = 888 mg/kg/d

Assessment Factors– no adjustments required for interspecies, exposure duration, dose response or quality of whole database as DNEL is based on an occupational limit for workers.

Final DNELs = Modified Dose; Worker – Inhalation DNEL = 500 mg/m³; Worker – Dermal DNEL =888 mg/kg/d

Absorption Data

Oral: Oral absorption is nearly 100% as evidenced by the nearly complete lack of radiolabel in feces for up to 168 hours following gavage administration of radiolabeled IPA (see toxicokinetic statement)

Inhalation: IPA has a molecular weight of <500 g/mol and a log Kow between 0 and 4; therefore, it is assumed to be well absorbed equivalently by the oral and inhalation route; therefore, inhalation absorption assumed to be 100%.

Dermal: Dermal absorption of IPA is rapid but limited. Following a 4-hour occlusive application 84 to 86% of the applied dose was recovered from the skin and 8 to 9% was lost (presumably to volatilization); thus, approximately 5 to 8% of the applied dose was absorbed systemically (see toxicokinetic statement). For the purpose of the DNEL calculation, dermal absorption was conservatively assumed to be 8%.

Ethanol:

INHALATION DNEL

The occupational exposure limit derived by the German MAK commission is used as the basis for the DNEL (inhalation) for ethanol.  A full criteria document reviewing the data and justifying the derived value is available.  There is no new data which questions the basis of this derivation.  The key parts of the derivation are shown below.  The underlying principle is that all humans are exposed to ethanol endogenously.  The OEL is based on the premise that the derived exposure limit does not give rise to a significant additional lifetime ethanol burden over and above what arises from natural exposure to ethanol.

The area under the blood-concentration/time curve (AUC), i.e. the product of the blood-ethanol concentration and the corresponding load time, can be used as a suitable starting point to calculate the internal ethanol lifetime dose. For naive controls, an AUC of 13.6-21.6 mg/1.year can be derived from the endogenous alcohol concentration in the blood of 0.17-0. 27mg/1 (based on the data of Sprung, 1981) and an assumed lifetime of 80 years.  This provides a measure of the lifetime internal ethanol dose, assuming that the endogenous blood-ethanol concentration is constant over the whole lifetime.  The mean steady-state ethanol concentrations in dynamic equilibrium in the blood of human volunteers has been established (Seeber, 1994).  It was demonstrated that there is a linear relationship between the ethanol concentration in the air inhaled and the mean steady-state concentration in the blood for inhalation concentrations up to 800ppm(1500mg/m3).

The slope of this line is 0.0029mg/(l.ppm) and it follows from this linear relationship that the kinetics of the elimination, in the concentration range studied, are first-order.  Additional lifetime contributions from the inhalation of ethanol vapour can then be calculated.  These are corrected as shown below to allow for the fact that exposures only occur 8hrs per day, 5 days per week and for a working life of 40 years:

AUC = 0.0029 mg/(l.ppm)xppm x 8/24 x 5/7 x 40years

Calculated AUC for different exposures:

ppm	Lifetime AUC contribution
100	2.75
200	5.5
500	13.8

The MAK commission concluded that because the Lifetime AUC contribution from daily occupational exposure to ethanol vapour at 500ppm contributes no more to the lifetime dose than endogenous ethanol exposure (and lies within the standard devation, then this limit can be considered safe without the need to consider the toxicology of the substance.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

114 mg/m³

Most sensitive endpoint:

carcinogenicity

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:

no-threshold effect and/or no dose-response information available

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

950 mg/m³

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

206 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

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:

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:

87 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

DNEL related information

Additional information - General Population

Ethanol:

