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EC number: 691-719-4 | CAS number: 1072957-71-1
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.478 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 12.5
- Modified dose descriptor starting point:
- NOAEC
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1.13 mg/m³
- Most sensitive endpoint:
- acute toxicity
DNEL related information
- Overall assessment factor (AF):
- 1 250
- Modified dose descriptor starting point:
- NOAEC
Local effects
Long term exposure
- Hazard assessment conclusion:
- no-threshold effect and/or no dose-response information available
Acute/short term exposure
- Hazard assessment conclusion:
- no-threshold effect and/or no dose-response information available
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 3.33 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 75
- Modified dose descriptor starting point:
- NOAEL
Acute/short term exposure
- Hazard assessment conclusion:
- no-threshold effect and/or no dose-response information available
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no-threshold effect and/or no dose-response information available
Acute/short term exposure
- Hazard assessment conclusion:
- no-threshold effect and/or no dose-response information available
Workers - Hazard for the eyes
Additional information - workers
Further details to the derivation of several DNEL values (workers)
Reference(s):
GIRCSA R.8: Guidance on information requirements and chemical safety assessment, ECHA, December 2010, Chapter R.8
W1) Worker-DNEL acute for inhalation route-systemic
Acute toxicity - rat
Dose-descriptor selection
Potential dose-descriptors are available resulting from an acute study (LC50, rat, inhalation, 4h exposure). Remark: The LC50 value determined in the study is "greater than 0.56 mg/L" (i.e. >560 mg/m3, at this concentration only one female rat out of five female and five male rats died). For the derivation of the DNEL, the value 0.56 mg/L has been used. Thus there is an additional margin of safety in the derived DNEL.
Assessment of mode of action
The identified endpoint and the observed effects have a threshold mode of action.
Dose-descriptor modification
The dose descriptor was modified based on GIRCSA R.8 R.8.4.2, Appendix R.8-2 and Appendix R.8-8, using the following default: inhalation absorption rat (ABSinh-rat) = inhalation absorption human (ABSinh-human). Extrapolation of the 4h-dose-descriptor to an exposure duration of 15 minutes, using modified Haber's law: c2 = ((c1n* (t1/t2))(1/n), c1: the concentration exposed to for duration t1, c2: the corresponding concentration with equal toxicity when exposed to for duration t2, n: regression coefficient; default value: n=3 (according to Appendix R.8-8: n=1 for extrapolating from shorter to longer exposure durations and n=3 for extrapolating from longer to shorter exposure durations)
LC50inh-human-0.25h = ((LC50inh-rat-4h)n * (4h/0.25h))(1/n) * (ABSinh-rat/ABSinh-human)
LC50inh-human-0.25h = ((560 mg/m3)3*(4/0.25))(1/3)* (1) = 1411 mg/m3
Assessment factors
The default assessment factors were applied according to GIRCSA R.8, R.8.4.3, R.8.4.3.1, R.8.4.3.3 and Appendix R.8-8. No explicit allometric scaling factor has been used, since the modified/corrected dose descriptor is expressed as a concentration (in mg/m3in air) and is assumed to be already scaled according to the allometric principle due to the direct dependence of the ventilation rate on the basal metabolic rate. Thus implicitly an allometric scaling factor between rat and human of 4 is taken into account.
Overall assessment factor: AF = AF1 * AF2 * AF3
AF1 (interspecies differences): 2.5 (differences in the metabolic rate are already taken into account by the implicit allometric scaling; for other interspecies differences an additional factor of 2.5 is applied)
AF2 (intraspecies differences): 5 (for worker)
AF3 (severity of effect): 100 (default value, for the extrapolation of a lethal concentration into a NOAEC)
AF = 2.5 * 5 * 100 = 1250
DNEL derivation
DNEL = NOAELcorr-inh-worker / AF = 1411 mg/m3/ 1250 = 1.13 mg/m3
worker-DNEL acute for inhalation route-systemic = 1.13 mg/m3
W2) Worker-DNEL long-term for dermal route-systemic
Repeat-dose toxicity - rat
Dose-descriptor selection
Potential dose-descriptors are also available resulting from a subacute study (rat, dermal, 28 day).
Assessment of mode of action
The identified endpoint and the observed effects have a threshold mode of action.
