Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
repeated dose toxicity
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 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
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:
7.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Value:
125 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
375 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Please refer to "Additional information".

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
1
Justification:
The default extrapolation factor for chronic exposure duration is used.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
The default value for interspecies differences is used.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
140 µg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor:
other: NOAEL 125 mg/kg bw
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. However, a correction for exposure duration for this study is not appropriate as the local effects are mainly driven by the exposure concentration. Therefore, the default assessment factor is not applied in this instance.
AF for interspecies differences (allometric scaling):
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: local effects are independent of the basal metabolic rate, allometric scaling should not be applied (allometric scaling factor of 1).
AF for other interspecies differences:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: 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) and to apply an additional factor 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. In this case the effects are not dependent on metabolic rate or systemic absorption and no further kinetic considerations apply. Therefore, the default factor for remaining uncertainties could be reduced to 1.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General

DNEL derivation for the TEA is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Long term, systemic DNEL – exposure via inhalation (workers)

An inhalation study performed with Triethanolamine (TEA, CAS 102-71-6) is available. No signs of systemic toxicity were observed in the available 28-day inhalation study at the highest concentration level of 500 mg/m3, while a LOAEC of 20 mg/m3was established for local effects. Therefore, local effects are considered to be more critical and the derived DNEL for local effects by inhalation exposure is considered to be sufficient to protect against possible systemic effects.

Acute, systemic DNEL- exposure via inhalation (workers)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute inhalation toxicity. Therefore, a DNEL is not required.

Long term, local DNEL- exposure via inhalation (workers)

For the substance Triethanolamine a German MAK value of 1 mg/m3 was determined in 2017. This OEL was derived from inhalation studies with aerosol. It should be noted that the saturated vapor concentration of Triethanolamine is 0.03 mg/m3 at 25°C. The MAK value is defined as the maximum concentration of a substance in the workplace air which generally does not have known adverse effects on the health of workers nor causes unreasonable annoyance, even when a person is repeatedly exposed during long periods, usually for 8 hours daily but assuming on average a 40-hour working week.

The MAK value for Triethanolamine is based on the NOAEL determined in a 28- inhalation toxicity study performed according to OECD guideline 412 and GLP (BASF SE, 1993). Wistar rats (10/sex/dose) were exposed head/nose only to 0, 0.02, 0.1 or 0.5 mg/L TEA for 6 hours/day and 5 days/week. No mortality was observed. No statistically significant differences between groups were observed in body weight, haematology and clinical chemistry. Differences in grip strength were judged not substance-related because of a lack of concentration- or time-related effect. No other abnormalities were observed during neurofunctional testing. A significant difference in red blood cells was observed in males of the mid-dose group compared to controls, but since this deviation was marginal, not observed in females, and not dose-related, this finding was considered of no toxicological significance. Local effects were characterized histopathologically by focal inflammatory changes in the submucosa of the larynx, with a concentration-dependent tendency in incidence and severity. No such effects were observed in females of the low dose, whereas minimal to slight effects were seen in males at this dose. Therefore, 0.02 mg/L (20 mg/m3) was considered to be the LOAEC for local effects with a BMDL05 of 14.1 mg/m3.

In conclusion, a long term local inhalation DNEL (worker) of 1 mg/m3 was derived according to MAK value by using additonal AFs for interspecies differences (3, according to Bruening et al 2014) and duration of exposure (6; progression of adverse effects was observed between day 5 (Dose-Range finding study) and day 28 (main study) showing that the duration of exposure may play a role in the development of observed effects).

Short term, local DNEL- exposure via inhalation (workers)

A DNEL short term - local effects is not established because the substance is not classified dangerous for skin/eye irritation/corrosion and skin sensitisation according to Regulation EC No 1272/2008.

 

Long term, systemic DNEL- dermal exposure (workers)

In a dermal carcinogenicity study in rats performed to a similar method as OECD guideline 451 and under GLP, Fischer rats (60/sex/dose) were dermally exposed to 0, 32, 63, or 125 mg/kg bw/day (males) and 0, 63, 125, or 250 mg/kg bw/day (females) TEA in acetone, 5 days/week for 103 weeks (NTP, 1999).The survival rate of females in the 250 mg/kg bw group was slightly less than that of the vehicle controls. The mean body weight of females administered 250 mg/kg bw ranged from 9% to 12% less than that of the vehicle controls between weeks 73 and 93. Male and female rats receiving triethanolamine had irritated skin at the site of application; in dosed females, the site of application also had a crusty appearance. The number of animals in which these findings were observed increased with increasing dose. At the 15-month interim evaluation, the absolute left and right kidney weights and relative right kidney weight of females administered 250 mg/kg bw were significantly greater than those of the vehicle controls.

