Isopropyl acetate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

275 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECETOC

Overall assessment factor (AF):

6

Dose descriptor starting point:

NOAEC

Value:

1 650 mg/m³

AF for dose response relationship:

1

Justification:

Default

AF for differences in duration of exposure:

2

Justification:

Default for extrapolation from sub-chronic to chronic data

AF for interspecies differences (allometric scaling):

1

Justification:

No factor applicable for inhalation route of exposure

AF for other interspecies differences:

1

Justification:

According to the ECETOC guidance document (ECETOC, 2010) , it is not appropriate in the majority of cases to apply an interspecies factor for ‘residual differences’ and that such a factor should only be supplied should the hazard data indicated a greater or lesser sensitivity of animals compared to man, eg significant differences in the mode of action. If such a factor was required, there would be evidence for it in a comparison of data between different animal species, as opposed to animals and humans. In a comparison of the repeat dose data between rats and mice, the ERASM project (see ECETOC reference) did not find evidence to support use of such a factor on a routine basis and any differences could be accounted for by allometric scaling factors alone. The data presented by ECETOC also support the conclusion that any ‘residual’ interspecies variability following allometric scaling is largely accounted for in the intraspecies factor, reflecting the interdependency of the individual assessment factors and avoiding ‘double counting’ of statistical variability. There is no scientific rationale provided in the ECHA document for the use of such a factor.

AF for intraspecies differences:

3

Justification:

According to the ECHA guidance document, deviation from the default ECHA assessment factors is possible where scientific justification exists. As summarized in the ECETOC technical report No. 86, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined by various groups (Hattis et al., 1987 and 1999; Hattis and Silver, 1994; Renwick and Lazarus, 1998). These evaluations included data from healthy adults of both sexes, as well as limited data from young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The authors came to the conclusion that a factor of 3 for workers (as a more homogenous group) or 5 for the general population is sufficiently conservative to account for intraspecies variability. This holds especially true for substances of low systemic toxicity, e.g. isopropyl acetate (isopropanol), for which transient behavioral clinical observations and transient body weight gain effects and other adaptive effects noted. As such it is considered that the lower assessment factors proposed and justified by ECETOC in the general case apply to isopropyl acetate (isopropanol). Thus, the factors proposed by ECETOC adequately address the intraspecies variability within the risk assessment.

AF for the quality of the whole database:

1

Justification:

Default

AF for remaining uncertainties:

1

Justification:

Default

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

558 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

227 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: Bespoke for substance

Overall assessment factor (AF):

1.2

Dose descriptor:

BMCL10

Value:

272 mg/m³

AF for dose response relationship:

1

Justification:

Default

AF for differences in duration of exposure:

2

Justification:

Default for sub-chronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

No factor applicable for local effects

AF for other interspecies differences:

0.2

Justification:

The PBPK model shows that for the end point that give the most conservative (lowest) value for the point of departure, the difference between the inhaled concentrations required to deliver the same concentrations of acetic acid in rats versus humans is a factor of 5.8. This is rounded down to 5 to give an AF for interspecies difference other than allometry of 0.2

AF for intraspecies differences:

3

Justification:

Intraspecies variations are built into the PBPK model of Teeguarden and are taken into account by using the bottom end of the range of predicted human equivalent concentrations. The range spans a factor of 2. However, as a conservative approach an additional factor of 3 is applied based on the ECETOC factor for intraspecies differences. (See justification for inhalation, systemic effects, long term exposure.)

AF for the quality of the whole database:

1

Justification:

Default

AF for remaining uncertainties:

1

Justification:

Default

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:

27 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: Route to route extrapolation

Overall assessment factor (AF):

24

Dose descriptor starting point:

NOAEC

Value:

1 675 mg/m³

Modified dose descriptor starting point:

NOAEL

Value:

637 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The inhalation NOAEC is multiplied by the factor of 0.38m3/kgbw.day as recommended in the guidance for route to route extrapolation.

