Registration Dossier
Registration Dossier
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EC number: 248-363-6 | CAS number: 27247-96-7
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.35 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):
- 100
- Dose descriptor starting point:
- NOAEL
- Value:
- 20 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 35 mg/m³
- Explanation for the modification of the dose descriptor starting point:
The dose was converted from oral in the 421 study to inhalation assuming that oral and inhalation have the same absorption.
- AF for dose response relationship:
- 1
- Justification:
- NOAEC is provided by study
- AF for differences in duration of exposure:
- 4
- Justification:
- ECHA guidance for study that is between sub-acute and sub-chronic to chronic difference
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Interspecies accounted for in modified dose descriptor
- AF for other interspecies differences:
- 2.5
- Justification:
- ECHA guidance for remaining differences
- AF for intraspecies differences:
- 5
- Justification:
- ECHA guidance for workers
- AF for the quality of the whole database:
- 2
- Justification:
- study quality is low for this study, but read across studies have higher NOAECs
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 data available: testing technically not feasible
Acute/short term exposure
- Hazard assessment conclusion:
- no data available: testing technically not feasible
DNEL related information
Workers - 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):
- 480
- 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:
- DNEL (Derived No Effect Level)
- Value:
- 44 µg/cm²
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 5
- Dose descriptor:
- other: NOAEL
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:
- low hazard (no threshold derived)
Additional information - workers
- No selection for reproductive toxicity (only one DNEL per route): 3.0 mg/kg/day (dermal) and 7.1 mg/m3 (inhalative)
- For repeated-dose toxicity, dermal route:
- For repeated-dose toxicity, inhalation:
1) Long-term systemic toxicity DNELs:
All starting points, their modification and the applied assessment factors are described and justified in the tables below. For repeated-dose systemic toxicity, two series of DNEL could be derived from two different studies (two starting points). The selection of the relevant values is explained after the table.
Justification for derivation of long-term systemic worker DNELs, for repeated-dose and reproductive toxicity, assuming 8h/day chronic exposure
| Route of human exposure (for all lines) | Dermal | Inhalation | ||
| Repeated-dose DNEL, based on 21-day dermal application in rabbit (K4 study) | ||||
| Point of departure: | 500 | mg/kg/day | NOAEL | Dermal route |
| Value | Justification | Value | Justification | |
| Absorption for human exposure route: | 1 | rabbit and human: same dermal absorption assumed | 10 | 10-fold higher inhalative than dermal absorption |
| Corrected point of departure: | 500 | mg/kg/day | 146 | mg/m3* |
| Assessment Factor type, subtype | Value | Justification | Value | Justification |
| Interspecies, kinetics | 2.4 | rabbit to human | NA | included in correction of starting point |
| Interspecies, dynamics | 2.5 | other differences | ||
| Intraspecies, kinetics x dynamics | 5 | worker | ||
| Exposure duration | 8 | 3 weeks to chronic (extrapolated from AFs for 4- and 13-week studies) | ||
| Dose-response relationship | 1 | NOAEL + standard dose-effect curve | ||
| Quality of whole database | 2 | no data on clinical signs, intercurrent parasitic infestation | ||
| Overall Assessment Factor | 480 | product of all above AFs | 200 | product of all above AFs |
| Resulting DNEL: | 1.0 | mg/kg/day | 0.73 | mg/m3 |
| Repeated-dose DNEL, based on oral OECD 421 study (K1 study) including some general toxicity data in parents | ||||
| Point of departure: | 20 | mg/kg/day | NOAEL | Oral route |
| Value | Justification | Value | Justification | |
| Absorption for human exposure route: | 0.333 | 3-fold lower dermal than oral absorption | 1 | oral and inhalative: same absorption |
| Corrected point of departure: | 60 | mg/kg/day | 35 | mg/m3** |
| Assessment Factor type, subtype | Value | Justification | Value | Justification |
| Interspecies, kinetics | 4 | rat to human | NA | included in correction of starting point |
| Interspecies, dynamics | 2.5 | other differences | ||
| Intraspecies, kinetics x dynamics | 5 | worker | ||
