Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
DNEL value:
638.4 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
allometric scaling not used for inhalation
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
53.2 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor:
NOAEC
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
no assessment factor required as critical effect (sensory irritation) is concentration dependant
AF for interspecies differences (allometric scaling):
1
Justification:
not required as human data are used
AF for other interspecies differences:
1
Justification:
not required as human data are used
AF for intraspecies differences:
1
Justification:
no assessment factor required as critical effect (sensory irritation) is mostly concentration dependant instead of influenced by interindividual differences
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
53.2 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor starting point:
NOAEC
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
1
Justification:
not required as human data are used
AF for other interspecies differences:
1
Justification:
not required as human data are used
AF for intraspecies differences:
1
Justification:
no assessment factor required as critical effect (sensory irritation) is mostly concentration dependant instead of influenced by interindividual differences
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
87.5
Modified dose descriptor starting point:
NOAEL
DNEL value:
2 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no repeated dermal toxicity study available, adequate toxicokinetic data to allow for assessment of dermal and oral absorption (10% dermal absorption )
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
chronic study available
AF for interspecies differences (allometric scaling):
7
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

WORKERS

  • Inhalation - systemic effects - long term exposure

There is only one inhalation toxicity study investigating systemic effects. In this 90-day repeated inhalation toxicity study in Wistar rats the NOAEC was the highest dose tested as no effects, neither systemic nor local, were observed (i.e. 120 ppm = 638.4 mg/m³).

DNEL derivation workers long term systemic effects is based on this study. And according to ECHA REACH Guidance R.8 the following assessment factors are used:

·        Interspecies:             0 allometry; 2.5 remaining differences

·        Intraspecies               5

·        Time                          2

Leading to the overall assessment factor of 25.

With the correction of starting concentration based on differences in between experimental and human conditions:

Corrected NOAEC = 638.4 * 6 h/d / 8 h/d * 6.7 mg/m³ / 10 mg/m³= 320.8 mg/m³

finally leads to a DNEL of 12.8 mg/m³ (≈ 2.4 ppm).

However, this systemic DNEL is based on the highest concentration tested in a study where no effects were seen and the no adverse effect level is unknown.

  • Inhalation - systemic effects - acute/short term exposure

There is no harmonised classification available for 2-EH. However based on available data within the registration dossier aerosols of 2-EH are classified as “Harmful if inhaled“(Acute Toxicity Category 4; H332). No classification for acute systemic effects is warranted for 2-EH vapours.

Local sensory irritation is obvious in humans already at concentrations when no other systemic effects are obvious. Therefore the DNEL for acute local effects also protects from possible systemic effects arising from exposure to 2-EH via inhalation.

  • Inhalation - local effects - long term exposure

DNEL derivation

The most adequate point of departure for DNEL derivation is the NOAEL presented by Kiesswetter et al. (2005) in the experiment with constant exposure conditions which investigated sensory irritation in humans. The results of the variable exposure conditions were not considered for DNEL derivation as they also included peak exposures e.g. up to 20 ppm in the mean 10 ppm exposure group and the decisive effect (sensory irritation) is essentially concentration dependent. With constant exposure conditions 20 volunteers were exposed to 1.5, 10 or 20 ppm of 2-ethylhexanol. As an objective measure for first signs of sensory irritation blinking frequency was statistically increased at the highest concentration tested (i.e. 20 ppm). No significant difference could be determined between the low and middle exposures. The resulting NOAEL is 10 ppm.

As human data are used no interspecies extrapolation has to be performed.

It is often stated that intraspecies variability is expected to be smaller in case of local effects. Sensory irritation is a trigeminal triggered effect and observed influences are mainly concentration dependent instead of interindividual differences (in toxicokinetics or –dynamics; please cf. also the derivation of OEL values presented below which did not use an intraspecies factor, too). Moreover in the study by Kiesswetter et al. (2005) 20 study subjects were investigated, which would most likely reveal any drastic interindividual effects. And even more as 8 study subjects in the experiment with constant exposure conditions had self-reported chemical sensitivity. In conclusion no intraspecies extrapolation was performed.

As explained above the underlying effect for the NOAEL is sensory irritation. The read out used in the study is objective and very sensitive for this kind of effect. With this mode of action no effects are to be expected, if the exposure is not exceeding the threshold for trigeminal stimulation. Thus no time extrapolation has to be performed. This is in line with ECHA Guidance R.8 Appendix R.8-9 where no assessment factor for exposure duration is explicitly foreseen concerning sensory irritation. This approach taken is also supported by (ECETOC, 2003; 2010).