LONG TERM EXPOSURE

Oral point of departure: NOAEL for repeat dose toxicity =1730mg/kg (male rats) No further correction is necessary for bioavailability or exposure conditions. Standard assessment factors would lead to an interspecies factor of 10, an intraspecies factor of 10 and a duration factor of 2. However, this is considered excessive as it would lead to a DNEL of 8.7mg/kg. It is generally recognised that oral consumption of 3 -4 units of alcoholic beverage for men or 2 -3 for women per day will not accrue significant health risk (Sensible Drinking, UK Dept of Health, 1995). (This excludes potential reprotoxicity risks but these are related to concentration rather than repeat dose effects). Assuming 7g ethanol per unit and taking the bottom end of the range, this would equate to human dose of 233 -400mg/kg (assuming a 70kg man and 60kg woman). The approach used is therefore to follow the ECETOC recommended assessment factors of 4 for interspecies kinetic effects and 5 for intraspecies effects (for the general population) to derive a combined assessment factor of 20 and an oral DNEL of 87mg/kg/day.

Route to route extrapolation for dermal: There is no specific data for humans. The oral DNEL is again the point of departure. NOAEL for repeat dose toxicity =1730mg/kg (male rats) No further correction is necessary for bioavailability or exposure conditions. Assessment factors recommended in the REACH guidance would lead to an interspecies factor of 10, an intraspecies factor of 10 and a duration factor of 2. This is however considered excessive and the approach adopted is to use the assessment factors of ECETOC (4 for interspecies kinetic factors, 5 for intraspecies for the general population and 2 for duration). Assuming a dermal absorption factor (worse case) of 21% (see chapter 7.1.2) leads to a NOAEL of 8238mg/kg for occlusive conditions. (Note that under non-occlusive conditions, the data available suggests that absorption is about 10% of that under occlusive conditions and therefore the DNEL will be a factor of 10 higher.) Application of the assessment factor of 40 leads to a DNEL of 206mg/kg/day.

Please see discussion for workers for calculation of departure point for inhalation DNEL calculation and a comparison with the assessment factor approach. The DNEL used here is derived in the same way as the DNEL for workers, however in this case no factors are used for daily or weekly exposure conditions. The AUC calculation becomes simply:

AUC = 0.0029 mg/(l.ppm)xppm x 80years

Lifetime AUC contributions then become:

ppm	Lifetime AUC contribution
50	11.6
60	13.9
100	23.2

Using the same criteria as for workers, a DNEL of 60ppm (114mg/m3) is derived.

Isopropanol:

Acute DNELs- General Population: Similar to above for worker, assessment of acute systemic effects should default to the long term systemic DNELs; IPA not classified as a skin irritant; default to systemic DNEL for inhalation local effects.

Long-term DNELs:

The long-term DNEL for the general population was derived from the worker OEL

Starting Dose for DNEL calculation:

500 mg/m³(based on occupational exposure of 8 hours/day, 5 days/week) (amortized below for continuous exposure)

Modified dose for DNEL Calculation

General Population – Inhalation = 500 mg/m³x10/6.7x 8/24 x 5/7 (amortized for continuous exposure) = 178 mg/m³

General Population – Oral =178 mg/m³x 20 m³/d/70 kg = 51 mg/kg/d (no adjustment for absorption)

General Population - Dermal =178 mg/m³x 20 m³/d/70 kg = 51 mg/kg/d; 51 mg/kg/d x 100%/8% (Absorption correction – see above under worker) = 638 mg/kg/d

Assessment Factors (AF)–

No adjustments required for interspecies, exposure duration, dose response or quality of whole database as DNEL is based on an occupational limit for workers.

An AF of 2 applied for differences between workers and general population (basis: when extrapolating from animal to human, the recommended AF is 10 for general population and 5 for worker – since the starting dose is amortized for continuous exposure an additional 2 fold AF for differences was considered sufficient)

Final DNELs = Modified Dose; General population – Dermal DNEL = 638mg/kg/d/2 = 319 mg/kg/d;General population – Inhalation DNEL178 mg/m³/2 = 89 mg/m³; General population – Oral DNEL = 51mg/kg/d/2 = 26 mg/kg/d