Amines, C10-14-tert-alkyl

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.5 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):

3

Dose descriptor starting point:

NOAEC

Value:

19 mg/m³

Modified dose descriptor starting point:

BMCL10

Value:

36.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

Time scaling to adjust for worker exposure (6hr rat/8 hr human) or general population exposure (6hr rat/24 hr human) is not necessary because effect is local irritation and is expected to be concentration and not accumulated dose-dependent. [See Guidance on Information Requirements Ch. R.8, page 25]

AF for dose response relationship:

1

Justification:

The dose-response relationship AF can be used to adjust results to a NOAEL(C). There is a clear NOAEL for Amines, C12-C14 tert-alkyl in the 4-week inhalation study. Additionally the BMDL is assumed to equal the NOAEL(C). The 28 day study design exceeded that of OECD 412 employing twice as many animals, 4 doses and use of all study data via a BMD analysis.

AF for differences in duration of exposure:

1

Justification:

The duration AF adjusts for toxicity data acquired from studies of less than chronic duration. The default AF for sub-acute (4-week study) to subchronic (90 days) is =2. While this factor can be adjusted downward to a base level of 1, there are no respiratory tract histopathology data for Amines, C12-C14 tert-alkyl in shorter exposure studies. [See Guidance on Information Requirements Ch. R.8, page 35; also see draft guidance assembled by ECETOC (2010; Section 3.3.2. Interspecies Extrapolation- Local Effects) ]

AF for interspecies differences (allometric scaling):

1

Justification:

Human route is inhalation and the effect is portal of entry irritation, so no allometric scaling from rats to humans is needed. Thus the allometric scaling factor of 4 (rats to humans) is not applied. Further, an additional factor of 2.5 to account for other potential species differences is also not applied because the effect is irritation.
The rat is a very sensitive model for estimating the potential effects of vapors that are cytotoxic to nasal tract respiratory and olfactory epithelium. Because rodents are obligate nose breathers while humans are not, a higher proportion of respired material passes over and is extracted into nasal epithelium in the rat.
Both rat and human nasal epithelium is capable of metabolizing substances to toxic metabolites. For long-chain alkylamines, metabolism is expected to proceed from the amine to respective carboxylic acids by oxidative deamination (catalyzed by monoamine oxidase) followed by oxidation (catalyzed by aldehyde dehydrogenase). These metabolic activities are well conserved across mammalian species and are present in both rats and humans. Both rats and humans are expected to metabolize long-chain alkylamines similarly (EU Risk assessment Report, October 2008).Thus, it is considered that Amines, C12-C14 tert-alkyl are metabolized to respective carboxylic acids which disturb pH balance within nasal tract epithelium resulting in cytotoxicity. The effect is concentration dependent; that is, toxicity occurs only when cellular buffering capacity is overwhelmed.
Sweeney et al, 2004 assembled a PB/PK model for nasal tract cytotoxicity of acrylic acid as a metabolite of ethyl acrylate in rat nasal tract. This analysis is analogous to the likely metabolic conversion of Amines, C12-C14 tert-alkyl to carboxylic acids in nasal epithelia. The authors concluded that the projected risk to rat nasal epithelium for cytotoxicity overestimates projected human risk by several fold due to both differences in metabolism and exposure.

AF for other interspecies differences:

1

AF for intraspecies differences:

3

Justification:

Intraspecies AF adjusts for individual sensitivity differences within humans. The default value is set at 5 for workers. [See Guidance on Information Requirements Ch. R.8, page 33-34]
The effect seen in the Amines, C12-C14 tert-alkyl 28-day repeat-dose inhalation toxicity study in rats is nasal respiratory tract cytotoxicity. This is a portal of entry adverse effect which is likely to be mediated by acid metabolites of amines that overwhelm cellular buffering capacity. Cellular buffering capacity is a process basic to cellular capacity and is not likely to vary much between individuals. An intraspecies assessment factor of 3 was used in calculation of a DNEL. This value is consistent with guidance developed by the World Health Organization (WHO, 2005) and with draft guidance assembled by ECETOC (2010; Section 3.2. Inter- and Intra-species factor for interdependency).

AF for the quality of the whole database:

1

Justification:

The ‘quality of the data base ‘AF is used to adjust for substances which have very little data. Amines, C12-C14 tert-alkyl has a full data base and further adjustment is not necessary. The effect of concern is cytotoxicity to the nasal tract respiratory and olfactory mucosa. This local effect is concentration dependent and not cumulative dose dependent. Irritation to the respiratory tract has been reported for other long-chain alkylamines as noted in the EU RAR (2005).