As the data are valid and no further issues related to concentration-response relationship or the overall quality of the database arise and no further assessment factor has to be considered.

Thus using the NOAEL of 10 ppm and applying no assessment factors (AF) a

DNEL of 53.2 mg/m³ (10 ppm)

results.

This DNEL would then be adequate to protect workers from long term local effects when exposed to 2-EH via inhalation.

 

The DNEL derivation is further supported by several regulatory bodies which used the data by Kiesswetter, van Thriel and colleagues for establishment of their respective guideline values. Thus stating the adequacy and overall quality of the data. Blinking frequency and thus trigeminal sensory irritation was regarded as valid endpoint.

  • European OEL (SCOEL, 2011)

A health based 8-h OEL was set by the European Scientific Committee on Occupational Exposure Limits (SCOEL) to 1 ppm.

This OEL value is based on the experimental data with human volunteers as reported by van Thriel and colleagues (Kiesswetter et al., 2005; van Thriel et al., 2007; van Thriel et al., 2005; van Thriel et al., 2003). Exposure of volunteers to 1.5, 10 and 20 ppm 2-EH, with both constant and variable exposures, induced a concentration dependent increase in self-rated eye irritation, nasal irritation and annoyance. The objective measurement of blink frequency showed an increase at 10 and 20 ppm. Additionally, at 20 ppm nasal air flow was decreased and substance P in nasal lavage was increased. As no objective effects were seen at 1.5 ppm and the self-reported irritation symptoms were minimal SCOEL inferred a NOAEL for irritation of 1.5 ppm from the study.

Further exposure chamber tests with human volunteers, who were exposed for 2 hours at 0.2 ppm, did not find any significant effects on nasal irritation, throat irritation, headache, dyspnoea, fatigue, dizziness and nausea. And no exposure related effects on blink frequency, eye tear film break-up time, vital staining of the eye, nasal lavage biomarkers, transfer tests of spirometric and rhinometric measures were seen. Only a minimal increase in the rating of subjective eye irritation was reported (Ernstgard et al., 2010). The findings from Ernstgard and colleagues were evaluated as supportive for the findings from van Thriel and colleagues by SCOEL.

As mentioned above the results of the variable exposure conditions (as relied upon by SCOEL) were not considered for DNEL derivation as they also included peak exposures e.g. up to 20 ppm in the mean 10 ppm exposure group and the decisive effect (sensory irritation) is essentially concentration dependent. Therefore the experiment with constant exposure conditions and the objective eye blink measurements was considered adequate, thus leading to a relevant NOAEL of 10 ppm (only the high exposure (20 ppm) showed a significant increase in blinking rate). The difference in NOAELs used to begin with, then leads to the observed differences for the reference value determined by SCOEL in comparison to the DNEL derived here.

  • German OEL (MAK)

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK-Kommission) has recently revised the evaluation of 2-EH and has set the Maximum Concentration in the Workplace air (MAK value) to 10 ppm (former MAK value: 20 ppm; Hartwig, 2012). This value should not be exceeded, even not in case of a short time peak exposure.

The MAK value is based on the experimental data with human volunteers as reported by van Thriel and colleagues. A benchmark dose analysis for eye blinks has been performed on basis of the pooled data obtained after constant and variable exposure (Kiesswetter et al., 2005). An increase of the eye blink frequency (starting point 14.3 per minute) of one standard error (7.3 per minute) was chosen as critical effect size. This resulted in a BMD of 20.5 ppm and a BMDL or 14.7 ppm. The MAK value was set to 10 ppm, although subjective findings on eye and nose irritation could not completely be excluded, but physiological reactions of the trigeminal system seem to be unlikely, according to the MAK commission.

Short term peak exposure should not exceed the MAK value. The MAK commission justified this decision on peak exposure with the observations from the experimental studies: Peak exposures of 20 ppm might result in a significant increase of the eye blink frequency. This increase in the eye blink frequency is not completely reversible during exposures with low 2-EH concentrations. Therefore, the MAK value should not be exceeded, even not for short periods.