Dose-descriptor modification
The dose descriptor was modified according to GIRCSA R.8, R.8.4.2 and Appendix R.8-2, using the following defaults: dermal absorption rat (ABSdermal-rat) = dermal absorption human (ABSdermal-human), allometric scaling factor (AS) = 4 (between rat and human).
NOAELcorr-dermal-human = NOAELdermal-rat * (1/AS) * (ABSdermal-rat/ABSdermal-human)
NOAELcorr-dermal-human = 1000 mg/kg bw/day * (1/4) * (1) = 250 mg/kg bw/day
Assessment factors
The default assessment factors were applied according to GIRCSA R.8, R.8.4.3, R.8.4.3.1 and R.8.4.3.3. Allometric scaling has been accounted for (explicitly) in the dose-descriptor modification.
Overall assessment factor: AF = AF1 * AF2 * AF3 * AF4 * AF5
AF1 (interspecies differences): 2.5 (differences in the metabolic rate are already taken into account by the explicit allometric scaling during the dose-descriptor modification; for other interspecies differences an additional factor of 2.5 is applied)
AF2 (intraspecies differences): 5 (for worker population)
AF3 (differences in duration of exposure): 6 (extrapolation from subacute to chronic exposure)
AF4 (issues related to dose-response): 1 (dose descriptor is a NO(A)EL)
AF5 (quality of whole database): 1 (quality of database is appropriate)
AF = 2.5 * 5 * 6 * 1 * 1 = 75 (remark: the corresponding factor including the implicit allometric scaling factor of 4 is 300)
DNEL derivation
DNEL = NOAELcorr-dermal-human / AF = 250 mg/kg bw/day / 75 = 3.33 mg/kg bw/day
worker-DNEL long-term for dermal route-systemic = 3.33 mg/kg bw/day
W3) Worker-DNEL long-term for inhalation route-systemic
Repeat-dose toxicity - rat
Dose-descriptor selection
Potential dose-descriptors are available resulting from a combined chronic toxicity/carcinogenicity study (NOAEL, rat, oral dietary, 24 month).
Assessment of mode of action
The identified endpoint and the observed effects have a threshold mode of action. Remark: In males, at the highest dose tested, a treatment-related increase in the incidence of thyroid follicular cell adenomas has been observed. The substance was negative in allin vitroandin vivogenotoxicity tests conducted (i.e.in vitrogene mutation study in bacteria (Ames, OECD 471),in vitromammalian chromosome aberration test in human lymphocytes (i.e.in vitrocytogenetics study, IVC, OECD 473),in vitromammalian cell gene mutation test in mouse lymphoma L5178Y cells (OECD 476) andin vivorat bone marrow micronucleus test (OECD 474)). Thus despite the finding of tumours there is no evidence for genotoxic carcinogenicity (remark: in case of genotoxic carcinogenicity a non-threshold mode of action would often have to be assumed, unless a threshold mechanism of action can be clearly demonstrated).
Dose-descriptor modification
The dose descriptor was modified according to GIRCSA R.8, R.8.4.2 and Appendix R.8-2 using extrapolation from the oral to the inhalation route (assumed no first-pass effect) and the following defaults: light-work respiratory volume of the worker, 100% inhalation absorption (ABSinh-human), assumed standard respiratory volume (sRV) of a rat for a given exposure period: 0.384 m3/kg bw for 8 h exposure (based on a standard respiratory volume of a rat of 0.8 L/min/kg bw corresponding to 0.2 L/min/rat and a body weight (bw) of a rat of 0.25 kg), assumed standard respiratory volume (sRV) of a human for a given exposure period: 6.72 m3/person for 8 h exposure and 20.16 m3/person for 24 h exposure (based on a standard respiratory volume of a human of 0.2 L/min/kg bw {derived from a standard respiratory volume of a rat of 0.8 L/min/kg bw, using an allometric scaling factor between rat and human of 4} and a body weight of 70 kg), assumed respiratory volume of a worker (wRV) for an 8 h exposure period at light activity: 10 m3/person.
