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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

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:

  • 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:

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)

  • For repeated-dose toxicity, inhalation:

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

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:

  • 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:

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)

  • For repeated-dose toxicity, oral route:

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

  • For repeated-dose toxicity, inhalation:

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