  • Inhalation - local effects - acute/short term exposure

As mentioned in ECHA guidance R.8 “a DNEL for acute toxicity is only established for the effects of peak exposures as these peaks can be significantly higher than the average daily exposure and the long term DNEL may be insufficient to limit them”.

For the critical effect –sensory irritation – human data are available. As mentioned before this effect is considered to be concentration dependent and not time dependent based on this reasoning the DNEL acute local effects would have to be the same as the DNEL long term local effects.

This view is also supported by the “MAK-Kommission”. In experiments of Kiesswetter et al. (2005) with variable exposure, peaks up to 20 ppm resulted in an (not completely reversible) increase of blinking frequency at intervals with exposure to low concentrations. The “MAK-Kommission” therefore did not allow exceedance of their long term OEL for short term exposures.

If the reasoning behind this value of the “MAK-Kommission” is adopted, i.e. no exceedance of long term OEL derived, the most stringent interpretation of the data would result in a

DNEL of 10 ppm (53.2 mg/m³)

as this was set for long term local effects.

  • Dermal - systemic effects - long term exposure

There is no reliable sub-chronic or chronic dermal toxicity study available using 2-ethylhexanol as test material. Therefore both DNELs for dermal systemic effects and long term exposure for workers and general population depend on the same oral chronic carcinogenicity study.

Astill et al., 1996 presented the results of two chronic oral toxicity studies using either mice or rats as study subjects. In both studies animals were exposed to 2-ethylhexanol via gavage. The NOAEL presented for B6C3F1 mice was 200 mg/kg bw/d based on increased mortality, reduced body weights and hepatotoxic effects in the high dose group. The NOAEL for the study with Fischer 344 rats is 150 mg/kg bw/d (increased mortality in high dose group).

The basis for this DNEL derivation was the NOAEL for systemic toxicity observed in the carcinogenicity study on mice, as due to the higher assessment factor for allometric differences of mice the lower DNEL will result from the study with the slightly higher NOAEL.

Based on the toxicokinetic data available for 2-EH (especially Deisinger et al., 1994) dermal absorption was assumed to be at the very most 10% of oral absorption capacity. The route-to-route extrapolation was performed based on this value. This procedure seems adequate and reasonable according to ECHA Guidance R.8.

Correction of oral NOAEL:

Corrected dermal NOAEL = 200 mg/kg bw/d (NOAEL oral) * 100% absorption oral / 10% absorption dermal

                                      = 2000 mg/kg bw/d

Derivation of DNEL:

NOAEL (2000 mg/kg bw/d) / AF (7 allometry; 2.5 remaining differences; 5 intraspecies)

DNEL =23 mg/kg bw/d

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
DNEL value:
638.4 mg/m³
Explanation for the modification of the dose descriptor starting point:
not required
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
allometric scaling not used for inhalation
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
26.6 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
2
Dose descriptor:
NOAEC
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
no assessment factor required as critical effect (sensory irritation) is concentration dependant
AF for interspecies differences (allometric scaling):
1
Justification:
not required as human data are used
AF for other interspecies differences:
1
Justification:
not required as human data are used
AF for intraspecies differences:
2
Justification:
no assessment factor required as critical effect (sensory irritation) is mostly concentration dependant instead of influenced by interindividual differences, however a factor of 2 was applied in order to attribute for differences of default assessment factors of workers and general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
26.6 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
2
Dose descriptor starting point:
NOAEC
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
1
Justification:
not required as human data are used
AF for other interspecies differences:
1
Justification:
not required as human data are used
AF for intraspecies differences:
2
Justification:
no assessment factor required as critical effect (sensory irritation) is mostly concentration dependant instead of influenced by interindividual differences, however a factor of 2 was applied in order to attribute for differences of default assessment factors of workers and general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
175
Modified dose descriptor starting point:
NOAEL
DNEL value:
2 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no repeated dermal toxicity study available, adequate toxicokinetic data to allow for assessment of dermal and oral absorption (10% dermal absorption )
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
chronic study available
AF for interspecies differences (allometric scaling):
7
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
175
Modified dose descriptor starting point:
NOAEL
DNEL value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation required
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
chronic study available
AF for interspecies differences (allometric scaling):
7
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

GENERAL POPULATION

  • Inhalation - systemic effects - long term exposure

As there is only one inhalation toxicity study investigating systemic effects, the DNEL long term systemic effects for general population is based on this 90-day repeated inhalation toxicity study in Wistar rats with a NOAEC of 638.4 mg/m³ (i.e. 120 ppm; highest dose tested and neither systemic nor local effects).