Oral absorption (ABSoral-rat): 70%, based on the following experimental data: the oral absorption of the substance was estimated following a single low or high oral gavage dose to male and female rats. Absorption following 1 mg/kg bw (low dose) was estimated to be 81 % in males and 79 % in females. Following the 40 mg/kg bw (high dose), absorption was estimated to be 61 % and 62% in males and females, respectively. According to GIRCSA R.8, R.8.4.2, substance-specific data on absorption via the different routes are to be preferred. The daily dose corresponding to the NOAEL, which is used for the DNEL derivation (i.e. 4.88 mg/kg bw/day), is between the low and the high dose of the absorption tests and the absorption value is not sex specific. The mean of the four absorption values is 70.75 %. Thus an oral absorption value of 70 % has been used for the DNEL derivation instead of the default value of 50 %.
NOAELcorr-inh-worker = NOAELoral-rat * (1/sRVrat) * (ABSoral-rat/ABSinh-rat) * (ABSinh-rat/ABSinh-human) * (sRVhuman/wRV) = NOAELoral-rat * (1/sRVrat) * (ABSoral-rat/ ABSinh-human) * (sRVhuman/wRV)
NOAELcorr-inh-worker = 4.88 mg/kg bw/day * (1/(0.384 m3/kg bw/day)) * (0.7/1) * ((6.72 m3/person)/(10 m3/person)) = 5.978 mg/m3
Assessment factors
The default assessment factors were applied according to GIRCSA R.8, R.8.4.3, R.8.4.3.1 and R.8.4.3.3. No explicit allometric scaling factor has been used, since the modified/corrected dose descriptor is expressed as a concentration (in mg/m3in air) and is assumed to be already scaled according to the allometric principle due to the direct dependence of the ventilation rate on the basal metabolic rate. Thus implicitly an allometric scaling factor between rat and human of 4 is present.
Overall assessment factor: AF = AF1 * AF2 * AF3 * AF4 * AF5
AF1 (interspecies differences): 2.5 (differences in the metabolic rate are already taken into account by the implicit allometric scaling; for other interspecies differences an additional factor of 2.5 is applied)
AF2 (intraspecies differences): 5 (for worker population)
AF3 (differences in duration of exposure): 1 (dose descriptor from chronic study, thus no extrapolation to chronic exposure needed)
AF4 (issues related to dose-response): 1 (dose descriptor is a NO(A)EL)
AF5 (quality of whole database): 1 (quality of database is appropriate)
AF = 2.5 * 5 * 1 * 1 * 1 = 12.5
DNEL derivation
DNEL = NOAELcorr-inh-worker / AF = 5.978 mg/m3/ 12.5 = 0.478 mg/m3
worker-DNEL long-term for inhalation route-systemic = 0.478 mg/m3
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.119 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 25
- Modified dose descriptor starting point:
- NOAEC
Acute/short term exposure
- Hazard assessment conclusion:
- exposure based waiving
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- exposure based waiving
Acute/short term exposure
- Hazard assessment conclusion:
- exposure based waiving
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1.67 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 150
- Modified dose descriptor starting point:
- NOAEL
Acute/short term exposure
- Hazard assessment conclusion:
- exposure based waiving
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- exposure based waiving
Acute/short term exposure
- Hazard assessment conclusion:
- exposure based waiving
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.049 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- Overall assessment factor (AF):
- 25
- Modified dose descriptor starting point:
- NOAEL
Acute/short term exposure
- Hazard assessment conclusion:
- exposure based waiving
DNEL related information
General Population - Hazard for the eyes
Additional information - General Population
Further details to the derivation of several DNEL values (general population)
Reference(s):
GIRCSA R.8: Guidance on information requirements and chemical safety assessment, ECHA, December 2010, Chapter R.8
GP1) General population-DNEL long-term for dermal route-systemic
Repeat-dose toxicity - rat
Dose-descriptor selection
Potential dose-descriptors are also available resulting from a subacute study (rat, dermal, 28 day).
Assessment of mode of action
The identified endpoint and the observed effects have a threshold mode of action.
Dose-descriptor modification
The dose descriptor was modified according to GIRCSA R.8, R.8.4.2 and Appendix R.8-2, using the following defaults: dermal absorption rat (ABSdermal-rat) = dermal absorption human (ABSdermal-human), allometric scaling factor (AS) = 4 (between rat and human).