| Exposure duration | 4 | 42-47 days (females) to chronic (interpolated from AFs for 28, 90 days) | ||
| Dose-response relationship | 1 | NOAEL + standard dose-effect curve | ||
| Quality of whole database | 2 | no laboratory investigations, histology limited to reproductive organs | ||
| Overall Assessment Factor | 400 | product of all above AFs | 100 | product of all above AFs |
| Resulting DNEL: | 0.15 | mg/kg/day | 0.35 | mg/m3 |
| Reproductive toxicity DNEL, based on oral OECD 421 screening study (K1 study) | ||||
| Point of departure: | 100 | mg/kg/day | NOAEL | Oral route |
| Value | Justification | Value | Justification | |
| Absorption for human exposure route: | 0.333 | 3-fold lower dermal than oral absorption | 1 | oral and inhalative: same absorption assumed |
| Corrected point of departure: | 300 | mg/kg/day | 176 | mg/m3** |
| Assessment Factor type, subtype | Value | Justification | Value | Justification |
| Interspecies, kinetics | 4 | rat to human | NA | included in correction of starting point |
| Interspecies, dynamics | 2.5 | other differences | ||
| Intraspecies, kinetics x dynamics | 5 | worker | ||
| Exposure duration | 1 | not required for reprotox | ||
| Dose-response relationship | 1 | NOAEL + standard dose-effect curve | ||
| Quality of whole database | 2 | screening assay only | ||
| Overall Assessment Factor | 100 | product of all above AFs | 25 | product of all above AFs |
| Resulting DNEL: | 3.0 | mg/kg/day | 7.1 | mg/m3 |
*,**: ECHA Guidance for correction of starting point (table R.8-2 and figures R.8-2, R.8-3) applied using a sRV of 0.38 m3/kg/8h (**: rat) or 0.23 m3/kg/8h (*: rabbit, determined by allometric scaling from rat sRV)
Selection of the DNEL:
The value of 1.0 mg/kg/day from the 3-week dermal study in rabbits was retained as being more reliable because:
- the study included much more repeated-dose toxicity investigations than the OECD 421 study (not intended for this purpose)
- using a study done by dermal route, avoids route-to-route extrapolation
- oral-to-dermal extrapolation, as done for the OECD 421 study, leads to excessive conservatism because of the limited dermal absorption (due to high log Kow)
It can be noted that a 2-week inhalation study was ignored because of:
- absence of report (only a two-page summary): K4
- very short exposure duration (10 doses) leading to excessive uncertainty for extrapolation to chronic exposures
- absence of data on respiratory effects (incl. at pathology) so that this study does not provide any route-specific data
Between the two remaining DNELs, 0.35 mg/m3 from the oral OECD 421 study was retained as being more reliable because:
- oral-to-inhalation (similar, possibly total absorption expected) is preferred to dermal-to-inhalation (low dermal absorption expected) extrapolation
- the K4 2-week inhalation toxicity study evidenced several effects in the liver, so that first-pass effect (leading to enhanced liver exposure by oral route) is not an issue for route-to-route extrapolation
- the exposure duration was much longer, 42-47 days in females of OECD 421 vs. 3 weeks in the dermal study, limiting the uncertainty for extrapolation to chronic exposure
- it was the lowest of both DNELs, and stayed consistent with that derived from the 3-week dermal study
These DNELs however stay provisional because each point of departure was suboptimal (screening status or deviations). Several repeated-dose and reproductive toxicity inhalative studies are poposed, that will lead to much more reliable DNEL values, by the major exposure route for a volatile substance.
2) Long-term local toxicity DNELdermal:
Justification for derivation of long-term local worker DNEL for chronic dermal exposure
| Point of departure: | 0.22 | mg/cm2/day - NOAEC |
| Value | Justification | |
| Absorption for human exposure route: | 1 | correction for absorption not applicable for a local effect |
| Corrected point of departure: | 0.22 | mg/cm2/day |
| Assessment Factor type, subtype | Value | Justification |
| Interspecies, kinetics | 1 | no impact of ADME for local effects |
| Interspecies, dynamics | 1 | |
| Intraspecies, kinetics x dynamics | 5 | worker |
| Exposure duration | 1 | local effects depend on concentration and not on cumulative dose |
| Dose-response relationship | 1 | consertaive BMD was derived in absence of NOAEC |
| Quality of whole database | 1 | repeated application: high sensitivity study |
| Overall Assessment Factor | 5 | product of all above AFs |
| Resulting DNEL: | 44 | µg/cm2/day |
This DNEL was selected for risk assessment of local effects upon repeated exposure.