Using the following assessment factors according to ECHA REACH Guidance R.8 for:

·        Interspecies:             0 Allometrie; 2.5 remaining differences

·        Intraspecies               10

·        Time                          2

leads to the overall assessment factor of 50.

With the correction of starting concentration based on differences in between experimental and human conditions:

Corrected NOAEC = 638.4 * 6 h/d / 24 h/d * 5d / 7d= 114 mg/m³

finally leads to the DNEL of 2.3 mg/m³ (≈ 0.43 ppm).

  • Inhalation - systemic effects - acute/short term exposure

There is no harmonised classification available for 2-EH. However based on available data within the registration dossier aerosols of 2-EH are classified as “Harmful if inhaled“(Acute Toxicity Category 4; H332). No classification for acute systemic effects is warranted for 2-EH vapours.

Local sensory irritation is obvious in humans already at concentrations when no other systemic effects are obvious. Therefore the DNEL for acute local effects also protects from possible systemic effects arising from exposure to 2-EH via inhalation.

  • Inhalation - local effects - long term exposure

Based on the presented reasoning in the discussion paragraph of DNEL derivation for workers the DNEL long term local effects for the general population would be derived from the NOAEL of 10 ppm from the Kiesswetter et al., 2005 study. But unlike for workers an intraspecies factor of 2 is used in order to attribute for the differences in default values given in ECHA Guidance on information requirements and chemical safety assessment Chapter R.8 (default values for intraspecies differences: workers = 5 versus general population = 10 , therefore factor of 2).

Thus using the NOAEL of 10 ppm and applying an AF of 2 a

DNEL of 5 ppm (26.6 mg/m³)

would result for the general population.

  • Inhalation - local effects - acute/short term exposure

Based on the presented reasoning in the discussion paragraph of DNEL derivation for workers the DNEL acute local effectsfor the general population would be the same as for long term local effects, i.e. 5 ppm (26.6 mg/m³).

  • Dermal - systemic effects - long term exposure

Based on the presented reasoning in the discussion paragraph of DNEL derivation for workers the dermal DNEL long term systemic effects for the general population will be derived from the oral NOAEL presented for B6C3F1 mice of 200 mg/kg bw/d (based on increased mortality, reduced body weights and hepatotoxic effects in the high dose group; Astill et al., 1996). For route-to-route extrapolation dermal absorption was assumed to be at the very most 10% of oral absorption capacity based on the toxicokinetic data available for 2-EH(especially Deisinger et al., 1994).

Correction of oral NOAEL:

Corrected dermal NOAEL = 200 mg/kg bw/d (NOAEL oral) *

                                      = 2000 mg/kg bw/d

Derivation of DNEL:

NOAEL (2000 mg/kg bw/d) / AF (7 allometry; 2.5 remaining differences; 10 intraspecies)

DNEL =11.4 mg/kg bw/d

  • Oral - systemic effects - long term exposure

There are two chronic oral toxicity studies performed using either mice or rats as study subjects. In both studies animals were exposed via gavage(Astill et al., 1996). The basis of this DNEL was the NOAEL for systemic toxicity observed in the carcinogenicity study on mice The NOAEL presented for B6C3F1 mice was 200 mg/kg bw/d based on increased mortality, reduced body weights and hepatotoxic effects in the high dose group.

In the same publication the results of the comparable carcinogenicity study in Fischer 344 rats are given. In the registration dossier a LOAEL for systemic toxicity of 500 mg/kg bw/d is presented based on increased mortality at this dose group. No NOAEL is given in the publication. However consequently to the LOAEL presented the NOAEL is assumed to be the next lower dose level (i.e. 150 mg/kg bw/d).

Having the results from these reliable chronic toxicity studies, DNEL derivation was based on the study with mice which resulted in the lower DNEL because of the higher allometric scaling factor used for mice.

DNEL based on data of mice:

NOAEL (200 mg/kg bw/d) / AF (7 allometry; 2.5 remaining differences; 10 intraspecies)

DNEL = 1.1 mg/kg bw/d(currently used in registration dossier)

(For comparison DNEL based on data of rats:

NOAEL (150 mg/kg bw/d) / AF (4 allometry; 2.5 remaining differences; 10 intraspecies)

DNEL = 1.5 mg/kg bw/d)