NOAELcorr-dermal-human = NOAELdermal-rat * (1/AS) * (ABSdermal-rat/ABSdermal-human)
NOAELcorr-dermal-human = 1000 mg/kg bw/day * (1/4) * (1) = 250 mg/kg bw/day
Assessment factors
The default assessment factors were applied according to GIRCSA R.8, R.8.4.3, R.8.4.3.1 and R.8.4.3.3. Allometric scaling has been accounted for (explicitly) in the dose-descriptor modification.
Overall assessment factor: AF = AF1 * AF2 * AF3 * AF4 * AF5
AF1 (interspecies differences): 2.5 (differences in the metabolic rate are already taken into account by the explicit allometric scaling during the dose-descriptor modification; for other interspecies differences an additional factor of 2.5 is applied)
AF2 (intraspecies differences): 10 (for general population)
AF3 (differences in duration of exposure): 6 (extrapolation from subacute to chronic exposure)
AF4 (issues related to dose-response): 1 (dose descriptor is a NO(A)EL)
AF5 (quality of whole database): 1 (quality of database is appropriate)
AF = 2.5 * 10 * 6 * 1 * 1 = 150 (remark: the corresponding factor including the implicit allometric scaling factor of 4 is 600)
DNEL derivation
DNEL = NOAELcorr-dermal-human / AF = 250 mg/kg bw/day / 150 = 1.67 mg/kg bw/day
general population-DNEL long-term for dermal route-systemic = 1.67 mg/kg bw/day
GP2) General population-DNEL long-term for inhalation route-systemic
Repeat-dose toxicity - rat
Dose-descriptor selection
Potential dose-descriptors are available resulting from a combined chronic toxicity/carcinogenicity study (NOAEL, rat, oral dietary, 24 month).
Assessment of mode of action
The identified endpoint and the observed effects have a threshold mode of action. Remark: In males, at the highest dose tested, a treatment-related increase in the incidence of thyroid follicular cell adenomas has been observed. The substance was negative in allin vitroandin vivogenotoxicity tests conducted (i.e.in vitrogene mutation study in bacteria (Ames, OECD 471),in vitromammalian chromosome aberration test in human lymphocytes (in vitrocytogenetics study, IVC, OECD 473),in vitromammalian cell gene mutation test in mouse lymphoma L5178Y cells (OECD 476) andin vivorat bone marrow micronucleus test (OECD 474)). Thus despite the finding of tumours there is no evidence for genotoxic carcinogenicity (remark: in case of genotoxic carcinogenicity a non-threshold mode of action would often have to be assumed, unless a threshold mechanism of action can be clearly demonstrated).
Dose-descriptor modification
The dose descriptor was modified according to GIRCSA R.8, R.8.4.2 and Appendix R.8-2, using extrapolation from the oral to the inhalation route (assumed no first-pass effect) and the following defaults: 100% inhalation absorption (ABSinh-human), assumed standard respiratory volume (sRV) of a rat for a given exposure period: 1.152 m3/kg bw for 24 h exposure (based on a standard respiratory volume of a rat of 0.8 L/min/kg bw corresponding to 0.2 L/min/rat and a body weight (bw) of a rat of 0.25 kg).
Oral absorption (ABSoral-rat): 70%, based on the following experimental data: the oral absorption of the substance was estimated following a single low or high oral gavage dose to male and female rats. Absorption following 1 mg/kg bw (low dose) was estimated to be 81 % in males and 79 % in females. Following the 40 mg/kg bw (high dose), absorption was estimated to be 61 % and 62% in males and females, respectively. According to GIRCSA R.8, R.8.4.2, substance-specific data on absorption via the different routes are to be preferred. The daily dose corresponding to the NOAEL, which is used for the DNEL derivation (i.e. 4.88 mg/kg bw/day), is between the low and the high dose of the absorption tests and the absorption value is not sex specific. The mean of the four absorption values is 70.75 %. Thus an oral absorption value of 70 % has been used for the DNEL derivation instead of the default value of 50 %.