AF for dose response relationship:

1

Justification:

Default

AF for differences in duration of exposure:

2

Justification:

Standard assessment factor for sub-chronic to chronic extrapolation

AF for interspecies differences (allometric scaling):

4

Justification:

Standard assessment factor for allometric scaling from rat to human

AF for other interspecies differences:

1

Justification:

According to the ECETOC guidance document (ECETOC, 2010) , it is not appropriate in the majority of cases to apply an interspecies factor for ‘residual differences’ and that such a factor should only be supplied should the hazard data indicated a greater or lesser sensitivity of animals compared to man, eg significant differences in the mode of action. If such a factor was required, there would be evidence for it in a comparison of data between different animal species, as opposed to animals and humans. In a comparison of the repeat dose data between rats and mice, the ERASM project (see ECETOC reference) did not find evidence to support use of such a factor on a routine basis and any differences could be accounted for by allometric scaling factors alone. The data presented by ECETOC also support the conclusion that any ‘residual’ interspecies variability following allometric scaling is largely accounted for in the intraspecies factor, reflecting the interdependency of the individual assessment factors and avoiding ‘double counting’ of statistical variability. There is no scientific rationale provided in the ECHA document for the use of such a factor.

AF for intraspecies differences:

3

Justification:

According to the ECHA guidance document, deviation from the default ECHA assessment factors is possible where scientific justification exists. As summarized in the ECETOC technical report No. 86, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined by various groups (Hattis et al., 1987 and 1999; Hattis and Silver, 1994; Renwick and Lazarus, 1998). These evaluations included data from healthy adults of both sexes, as well as limited data from young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The authors came to the conclusion that a factor of 3 for workers (as a more homogenous group) or 5 for the general population is sufficiently conservative to account for intraspecies variability. This holds especially true for substances of low systemic toxicity, e.g. isopropyl acetate (isopropanol), for which transient behavioral clinical observations and transient body weight gain effects and other adaptive effects noted. As such it is considered that the lower assessment factors proposed and justified by ECETOC in the general case apply to isopropyl acetate (isopropanol). Thus, the factors proposed by ECETOC adequately address the intraspecies variability within the risk assessment.

AF for the quality of the whole database:

1

Justification:

Default

AF for remaining uncertainties:

1

Justification:

Default

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

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:

no hazard identified

Additional information - workers

There is no data available on the substance itself.   According to the Guidance on Information Requirements and Chemical Safety Assessment Appendix R8-13), in cases where toxicological information and evaluations of health effects are used for setting a national OEL and are documented and available these may be used and taken into account in deriving the DNEL.  A German MAK value of 100ppm (420mg/m3) 8hr TWA is available along with the criteria document.  The value is based on irritation data in human volunteers (Silverman et al 1946 - see chapter 7.10.5 of this dossier). According to the MAK documentation the Silverman study reported irritation after 15 min exposure to 200 ppm of isopropyl acetate. However, the study concluded that 100 ppm would be an acceptable workplace concentration for 8 hour exposures. As the available studies with n- and iso-propyl acetate in humans are rather old, the MAK document also refers to more recent supporting data from the similar substances ethyl acetate and n-butyl acetate. The MAK values for ethyl- and butyl- acetate are 400 ppm and 100 ppm, respectively. As the data suggests that the irritation potential increases with increasing chain length of the molecule, the MAK documents concludes that the OEL for isopropyl acetate should be closer to the butyl-acetate value. It is not possible to derive a DNEL by a 'conventional' approach as there is not sufficient data on isopropyl acetate itself.  It should be noted that there is an IOEL for ethyl acetate of 200ppm. The derived DNELS using the method more in line with the ECHA guidance, even with refined assessment factors, provide more conservative values than those derived by other authorities.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

168 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: ECETOC factors

Overall assessment factor (AF):

10

Dose descriptor starting point:

NOAEC

Value:

1 675 mg/m³

AF for dose response relationship:

1

Justification:

Default

AF for differences in duration of exposure:

2

Justification:

Default for sub-chronic to chronic extrapolation

AF for interspecies differences (allometric scaling):

1

Justification:

Not applicable for inhalation route

AF for other interspecies differences:

1

Justification:

According to the ECETOC guidance document (ECETOC, 2010) , it is not appropriate in the majority of cases to apply an interspecies factor for ‘residual differences’ and that such a factor should only be supplied should the hazard data indicated a greater or lesser sensitivity of animals compared to man, eg significant differences in the mode of action. If such a factor was required, there would be evidence for it in a comparison of data between different animal species, as opposed to animals and humans. In a comparison of the repeat dose data between rats and mice, the ERASM project (see ECETOC reference) did not find evidence to support use of such a factor on a routine basis and any differences could be accounted for by allometric scaling factors alone. The data presented by ECETOC also support the conclusion that any ‘residual’ interspecies variability following allometric scaling is largely accounted for in the intraspecies factor, reflecting the interdependency of the individual assessment factors and avoiding ‘double counting’ of statistical variability. There is no scientific rationale provided in the ECHA document for the use of such a factor.

AF for intraspecies differences:

5

Justification:

According to the ECHA guidance document, deviation from the default ECHA assessment factors is possible where scientific justification exists. As summarized in the ECETOC technical report No. 86, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined by various groups (Hattis et al., 1987 and 1999; Hattis and Silver, 1994; Renwick and Lazarus, 1998). These evaluations included data from healthy adults of both sexes, as well as limited data from young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The authors came to the conclusion that a factor of 3 for workers (as a more homogenous group) or 5 for the general population is sufficiently conservative to account for intraspecies variability. This holds especially true for substances of low systemic toxicity, e.g. isopropyl acetate (isopropanol), for which transient behavioral clinical observations and transient body weight gain effects and other adaptive effects noted. As such it is considered that the lower assessment factors proposed and justified by ECETOC in the general case apply to isopropyl acetate (isopropanol). Thus, the factors proposed by ECETOC adequately address the intraspecies variability within the risk assessment.

AF for the quality of the whole database:

1

Justification:

Default

AF for remaining uncertainties:

1

Justification:

Default

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

335 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

136 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: bespoke for substance

Overall assessment factor (AF):

2

Dose descriptor:

BMCL10

Value:

272 mg/m³

AF for dose response relationship:

1

Justification:

Default

AF for differences in duration of exposure:

2

Justification:

Factor for sub-chronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

No factor required for local effects

AF for other interspecies differences:

0.2

Justification:

The PBPK model shows that for the end point that give the most conservative (lowest) value for the point of departure, the difference between the inhaled concentrations required to deliver the same concentrations of acetic acid in rats versus humans is a factor of 5.8. This is rounded down to 5 to give an AF for interspecies difference other than allometry of 0.2

AF for intraspecies differences:

5

Justification:

Intraspecies variations are built into the PBPK model of Teeguarden and are taken into account by using the bottom end of the range of predicted human equivalent concentrations. The range spans a factor of 2. However, as a conservative approach an additional factor of 5 is applied based on the ECETOC factor for intraspecies differences for the general population. (See justification for inhalation, systemic effects, long term exposure.)

AF for the quality of the whole database:

1

Justification:

Default

AF for remaining uncertainties:

1

Justification:

Default

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:

DNEL (Derived No Effect Level)

Value:

16 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: Route to route extrapolation

Overall assessment factor (AF):

40

Dose descriptor starting point:

NOAEC

Value:

1 675 mg/m³

Modified dose descriptor starting point:

NOAEL

Value:

637 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The inhalation NOAEC is multiplied by the factor of 0.38m3/kgbw.day as recommended in the guidance for route to route extrapolation.

