Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
147.9 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
Value:
881.6 mg/m³
Explanation for the modification of the dose descriptor starting point:

Per ECHA guidance (Pg21, Figure R.8-3, Chapter R.8:Characterisation of dose [concentration]-response for human health https://echa.europa.eu/documents/10162/13632/information_requirements_r8_en.pdf):


 


500mg/kg/d (oral NOAEL) was converted to an 8 hour worker inhalatory NOAEC using the following equation:


 


Inhalatory NOAEC = [oral NOAEL*(1/sRVrat)*(ABSoral-rat)/ABSinh-human)*(sRVhuman/wRV)]


Inhalatory NOAEC = [500mg/kg/d*(1/0.38m3/kg/d)*(100/100)*(6.7m3/10m3)]


Inhalatory NOAEC = 881.6mg/m3

AF for dose response relationship:
1
Justification:
The point of departure is a NOAEL from an OECD guideline study.
AF for differences in duration of exposure:
1
Justification:
The exposure window of the key study (per OECD 414 guideline) was approximately two weeks. However, the exposure duration encompassed the entire developmental window (GD6-20; from parturition to closing of the palate); as such, there is no applicable equivalent extrapolation for exposure duration to a chronic exposure, as the exposure duration in the study reflects the entire developmental window.
AF for interspecies differences (allometric scaling):
1
Justification:
Interspecies differences (allometric scaling) was accounted for in the ventilation rate adjustment during route-to-route extrapolation of the oral NOAEL (rat) to the inhalatory NOAEL (human).
AF for other interspecies differences:
1
Justification:
ECHA guidance states the following regarding interspecies differences:
“…the standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part). In case substance-specific information shows specific susceptibility differences between species, which are not related to differences in basal metabolic rate, the additional factor of 2.5 for ‘remaining differences’ should be modified accordingly.”
The Fraunhofer Institute for Toxicology and Experimental Medicine has published evidence that applying 2.5 as a standard ‘remaining’ interspecies differences is not necessarily applicable based on available evidence (Escher and Mangelsdorf, 2009; Batke et al, 2010; Bitsch et al, 2006). The RepDose database has been utilized to extract data on repeat dose toxicity studies, and probabilistic modeling exercises have examined time- and interspecies-extrapolations which included chemicals under comparable exposure and route of application to demonstrate the sufficiency of an allometric factor application to account for interspecies differences (Escher et al. 2013). At time of publication, the RepDose database contained 2500 repeat dose toxicity studies (rodent) with data on approximately 700 organic chemicals, and study authors utilized a subset of these studies to derive the geometric mean (GM) of fitted distributions and corrected for allometric scaling (GM = 0.91 median AF/1.03 all AF) to arrive at this conclusion (Escher et al. 2013). This conclusion aligns with previously reported GMs of 1 for interspecies differences (Schneider et al. 2005, Rennen et al. 2001).

See information panel attachment for references.
AF for intraspecies differences:
3
Justification:
While ECHA guidance suggests an AF of 5 to account for intraspecies variability within worker populations, this can be further refined with published analyses. An AF of 3 is applied for worker populations, based on assessments of variability in toxicokinetics and toxicodynamics in healthy, adult human populations. A small study (7 toxicokinetic and 8 toxicodynamic studies) concluded that an AF of 3-4 would address the uncertainty in 99% of the healthy adult population for 80% of the substances assessed (Renwick, 1991). A more extensive study analyzed a more robust dataset (toxicokinetic data on 60 substances and 49 substances with toxicodynamic data) to assess human variability and resulted in recommendation of an AF for 3.2 to cover 95% of the population; since most of the studies included health young adults only, this AF recommendation is more appropriate for workers than the general population (Renwick and Lazarus, 1998). Further research was conducted to refine our understanding of metabolism in healthy adult populations in which variability of key metabolic enzymes in healthy populations (ie polymorphisms do not impact susceptibility), and determined that an AF of 3.2 would cover ≥99% of healthy adults (Falk-Filipsson, 2007).
Falk-Filipsson A, Hanberg A, Victorin K, Warholm M, Wallen M. 2007. Assessment factors— Applications in health risk assessment of chemicals. Environ Res 104:108-127.
Renwick AG. 1991. Safety factors and establishment of acceptable daily intakes. Food Additives and Contaminants: Part A: Chemistry, Analysis, Control, Exposure and Risk Assessment, 1944-0057, 8(2):135-149.
Renwick AG, Lazarus NR. 1998. Human variability and noncancer risk assessment – an analysis of the default uncertainty factor. Regul Toxicol Pharmacol 27:3-20.
AF for the quality of the whole database:
1
Justification:
The test substance is part of a well-understood category of aliphatic alcohols, for which category documents are available (OECD SIDS, USEPA HPV), in addition to product registrations through EU REACH. The key study for the derivation of the DNELs in this dossier are from an OECD guideline developmental study done to GLP standards (Charles River Laboratories, Study ID 438046, 2020). Because this assessment factor is intended to adjust for missing data on sensitive endpoints (ie developmental exposures), the database on this substance is considered sufficiently robust.
AF for remaining uncertainties:
2
Justification:
Route-to-route extrapolation uncertainty in characterizing an inhalation hazard using an oral exposure study.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
417 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
12
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
5 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Based on Guidance on information requirements and chemical safety assessment, (Chapter R.7a) the following considerations for dermal absorptions were made:


1) The log Kow is 4.8; therefore the substance is not expected to migrate from the stratum corneum to the epidermidis (log Kow>4 is associated with high lipophilicity) (OECD, 2011)


2) The molecular weight is 200 g/mol, so it does not meet the threshold of dermal absorption (below 100: in favor of dermal absorption, above 500, not in favor of absorption) 


3) Although the substance is classified as a Category 2 skin irritant, the likelihood of systemic effects after dermal exposure is low based on dermal LD50 >2600 mg/kg bw (highest dose tested).


Therefore, dermal absorption is set to 10%.


 


OECD (2011) Guidance Notes On Dermal Absorption. Environment, Health and Safety Publications, Series on Testing and Assessment No. 156 (ENV/JM/MONO(2011)36).

AF for dose response relationship:
1
Justification:
The point of departure is a NOAEL from an OECD guideline study.
AF for differences in duration of exposure:
1
Justification:
The exposure window of the key study (per OECD 414 guideline) was approximately two weeks. However, the exposure duration encompassed the entire developmental window (GD6-20; from parturition to closing of the palate); as such, there is no applicable equivalent extrapolation for exposure duration to a chronic exposure, as the exposure duration in the study reflects the entire developmental window.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA guidance states that “If no substance-specific data are available, the standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling)…Allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results in different default allometric scaling factors for the different animal species when compared with humans.”
Thus, for the key study, the allometric factor is 4 (rat-human extrapolation).
AF for other interspecies differences:
1
Justification:
ECHA guidance states the following regarding interspecies differences:
“…the standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part). In case substance-specific information shows specific susceptibility differences between species, which are not related to differences in basal metabolic rate, the additional factor of 2.5 for ‘remaining differences’ should be modified accordingly.”
The Fraunhofer Institute for Toxicology and Experimental Medicine has published evidence that applying 2.5 as a standard ‘remaining’ interspecies differences is not necessarily applicable based on available evidence (Escher and Mangelsdorf, 2009; Batke et al, 2010; Bitsch et al, 2006). The RepDose database has been utilized to extract data on repeat dose toxicity studies, and probabilistic modeling exercises have examined time- and interspecies-extrapolations which included chemicals under comparable exposure and route of application to demonstrate the sufficiency of an allometric factor application to account for interspecies differences (Escher et al. 2013). At time of publication, the RepDose database contained 2500 repeat dose toxicity studies (rodent) with data on approximately 700 organic chemicals, and study authors utilized a subset of these studies to derive the geometric mean (GM) of fitted distributions and corrected for allometric scaling (GM = 0.91 median AF/1.03 all AF) to arrive at this conclusion (Escher et al. 2013). This conclusion aligns with previously reported GMs of 1 for interspecies differences (Schneider et al. 2005, Rennen et al. 2001).
AF for intraspecies differences:
3
Justification:
While ECHA guidance suggests an AF of 5 to account for intraspecies variability within worker populations, this can be further refined with published analyses. An AF of 3 is applied for worker populations, based on assessments of variability in toxicokinetics and toxicodynamics in healthy, adult human populations. A small study (7 toxicokinetic and 8 toxicodynamic studies) concluded that an AF of 3-4 would address the uncertainty in 99% of the healthy adult population for 80% of the substances assessed (Renwick, 1991). A more extensive study analyzed a more robust dataset (toxicokinetic data on 60 substances and 49 substances with toxicodynamic data) to assess human variability and resulted in recommendation of an AF for 3.2 to cover 95% of the population; since most of the studies included health young adults only, this AF recommendation is more appropriate for workers than the general population (Renwick and Lazarus, 1998). Further research was conducted to refine our understanding of metabolism in healthy adult populations in which variability of key metabolic enzymes in healthy populations (ie polymorphisms do not impact susceptibility), and determined that an AF of 3.2 would cover ≥99% of healthy adults (Falk-Filipsson, 2007).
Falk-Filipsson A, Hanberg A, Victorin K, Warholm M, Wallen M. 2007. Assessment factors— Applications in health risk assessment of chemicals. Environ Res 104:108-127.
Renwick AG. 1991. Safety factors and establishment of acceptable daily intakes. Food Additives and Contaminants: Part A: Chemistry, Analysis, Control, Exposure and Risk Assessment, 1944-0057, 8(2):135-149.
Renwick AG, Lazarus NR. 1998. Human variability and noncancer risk assessment – an analysis of the default uncertainty factor. Regul Toxicol Pharmacol 27:3-20.
AF for the quality of the whole database:
1
Justification:
The test substance is part of a well-understood category of aliphatic alcohols, for which category documents are available (OECD SIDS, USEPA HPV), in addition to product registrations through EU REACH. The key study for the derivation of the DNELs in this dossier are from an OECD guideline developmental study done to GLP standards (Charles River Laboratories, Study ID 438046, 2020). Because this assessment factor is intended to adjust for missing data on sensitive endpoints (ie developmental exposures), the database on this substance is considered sufficiently robust.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
43.5 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
434.78 mg/m³
Explanation for the modification of the dose descriptor starting point:

Per ECHA guidance (Pg21, Figure R.8-3, Chapter R.8:Characterisationof dose [concentration]-response for human healthhttps://echa.europa.eu/documents/10162/13632/information_requirements_r8_en.pdf):


 


500mg/kg/d (oral NOAEL) was converted to a 24 hour general population inhalatory NOAEC using the following equation:


 


Inhalatory NOAEC = [oral NOAEL*(1/sRVrat)*(ABSoral-rat)/ABSinh-human)*(ABSinh-rat/ABSinh-human)]


Inhalatory NOAEC = [500mg/kg/d*(1/1.15m3/kg/d)*(100/100)*(100/100)]


Inhalatory NOAEC = 434.78mg/m3

AF for dose response relationship:
1
Justification:
The point of departure is a NOAEL from an OECD guideline study.
AF for differences in duration of exposure:
1
Justification:
The exposure window of the key study (per OECD 414 guideline) was approximately two weeks. However, the exposure duration encompassed the entire developmental window (GD6-20; from parturition to closing of the palate); as such, there is no applicable equivalent extrapolation for exposure duration to a chronic exposure, as the exposure duration in the study reflects the entire developmental window.
AF for interspecies differences (allometric scaling):
1
Justification:
Interspecies differences (allometric scaling) was accounted for in the ventilation rate adjustment during route-to-route extrapolation of the oral NOAEL (rat) to the inhalatory NOAEL (human).
AF for other interspecies differences:
1
Justification:
ECHA guidance states the following regarding interspecies differences:
“…the standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part). In case substance-specific information shows specific susceptibility differences between species, which are not related to differences in basal metabolic rate, the additional factor of 2.5 for ‘remaining differences’ should be modified accordingly.”
The Fraunhofer Institute for Toxicology and Experimental Medicine has published evidence that applying 2.5 as a standard ‘remaining’ interspecies differences is not necessarily applicable based on available evidence (Escher and Mangelsdorf, 2009; Batke et al, 2010; Bitsch et al, 2006). The RepDose database has been utilized to extract data on repeat dose toxicity studies, and probabilistic modeling exercises have examined time- and interspecies-extrapolations which included chemicals under comparable exposure and route of application to demonstrate the sufficiency of an allometric factor application to account for interspecies differences (Escher et al. 2013). At time of publication, the RepDose database contained 2500 repeat dose toxicity studies (rodent) with data on approximately 700 organic chemicals, and study authors utilized a subset of these studies to derive the geometric mean (GM) of fitted distributions and corrected for allometric scaling (GM = 0.91 median AF/1.03 all AF) to arrive at this conclusion (Escher et al. 2013). This conclusion aligns with previously reported GMs of 1 for interspecies differences (Schneider et al. 2005, Rennen et al. 2001).