The AFs are based on following quotations from ECHA Guidance R8:
"Since the mechanism (direct chemical reactivity with cell membranes) of skin irritation/corrosion is considered to be the same in experimental animals and in human, no inter-species AF should be applied to the NOAEC or to the LOAEC"
"since irritation and corrosion are local effects and metabolism in skin tissues is limited, there are no species differences in toxicokinetics"
"the relevant effect is deemed to be more concentration rather than dose dependent (which is not always the default position to take for local cytotoxic effects), then the duration of exposure is likely to be of little consequence, and hence, time extrapolation would be inappropriate."
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 87 µg/m³
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 200
- 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:
- no data available: testing technically not feasible
Acute/short term exposure
- Hazard assessment conclusion:
- no data available: testing technically not feasible
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.52 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 960
- 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:
- DNEL (Derived No Effect Level)
- Value:
- 22 µg/cm²
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 10
- Dose descriptor:
- other: NOAEL
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:
- 25 µg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 800
- 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
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- low hazard (no threshold derived)
Additional information - General Population
- No selection for reproductive toxicity (only one DNEL per route): 1.50 (dermal) and 0.5 mg/kg/day (oral) and 1.7 mg/m3 (inhalative)
- For repeated-dose toxicity, dermal route:
- For repeated-dose toxicity, oral route:
- For repeated-dose toxicity, inhalation:
Based on the use descriptor system and exposure scenarii, there is only one possibility of direct use of the substance by the general population: pouring in the car tank a product containing 2-ethylhexyl nitrate to improve the fuel's cetane index. This operation would last a few minutes, much less than once per day, because any frequent use would mean professional use.
Therefore, the only possibility of exposure for 24-hour per day (as considered by default) is indirect exposure via the environment.
A) DNELs for chronic permanent indirect exposure via the environment
1) Long-term systemic toxicity DNELs:
All starting points, their modification and the applied assessment factors are described and justified in the tables below. For repeated-dose systemic toxicity, two series of DNEL could be derived from two different studies (two starting points). The selection of the relevant values is explained after the table.
Justification of derivation of long-term systemic general population DNELs, for repeated-dose and reproductive toxicity, assuming 24h/day chronic indirect exposure via the environment
| Route of human exposure (for all lines) | Dermal | Oral | Inhalative | |||
| Repeated-dose DNEL, based on 21-day dermal application in rabbit (K4 study) | ||||||
| Point of departure: | 500 | mg/kg/day, NOAEL dermal route | ||||
| Value | Justification | Value | Justification | Value | Justification | |
| Absorption for human exposure route: | 1 | rabbit and human: same dermal absorption assumed | 10 | 10-fold higher oral than dermal absorption | 10 | 10-fold higher inhalative than dermal absorption |
| Corrected point of departure: | 500 | mg/kg/day | 50 | mg/kg/day | 49 | mg/m3* |
| Assessment Factor type, subtype | Value | Justification | Value | Justification | Value | Justification |
| Interspecies, kinetics | 2.4 | rabbit to human | 2.4 | rabbit to human | NA | included in correction of starting point |
| Interspecies, dynamics | 2.5 | other differences | ||||
| Intraspecies, kinetics x dynamics | 10 | general population | ||||
| Exposure duration | 8 | 3 weeks to chronic (extrapolated from AFs for 4- and 13-week studies) | ||||
| Dose-response relationship | 1 | NOAEL + standard dose-effect curve | ||||
| Quality of whole database | 2 | deviations possibly limiting sensitivity: no data on clinical signs, intercurrent parasitic infestation | ||||
| Overall Assessment Factor | 960 | product of all above AFs | 960 | product of all above AFs | 400 | product of all above AFs |
| Resulting DNEL: | 0.52 | mg/kg/day | 0.052 | mg/kg/day | 0.12 | mg/m3 |
| Repeated-dose DNEL, based on oral OECD 421 study (K1 study) including some general toxicity data in parents | ||||||
| Point of departure: | 20 | mg/kg/day, NOAEL oral route | ||||
| Value | Justification | Value | Justification | Value | Justification | |