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.1 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Overall assessment factor (AF):

3

Dose descriptor:

BMCL10

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:

no hazard identified

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:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

NOAEL in rat 4 –week inhalation study = 19 mg/m3; BMDL10 = 36.2 mg/m3

 

Time scaling to adjust for worker exposure (6hr rat/8 hr human) or general population exposure (6hr rat/24 hr human) is not necessary because effect is local irritation and is expected to be concentration and not accumulated dose-dependent. [See Guidance on Information Requirements Ch. R.8, page 25]

 

Human route is inhalation and the effect is portal of entry irritation, so no allometric scaling from rats to humans is needed. Thus the allometric scaling factor of 4 (rats to humans) is not applied. Further, an additional factor of 2.5 to account for other potential species differences is also not applied because the effect is irritation and assumed to be the same across species. [See Guidance on Information Requirements Ch. R.8, page 33]

There is information to indicate that the rat is a very sensitive model for estimating the potential effects of vapors that are cytotoxic to nasal tract respiratory and olfactory epithelium. Because rodents are obligate nose breathers while humans are not, a higher proportion of respired material passes over and is extracted into nasal epithelium in the rat.

 

Both rat and human nasal epithelium is capable of metabolizing substances to toxic metabolites. For long-chain alkylamines, metabolism is expected to proceed from the amine to respective carboxylic acids by oxidative deamination (catalyzed by monoamine oxidase) followed by oxidation (catalyzed by aldehyde dehydrogenase). These metabolic activities are well conserved across mammalian species and are present in both rats and humans. Both rats and humans are expected to metabolize long-chain alkylamines similarly (EU Risk assessment Report, October 2008).Thus, it is considered that the test material is metabolized to respective carboxylic acids which disturb pH balance within nasal tract epithelium resulting in cytotoxicity. The effect is concentration dependent; that is, toxicity occurs only when cellular buffering capacity is overwhelmed.

 

Sweeney et al, 2004 assembled a PB/PK model for nasal tract cytotoxicity of acrylic acid as a metabolite of ethyl acrylate in rat nasal tract. This analysis is analogous to the likely metabolic conversion of the test material to carboxylic acids in nasal epithelia. The authors concluded that the projected risk to rat nasal epithelium for cytotoxicity overestimates projected human risk by several fold due to both differences in metabolism and exposure.

Thus, Interspecies Assessment Factor (AF) = 1. 

 

Intraspecies AF adjusts for individual sensitivity differences within humans. The default value is set at 5 for workers. [See Guidance on Information Requirements Ch. R.8, page 33-34]

 

The effect seen in the test material 28-day repeat-dose inhalation toxicity study in rats is nasal respiratory tract cytotoxicity. This is a portal of entry adverse effect which is likely to be mediated by acid metabolites of amines that overwhelm cellular buffering capacity. Cellular buffering capacity is a process basic to cellular capacity and is not likely to vary much between individuals. An intraspecies assessment factor of 3 was used in calculation of a DNEL. This value is consistent with guidance developed by the World Health Organization (WHO, 2005) and with draft guidance assembled by ECETOC (2010; Section 3.2. Inter- and Intra-species factor for interdependency).

Thus, Intraspecies Assessment Factor (AF) = 3 for workers

 

 

The duration AF adjusts for toxicity data acquired from studies of less than chronic duration. The default AF for sub-acute (4-week study) to subchronic (90 days) is =2. While this factor can be adjusted downward to a base level of 1, there are no respiratory tract histopathology data for the test material in shorter exposure studies. [See Guidance on Information Requirements Ch. R.8, page 35; also see draft guidance assembled by ECETOC (2010; Section 3.3.2. Interspecies Extrapolation- Local Effects) ]

Thus, Duration Assessment Factor (AF) = 1.

 

 

The dose-response relationship AF can be used to adjust results to a NOAEL(C). There is a clear NOAEL for the test material in the 4-week inhalation study. Additionally the BMDL is assumed to equal the NOAEL(C). The 28 day study design exceeded that of OECD 412 employing twice as many animals, 4 doses and use of all study data via a BMD analysis.

Thus, dose-response relationship AF = 1.

 

The ‘quality of the data base ‘AF is used to adjust for substances which have very little data. The test material has a full data base and further adjustment is not necessary. The effect of concern is cytotoxicity to the nasal tract respiratory and olfactory mucosa. This local effect is concentration dependent and not cumulative dose dependent. Irritation to the respiratory tract has been reported for other long-chain alkylamines as noted in the EU RAR (2005).

The default ‘quality of the data base AF = 1 and is applied for the test material.

 

Maternal and Fetal NOAEL in oral 1 G Reproductive Toxicity Study = 250 ppm (19 mg/kg); BMDL10 42.4 mg/kg/day

 

Adjustment of the oral rat NOAEL to corrected human inhalation NOAEC is accomplished by the following equation. [See Guidance on Information Requirements Ch. R.8, APPENDIX R.8-2, part 2 example B3] 

 

Corrected human inhalation NOAEC = rat oral NOAEL X 1/ RVrat. X ABS oral rat / ABS inh human

 

RVrat = respiratory volume for rat. 1.15 m3/kg for 24 hr or 0.38 m3/kg for 8 hr

ABS oral rat = % absorption of substance upon oral dosing

ABS inh human = % absorption of substance upon inhalation exposure

Worker exposure is assumed to occur under light load indicating a higher respiratory rate by factor of 1.6.