See information panel attachment for references.
AF for intraspecies differences:
5
Justification:
General Population: While ECHA guidance suggests an AF of 10 to account for intraspecies variability across the general population, this can be further refined with published analyses of extensive databases. An AF of 5 is applied for the general population, based on analysis of a database of 447 data groups of toxicokinetic and toxicodynamic data and resulted in the 95th or the 90th percentile for the intraspecies AF of the general human population estimated as approximately 6 and 4, respectively (Hattis, 2002).
Additionally, there is little scientific basis for the need of an additional AF for children of 6-12 months due to the rapid maturation of liver and kidney function in young children (ie within a few months of age) (Renwick, 1998). Because animals show similar patterns of immaturity to those found in humans, an increased AF would not be required because the DNEL is derived from a high quality developmental study in rats.
Hattis D, Baird S, Goble R. 2002. Drug Chem Toxico 25:403-436.
Renwick AG. 1998. Food Additives and Contaminants: Part A: Chemistry, Analysis, Control, Exposure and Risk Assessment, 1944-0057, 15(1):17-35.
AF for the quality of the whole database:
1
Justification:
The test substance is part of a well-understood category of aliphatic alcohols, for which category documents are available (OECD SIDS, USEPA HPV), in addition to product registrations through EU REACH. The key study for the derivation of the DNELs in this dossier are from an OECD guideline developmental study done to GLP standards (Charles River Laboratories, Study ID 438046, 2020). Because this assessment factor is intended to adjust for missing data on sensitive endpoints (ie developmental exposures), the database on this substance is considered sufficiently robust.
AF for remaining uncertainties:
2
Justification:
Route-to-route extrapolation uncertainty in characterizing an inhalation hazard using an oral exposure study.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
250 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
20
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
5 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Based on Guidance on information requirements and chemical safety assessment, (Chapter R.7a) the following considerations for dermal absorptions were made:


1) The log Kow is 4.8; therefore the substance is not expected to migrate from the stratum corneum to the epidermidis (log Kow>4 is associated with high lipophilicity) (OECD, 2011)


2) The molecular weight is 200 g/mol, so it does not meet the threshold of dermal absorption (below 100: in favor of dermal absorption, above 500, not in favor of absorption) 


3) Although the substance is classified as a Category 2 skin irritant, the likelihood of systemic effects after dermal exposure is low based on dermal LD50 >2600 mg/kg bw (highest dose tested).


Therefore, dermal absorption is set to 10%.


 


OECD (2011) Guidance Notes On Dermal Absorption. Environment, Health and Safety Publications, Series on Testing and Assessment No. 156 (ENV/JM/MONO(2011)36).

AF for dose response relationship:
1
Justification:
The point of departure is a NOAEL from an OECD guideline study.
AF for differences in duration of exposure:
1
Justification:
The exposure window of the key study (per OECD 414 guideline) was approximately two weeks. However, the exposure duration encompassed the entire developmental window (GD6-20; from parturition to closing of the palate); as such, there is no applicable equivalent extrapolation for exposure duration to a chronic exposure, as the exposure duration in the study reflects the entire developmental window.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA guidance states that “If no substance-specific data are available, the standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling)…Allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results in different default allometric scaling factors for the different animal species when compared with humans.”
Thus, for the key study, the allometric factor is 4 (rat-human extrapolation).
AF for other interspecies differences:
1
Justification:
ECHA guidance states the following regarding interspecies differences:
“…the standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part). In case substance-specific information shows specific susceptibility differences between species, which are not related to differences in basal metabolic rate, the additional factor of 2.5 for ‘remaining differences’ should be modified accordingly.”
The Fraunhofer Institute for Toxicology and Experimental Medicine has published evidence that applying 2.5 as a standard ‘remaining’ interspecies differences is not necessarily applicable based on available evidence (Escher and Mangelsdorf, 2009; Batke et al, 2010; Bitsch et al, 2006). The RepDose database has been utilized to extract data on repeat dose toxicity studies, and probabilistic modeling exercises have examined time- and interspecies-extrapolations which included chemicals under comparable exposure and route of application to demonstrate the sufficiency of an allometric factor application to account for interspecies differences (Escher et al. 2013). At time of publication, the RepDose database contained 2500 repeat dose toxicity studies (rodent) with data on approximately 700 organic chemicals, and study authors utilized a subset of these studies to derive the geometric mean (GM) of fitted distributions and corrected for allometric scaling (GM = 0.91 median AF/1.03 all AF) to arrive at this conclusion (Escher et al. 2013). This conclusion aligns with previously reported GMs of 1 for interspecies differences (Schneider et al. 2005, Rennen et al. 2001).