| Absorption for human exposure route: | 0.333 | 3-fold lower dermal than oral absorption | 1 | rat and human: same oral absorption assumed | 1 | oral and inhalative: same absorption |
| Corrected point of departure: | 60 | mg/kg/day | 20 | mg/kg/day | 17.4 | mg/m3** |
| Assessment Factor type, subtype | Value | Justification | Value | Justification | Value | Justification |
| Interspecies, kinetics | 4 | rat to human | 4 | rat to human | NA | included in correction of starting point |
| Interspecies, dynamics | 2.5 | other differences | ||||
| Intraspecies, kinetics x dynamics | 10 | general population | ||||
| Exposure duration | 4 | 42-47 days (females) to chronic (interpolated from AFs for 28, 90 days) | ||||
| Dose-response relationship | 1 | NOAEL + standard dose-effect curve | ||||
| Quality of whole database | 2 | no laboratory investigations, histology limited to reproductive organs | ||||
| Overall Assessment Factor | 800 | product of all above AFs | 800 | product of all above AFs | 200 | product of all above AFs |
| Resulting DNEL: | 0.075 | mg/kg/day | 0.025 | mg/kg/day | 0.087 | mg/m3 |
| Reproductive toxicity DNEL, based on oral OECD 421 screening study (K1 study) | ||||||
| Point of departure: | 100 | mg/kg/day, NOAEL oral route | ||||
| Value | Justification | Value | Justification | Value | Justification | |
| Absorption for human exposure route: | 0.333 | 3-fold lower dermal than oral absorption | 1 | rat and human: same oral absorption assumed | 1 | oral and inhalative: same absorption assumed |
| Corrected point of departure: | 300 | mg/kg/day | 100 | mg/kg/day | 87.0 | mg/m3** |
| Assessment Factor type, subtype | Value | Justification | Value | Justification | Value | Justification |
| Interspecies, kinetics | 4 | rat to human | 4 | rat to human | NA | included in correction of starting point |
| Interspecies, dynamics | 2.5 | other differences | ||||
| Intraspecies, kinetics x dynamics | 10 | general population | ||||
| Exposure duration | 1 | not required for reprotox | ||||
| Dose-response relationship | 1 | NOAEL + standard dose-effect curve | ||||
| Quality of whole database | 2 | screening assay only | ||||
| Overall Assessment Factor | 200 | product of all above AFs | 200 | product of all above AFs | 50 | product of all above AFs |
| Resulting DNEL: | 1.5 | mg/kg/day | 0.50 | mg/kg/day | 1.7 | mg/m3 |
*,**: ECHA Guidance for correction of starting point (table R.8-2 and figures R.8-2, R.8-3) applied using a sRV of 1.15 m3/kg/24h (**: rat) or 0.69 m3/kg/24h (*: rabbit, determined by allometric scaling from rat sRV)
Selection of the DNEL:
The value of 0.52 mg/kg/day from the 3-week dermal study in rabbits was retained as being more reliable because:
- the study included much more repeated-dose toxicity investigations than the OECD 421 study (not intended for this purpose)
- using a study done by dermal route, avoids route-to-route extrapolation
- oral-to-dermal extrapolation, as done for the OECD 421 study, leads to excessive conservatism because of the limited dermal absorption (due to high log Kow)
The value of 25 µg/kg/day from the oral OECD 421 study was retained as being more reliable because:
- using a study done by oral route, avoids route-to-route extrapolation
- dermal-to-oral extrapolation, as done for the 3-week dermal study, leads to uncertainty about the safety level
- it was the lowest of both DNELs, and stayed consistent with that derived from the 3-week dermal study
It can be noted that a 2-week inhalation study was ignored because of:
- absence of report (only a two-page summary): K4
- very short exposure duration (10 doses) leading to excessive uncertainty for extrapolation to chronic exposures
- absence of data on respiratory effects (incl. at pathology) so that this study does not provide any route-specific data
Between the two remaining DNELs, 87 µg/m3 from the oral OECD 421 study was retained as being more reliable because:
- oral-to-inhalation (similar, possibly total absorption expected) is preferred to dermal-to-inhalation (low dermal absorption expected) extrapolation
- the K4 2-week inhalation toxicity study evidenced several effects in the liver, so that first-pass effect (leading to enhanced liver exposure by oral route) is not an issue for route-to-route extrapolation
- the exposure duration was much longer, 42-47 days in females of OECD 421 vs. 3 weeks in the dermal study, limiting the uncertainty for extrapolation to chronic exposure
- it was the lowest of both DNELs, and stayed consistent with that derived from the 3-week dermal study
These DNELs however stay provisional because each point of departure was suboptimal (screening status or deviations). Several repeated-dose and reproductive toxicity inhalative studies are poposed, that will lead to much more reliable DNEL values, by the major exposure route for a volatile substance.