In converting dose metric from oral to inhalation exposure, a default factor of 2 is applied to account for potential differences in absorption by route. That is, twice as much absorption is assumed to occur by inhalation, or the NOAEL is reduced by a factor of 2. [See Guidance on Information Requirements Ch. R.8, page 25]

No allometric scaling is necessary. [See Guidance on Information Requirements Ch. R.8, page 32]

 

ECETOC has analyzed extensive data and concluded that for repeat-dose data, inter- and intra-species AFs are interdependent. An AF of 3 is appropriate for the observed effects draft guidance assembled by ECETOC (2010; Section 3.2. Inter- and Intra-species factor for interdependency)

 

A default interspecies assessment factor of 3 is applied. There are no data to support an alternate value.[See Guidance on Information Requirements Ch. R.8, pages 29-30] 

 

Intraspecies AF adjusts for individual sensitivity differences within humans. The default value for workers is 5.[See Guidance on Information Requirements Ch. R.8, page 33-34]

The default value was not used in this case because the effect seen was depression in fetal body weight. This effect is non-specific and occurred only at doses that also caused reductions in body weight gain in maternal animals. It is judged that there will be little variation from individual to individual for induction of this maternal toxicity.

 

Thus, Intraspecies Assessment Factor (AF) = 1 for workers.

 

The duration AF accounts for differences in actual exposure duration vs. complete exposure duration to cover the toxicologic endpoint of interest. For the reproductive toxicity test in rats, the exposure was across one generation.Thus, a duration AF = 1 was selected.

 

The dose-response relationship AF can be used to adjust results to a NOAEL(C). There is a clear NOAEL for the test material in the one generation reproduction study. Additionally the BMD5 is assumed to equal the NOAEL(C).

Thus, dose-response relationship AF=1.

 

The ‘quality of the data base ‘AF is used to adjust the DNEL for substances which have very little data. The test material has a full data base and further adjustment is not necessary.

The default ‘quality of the data base AF = 1 and is applied for the test material.

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

DNEL related information

Overall assessment factor (AF):

30

Modified dose descriptor starting point:

BMCL10

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.2 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Overall assessment factor (AF):

30

Dose descriptor:

BMCL10

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:

no hazard identified

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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.35 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

30

Dose descriptor starting point:

NOAEL

Modified dose descriptor starting point:

BMDL10

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

NOAEL in rat 4 –week inhalation study = 19 mg/m3; BMDL10 = 36.2 mg/m3

 

Time scaling to adjust for worker exposure (6hr rat/8 hr human) or general population exposure (6hr rat/24 hr human) is not necessary because effect is local irritation and is expected to be concentration and not accumulated dose-dependent. [See Guidance on Information Requirements Ch. R.8, page 25]

 

Human route is inhalation and the effect is portal of entry irritation, so no allometric scaling from rats to humans is needed. Thus the allometric scaling factor of 4 (rats to humans) is not applied. Further, an additional factor of 2.5 to account for other potential species differences is also not applied because the effect is irritation and assumed to be the same across species. [See Guidance on Information Requirements Ch. R.8, page 33]

Modification of the starting point:

Corrected NOAEC = inhalatory NOAEC * exp.cond rat / exp.cond human

[See Guidance on Information Requirements Ch. R8, page 27]

 

Maternal and Fetal NOAEL in oral 1 G Reproductive Toxicity Study = 250 ppm (19 mg/kg); BMDL10 42.4 mg/kg/day

 

Adjustment of the oral rat NOAEL to corrected human inhalation NOAEC is accomplished by the following equation. [See Guidance on Information Requirements Ch. R.8, APPENDIX R.8-2, part 2 example B3] 

 

Corrected human inhalation NOAEC = rat oral NOAEL X 1/ RVrat. X ABS oral rat / ABS inh human

 

RVrat = respiratory volume for rat. 1.15 m3/kg for 24 hr or 0.38 m3/kg for 8 hr

ABS oral rat = % absorption of substance upon oral dosing

ABS inh human = % absorption of substance upon inhalation exposure

Worker exposure is assumed to occur under light load indicating a higher respiratory rate by factor of 1.6.

In converting dose metric from oral to inhalation exposure, a default factor of 2 is applied to account for potential differences in absorption by route. That is, twice as much absorption is assumed to occur by inhalation, or the NOAEL is reduced by a factor of 2. [See Guidance on Information Requirements Ch. R.8, page 25]

Oral DNEL Derivation- Systemic Effects

Allometric scaling from rats to humans is needed. The allometric scaling factor of 4 (rats to humans) is applied. Further, an additional factor of 2.5 to account for other potential species differences is also applied. [See Guidance on Information Requirements Ch. R.8, page 33]