See information panel attachment for references.
AF for intraspecies differences:
5
Justification:
General Population: While ECHA guidance suggests an AF of 10 to account for intraspecies variability across the general population, this can be further refined with published analyses of extensive databases. An AF of 5 is applied for the general population, based on analysis of a database of 447 data groups of toxicokinetic and toxicodynamic data and resulted in the 95th or the 90th percentile for the intraspecies AF of the general human population estimated as approximately 6 and 4, respectively (Hattis, 2002).
Additionally, there is little scientific basis for the need of an additional AF for children of 6-12 months due to the rapid maturation of liver and kidney function in young children (ie within a few months of age) (Renwick, 1998). Because animals show similar patterns of immaturity to those found in humans, an increased AF would not be required because the DNEL is derived from a high quality developmental study in rats.
Hattis D, Baird S, Goble R. 2002. Drug Chem Toxico 25:403-436.
Renwick AG. 1998. Food Additives and Contaminants: Part A: Chemistry, Analysis, Control, Exposure and Risk Assessment, 1944-0057, 15(1):17-35.
AF for the quality of the whole database:
1
Justification:
The test substance is part of a well-understood category of aliphatic alcohols, for which category documents are available (OECD SIDS, USEPA HPV), in addition to product registrations through EU REACH. The key study for the derivation of the DNELs in this dossier are from an OECD guideline developmental study done to GLP standards (Charles River Laboratories, Study ID 438046, 2020). Because this assessment factor is intended to adjust for missing data on sensitive endpoints (ie developmental exposures), the database on this substance is considered sufficiently robust.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
25 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
20
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
1
Justification:
The point of departure is a NOAEL from an OECD guideline study.
AF for differences in duration of exposure:
1
Justification:
The exposure window of the key study (per OECD 414 guideline) was approximately two weeks. However, the exposure duration encompassed the entire developmental window (GD6-20; from parturition to closing of the palate); as such, there is no applicable equivalent extrapolation for exposure duration to a chronic exposure, as the exposure duration in the study reflects the entire developmental window.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA guidance states that “If no substance-specific data are available, the standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling)…Allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results in different default allometric scaling factors for the different animal species when compared with humans.”
Thus, for the key study, the allometric factor is 4 (rat-human extrapolation).
AF for other interspecies differences:
1
Justification:
ECHA guidance states the following regarding interspecies differences:
“…the standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences, i.e. toxicokinetic differences not related to metabolic rate (small part) and toxicodynamic differences (larger part). In case substance-specific information shows specific susceptibility differences between species, which are not related to differences in basal metabolic rate, the additional factor of 2.5 for ‘remaining differences’ should be modified accordingly.”
The Fraunhofer Institute for Toxicology and Experimental Medicine has published evidence that applying 2.5 as a standard ‘remaining’ interspecies differences is not necessarily applicable based on available evidence (Escher and Mangelsdorf, 2009; Batke et al, 2010; Bitsch et al, 2006). The RepDose database has been utilized to extract data on repeat dose toxicity studies, and probabilistic modeling exercises have examined time- and interspecies-extrapolations which included chemicals under comparable exposure and route of application to demonstrate the sufficiency of an allometric factor application to account for interspecies differences (Escher et al. 2013). At time of publication, the RepDose database contained 2500 repeat dose toxicity studies (rodent) with data on approximately 700 organic chemicals, and study authors utilized a subset of these studies to derive the geometric mean (GM) of fitted distributions and corrected for allometric scaling (GM = 0.91 median AF/1.03 all AF) to arrive at this conclusion (Escher et al. 2013). This conclusion aligns with previously reported GMs of 1 for interspecies differences (Schneider et al. 2005, Rennen et al. 2001).

See information panel attachment for references.
AF for intraspecies differences:
5
Justification:
General Population: While ECHA guidance suggests an AF of 10 to account for intraspecies variability across the general population, this can be further refined with published analyses of extensive databases. An AF of 5 is applied for the general population, based on analysis of a database of 447 data groups of toxicokinetic and toxicodynamic data and resulted in the 95th or the 90th percentile for the intraspecies AF of the general human population estimated as approximately 6 and 4, respectively (Hattis, 2002).
Additionally, there is little scientific basis for the need of an additional AF for children of 6-12 months due to the rapid maturation of liver and kidney function in young children (ie within a few months of age) (Renwick, 1998). Because animals show similar patterns of immaturity to those found in humans, an increased AF would not be required because the DNEL is derived from a high quality developmental study in rats.
Hattis D, Baird S, Goble R. 2002. Drug Chem Toxico 25:403-436.
Renwick AG. 1998. Food Additives and Contaminants: Part A: Chemistry, Analysis, Control, Exposure and Risk Assessment, 1944-0057, 15(1):17-35.
AF for the quality of the whole database:
1
Justification:
The test substance is part of a well-understood category of aliphatic alcohols, for which category documents are available (OECD SIDS, USEPA HPV), in addition to product registrations through EU REACH. The key study for the derivation of the DNELs in this dossier are from an OECD guideline developmental study done to GLP standards (Charles River Laboratories, Study ID 438046, 2020). Because this assessment factor is intended to adjust for missing data on sensitive endpoints (ie developmental exposures), the database on this substance is considered sufficiently robust.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population