AF for dose response relationship:

1

Justification:

Default

AF for differences in duration of exposure:

2

Justification:

Default for sub-chronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Default for rat to human

AF for other interspecies differences:

1

Justification:

According to the ECETOC guidance document (ECETOC, 2010) , it is not appropriate in the majority of cases to apply an interspecies factor for ‘residual differences’ and that such a factor should only be supplied should the hazard data indicated a greater or lesser sensitivity of animals compared to man, eg significant differences in the mode of action. If such a factor was required, there would be evidence for it in a comparison of data between different animal species, as opposed to animals and humans. In a comparison of the repeat dose data between rats and mice, the ERASM project (see ECETOC reference) did not find evidence to support use of such a factor on a routine basis and any differences could be accounted for by allometric scaling factors alone. The data presented by ECETOC also support the conclusion that any ‘residual’ interspecies variability following allometric scaling is largely accounted for in the intraspecies factor, reflecting the interdependency of the individual assessment factors and avoiding ‘double counting’ of statistical variability. There is no scientific rationale provided in the ECHA document for the use of such a factor.

AF for intraspecies differences:

5

Justification:

According to the ECHA guidance document, deviation from the default ECHA assessment factors is possible where scientific justification exists. As summarized in the ECETOC technical report No. 86, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined by various groups (Hattis et al., 1987 and 1999; Hattis and Silver, 1994; Renwick and Lazarus, 1998). These evaluations included data from healthy adults of both sexes, as well as limited data from young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The authors came to the conclusion that a factor of 3 for workers (as a more homogenous group) or 5 for the general population is sufficiently conservative to account for intraspecies variability. This holds especially true for substances of low systemic toxicity, e.g. isopropyl acetate (isopropanol), for which transient behavioral clinical observations and transient body weight gain effects and other adaptive effects noted. As such it is considered that the lower assessment factors proposed and justified by ECETOC in the general case apply to isopropyl acetate (isopropanol). Thus, the factors proposed by ECETOC adequately address the intraspecies variability within the risk assessment.

AF for the quality of the whole database:

1

Justification:

Default

AF for remaining uncertainties:

1

Justification:

Default

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:

16 mg/kg bw/day

Most sensitive endpoint:

irritation (respiratory tract)

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: Route to route extrapolation

Overall assessment factor (AF):

40

Dose descriptor starting point:

NOAEC

Value:

1 675 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

637 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default

AF for differences in duration of exposure:

2

Justification:

Default for sub-chronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Default for rat to human

AF for other interspecies differences:

1

Justification:

According to the ECETOC guidance document (ECETOC, 2010) , it is not appropriate in the majority of cases to apply an interspecies factor for ‘residual differences’ and that such a factor should only be supplied should the hazard data indicated a greater or lesser sensitivity of animals compared to man, eg significant differences in the mode of action. If such a factor was required, there would be evidence for it in a comparison of data between different animal species, as opposed to animals and humans. In a comparison of the repeat dose data between rats and mice, the ERASM project (see ECETOC reference) did not find evidence to support use of such a factor on a routine basis and any differences could be accounted for by allometric scaling factors alone. The data presented by ECETOC also support the conclusion that any ‘residual’ interspecies variability following allometric scaling is largely accounted for in the intraspecies factor, reflecting the interdependency of the individual assessment factors and avoiding ‘double counting’ of statistical variability. There is no scientific rationale provided in the ECHA document for the use of such a factor.

AF for intraspecies differences:

5

Justification:

According to the ECHA guidance document, deviation from the default ECHA assessment factors is possible where scientific justification exists. As summarized in the ECETOC technical report No. 86, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined by various groups (Hattis et al., 1987 and 1999; Hattis and Silver, 1994; Renwick and Lazarus, 1998). These evaluations included data from healthy adults of both sexes, as well as limited data from young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The authors came to the conclusion that a factor of 3 for workers (as a more homogenous group) or 5 for the general population is sufficiently conservative to account for intraspecies variability. This holds especially true for substances of low systemic toxicity, e.g. isopropyl acetate (isopropanol), for which transient behavioral clinical observations and transient body weight gain effects and other adaptive effects noted. As such it is considered that the lower assessment factors proposed and justified by ECETOC in the general case apply to isopropyl acetate (isopropanol). Thus, the factors proposed by ECETOC adequately address the intraspecies variability within the risk assessment.

AF for the quality of the whole database:

1

Justification:

Default

AF for remaining uncertainties:

1

Justification:

Default

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:

no hazard identified