2) Long-term local toxicity DNELdermal:
Justification for derivation of long-term local general population DNEL for chronic dermal indirect exposure via the environment
| Point of departure: | 0.22 | mg/cm2/day - NOAEC |
| Value | Justification | |
| Absorption for human exposure route: | 1 | correction for absorption not applicable for a local effect |
| Corrected point of departure: | 0.22 | mg/cm2/day |
| Assessment Factor type, subtype | Value | Justification |
| Interspecies, kinetics | 1 | no impact of ADME for local effects |
| Interspecies, dynamics | 1 | |
| Intraspecies, kinetics x dynamics | 10 | general population |
| Exposure duration | 1 | local effects depend on concentration and not on cumulative dose |
| Dose-response relationship | 1 | consertaive BMD was derived in absence of NOAEC |
| Quality of whole database | 1 | repeated application: high sensitivity study |
| Overall Assessment Factor | 10 | product of all above AFs |
| Resulting DNEL: | 22 | µg/cm2/day |
This DNEL was selected for risk assessment.
The AFs are based on following quotations from ECHA Guidance R8:
"Since the mechanism (direct chemical reactivity with cell membranes) of skin irritation/corrosion is considered to be the same in experimental animals and in human, no inter-species AF should be applied to the NOAEC or to the LOAEC"
"since irritation and corrosion are local effects and metabolism in skin tissues is limited, there are no species differences in toxicokinetics"
"the relevant effect is deemed to be more concentration rather than dose dependent (which is not always the default position to take for local cytotoxic effects), then the duration of exposure is likely to be of little consequence, and hence, time extrapolation would be inappropriate."
B) DNELs for direct exposure: cetane improver poured in car tank
The DNELs set above considered daily/24h per day exposure. For use under Consexpo for the actual exposure scenario of consumers i.e. using a cetane improver bottle to fill the car fuel tank, they must be adapted as follows:
- No oral exposure is considered (non-supported use).
- Pattern of exposure is not chronic: the general population, outside any professional context, can be considered to use the cetane improver less than once a week, as opposed to 5 days/week exposure of workers and continuous exposure of consumer considered by default; therefore, assessment factor for exposure duration is halved.
- The appropriate unit for use of the exposure models is not mg/m3 (which depends on exposure duration and is therefore irrelevant for short exposures), but mg/kg/day. Correction of the dose descriptor is therefore useless.
- No local effect assessment is required: because of the isolated, distant use, no skin cracking/dryness should occur.
Dermal: 0.52 mg/kg/day (lowest value between reprotox DNEL and repeated-dose DNEL for consumer)
divided by 0.5 (halving of the exposure duration AF)
= 1.0 mg/kg/day using unrounded values
Inhalative: see below
Justification for derivation of medium-term general population inhalative DNEL for direct exposure via cetane improver use
| Repeated-dose DNEL, based on OECD 421 study (K1 study) including some general toxicity data in parents | ||
| Point of departure: | 20 | mg/kg/day, NOAEL oral route |
| Value | Justification | |
| Absorption for human exposure route: | 1 | oral and inhalative: same absorption |
| Corrected point of departure: | 20 | mg/kg/day |
| Assessment Factor type, subtype | Value | Justification |
| Interspecies, kinetics | 4 | rat to human |
| Interspecies, dynamics | 2.5 | other differences |
| Intraspecies, kinetics x dynamics | 10 | general population |
| Exposure duration | 2 | 42-47 days (females) to semi-chronic (< once per week) |
| Dose-response relationship | 1 | NOAEL + standard dose-effect curve |
| Quality of whole database | 2 | no laboratory investigations, histology limited to reproductive organs |
| Overall Assessment Factor | 400 | product of all above AFs |
| Resulting DNEL: | 0.050 | mg/kg/day |
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