NOAELcorr-inh-general population = NOAELoral-rat * (1/sRVrat) * (ABSoral-rat/ABSinh-rat) * (ABSinh-rat/ABSinh-human) = NOAELoral-rat * (1/sRVrat) * (ABSoral-rat/ ABSinh-human)
NOAELcorr-inh-general population = 4.88 mg/kg bw/day * (1/(1.152 m3/kg bw/day)) * (0.7/1) = 2.965 mg/m3
Assessment factors
The default assessment factors were applied according to GIRCSA R.8, R.8.4.3, R.8.4.3.1 and R.8.4.3.3. No explicit allometric scaling factor has been used, since the modified/corrected dose descriptor is expressed as a concentration (in mg/m3in air) and is assumed to be already scaled according to the allometric principle due to the direct dependence of the ventilation rate on the basal metabolic rate. Thus implicitly an allometric scaling factor between rat and human of 4 is present.
Overall assessment factor: AF = AF1 * AF2 * AF3 * AF4 * AF5
AF1 (interspecies differences): 2.5 (differences in the metabolic rate are already taken into account by the implicit allometric scaling; for other interspecies differences an additional factor of 2.5 is applied)
AF2 (intraspecies differences): 10 (for general population)
AF3 (differences in duration of exposure): 1 (dose descriptor from chronic study, thus no extrapolation to chronic exposure needed)
AF4 (issues related to dose-response): 1 (dose descriptor is a NO(A)EL)
AF5 (quality of whole database): 1 (quality of database is appropriate)
AF = 2.5 * 10 * 1 * 1 * 1 = 25
DNEL derivation
DNEL = NOAELcorr-inh-general population / AF = 2.965 mg/m3/ 25 = 0.119 mg/m3
general population -DNEL long-term for inhalation route-systemic = 0.119 mg/m3
GP3) General population-DNEL long-term for oral route-systemic
Repeat-dose toxicity - rat
Dose-descriptor selection
Potential dose-descriptors are available resulting from a combined chronic toxicity/carcinogenicity study (NOAEL, rat, oral dietary, 24 month).
Assessment of mode of action
The identified endpoint and the observed effects have a threshold mode of action. Remark: In males, at the highest dose tested, a treatment-related increase in the incidence of thyroid follicular cell adenomas has been observed. The substance was negative in allin vitroandin vivogenotoxicity tests conducted (i.e.in vitrogene mutation study in bacteria (Ames, OECD 471),in vitromammalian chromosome aberration test in human lymphocytes (in vitrocytogenetics study, IVC, OECD 473),in vitromammalian cell gene mutation test in mouse lymphoma L5178Y cells (OECD 476) andin vivorat bone marrow micronucleus test (OECD 474)). Thus despite the finding of tumours there is no evidence for genotoxic carcinogenicity (remark: in case of genotoxic carcinogenicity a non-threshold mode of action would often have to be assumed, unless a threshold mechanism of action can be clearly demonstrated).
Dose-descriptor modification
The dose descriptor was modified according to GIRCSA R.8, R.8.4.2 and Appendix R.8-2, using the following defaults: oral absorption rat (ABSoral-rat) = oral absorption human (ABSoral-human), allometric scaling factor AS = 4 (between rat and human).
NOAELcorr-oral-human = NOAELoral-rat * (ABSoral-rat/ABSoral-human) * (1/AS)
NOAELcorr-oral-human = 4.88 mg/kg bw/day * (1/1) * (1/4) = 1.22 mg/kg bw/day
Assessment factors
The default assessment factors were applied according to GIRCSA R.8, R.8.4.3, R.8.4.3.1 and R.8.4.3.3. Allometric scaling has been accounted for (explicitly) in the dose-descriptor modification.
Overall assessment factor: AF = AF1 * AF2 * AF3 * AF4 * AF5
AF1 (interspecies differences): 2.5 (differences in the metabolic rate are already taken into account by the explicit allometric scaling; for other interspecies differences an additional factor of 2.5 is applied)
AF2 (intraspecies differences): 10 (for general population)
AF3 (differences in duration of exposure): 1 (dose descriptor from chronic study, thus no extrapolation to chronic exposure needed)
AF4 (issues related to dose-response): 1 (dose descriptor is a NO(A)EL)
AF5 (quality of whole database): 1 (quality of database is appropriate)
AF = 2.5 * 10 * 1 * 1 * 1 = 25
DNEL derivation
DNEL = NOAELcorr-human / AF = 1.22 mg/kg bw/day / 25 = 0.0488 mg/kg bw/day
general population-DNEL long-term for oral route-systemic = 0.0488 mg/kg bw/day
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