The incidence of acanthosis at the site of application in males administered 125 mg/kg bw and the incidences of acanthosis, inflammation, and ulceration in dosed females were greater than in the vehicle controls at the 15-month interim evaluation and at the end of the 2-year study. Males in the 125 mg/kg bw group also had greater incidences of inflammation and ulceration than the vehicle controls, and females receiving 125 or 250 mg/kg bw had greater incidences of epidermal erosion than the vehicle controls at 2 years. There were no skin neoplasms at or away from the site of application that were considered related to treatment with triethanolamine. At the end of the study, renal tubule adenomas were observed in seven dosed males and in one vehicle control female and one female in the 63 mg/kg group. One male in the 125 mg/kg bw group and one female in the 250 mg/kg bw group had renal tubule hyperplasia. Extended (step-section) evaluation of the kidneys of all male rats revealed additional renal tubule adenomas in one vehicle control male, one male in the 32 mg/kg bw group, two males in the 63 mg/kg bw group, and three males in the 125 mg/kg bw group (including one male from the 15-month interim evaluation). An oncocytoma was also identified in one male in the 32 mg/kg bw group. Hyperplasia was identified in eight additional vehicle control males and in 19 additional dosed males. The total incidences (combined standard and extended evaluations) of renal tubule adenoma in dosed male rats were slightly greater than the vehicle control incidence (vehicle control, 1/50; 32 mg/kg bw, 2/50; 63 mg/kg bw, 6/49; 125 mg/kg bw, 4/50). The total incidence of hyperplasia in dosed and vehicle control males was similar (9/50, 8/50, 7/49, 6/50). The severity of hyperplasia in males in the 32 and 125 mg/kg bw groups was greater than that in the vehicle controls.

63 mg/kg bw/day was established to be the NOAEL for local effects in males, and the LOAEL in females, based on acanthosis and chronic active inflammation at the application site. A NOAEL of 125 mg/kg bw/day was established for systemic effects due to increased relative kidney weights observed in females.

Step 1: PoD: NOAEL = 125 mg/kg bw/day

An absorption, distribution, metabolism, and excretion study by the NTP (2004) found that after 72 hours of exposure, only 20% to 30% of the applied dermal dose of TEA (68 or 276 mg/kg) was absorbed in rats. In addition to animal studies, human skin penetration of TEA was tested in vitro using diffusion cell techniques (Kraeling, 2003). Oil-in-water emulsions containing 1% or 5%14C-TEA were added to the stratum corneum side of 200-300 µm thick human skin sections and penetration of radioactivity into and through the skin (into a receptor fluid, sampled up to 24 hours after application) was determined. At pH 8.0, 1.1 and 1.2% of the dose was absorbed into the receptor fluid with a total penetration of 22.0 and 16.5% for 1 and 5% TEA, respectively. At pH 7.0, 0.43 and 0.28% was absorbed into the receptor fluid with a total penetration of 9.8 and 5.8% after 24 hours for 1 and 5% TEA, respectively. After 48 hours at pH 7.0, 0.68 and 0.60% was absorbed into the receptor fluid with a total penetration of 9.6 and 6.9%, for 1 and 5% TEA respectively. This pH-related difference reflects the higher percentage of non-ionised test material at pH 8.0. A dermal absorption value of 10% was used for humans.

Step 2: Corrected NOAEL

= dermal NOAEL x (ABS derm-rat/ABS derm-human)

= 125 mg/kg bw/day x (30/10)

= 375 mg/kg bw/day

Step 2: Overall AF= 50

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Dose-response relationship AF: 1

Exposure duration AF: 1 (chronic)

In conclusion, long term systemic dermal DNEL, workers = 7.5 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (workers)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute dermal toxicity. Therefore, a DNEL is not required.

Long term, local DNEL- dermal exposure (workers)

The substance is not classified dangerous for skin/eye irritation/corrosion and skin sensitisation according to Regulation EC No 1272/2008. However, local skin effects were apparent in the mice and rat 90-day dermal repeated-dose studies (Battelle 1987b [mouse] and 1987b [rat]). A NOAEL of 125 mg/kg/d for local effects was established from the rat study.

Step 1: PoD: NOAEL local = 125 mg/kg bw/day

Step 2: Corrected NOAEL

The modification from NOAEL in mg/kg of body weight to NOAEL in mg/cm2/day is:

Based on the average weight of a rat of 250 g, that the dose is applied over an area which is approximately 10% of the total body surface, and an average total body surface of rats of 445 cm2, the corrected NOAEL is:

125 mg/kg x (0.25 kg/44.5 cm2) = 0.7 mg/cm2= 700 μg/cm2

Step 3: Overall AF= 5

Interspecies AF, remaining differences: 1 (for effects on skin via simple destruction of membranes)

Intraspecies AF (worker): 5

Dose-response relationship AF: 1

Exposure duration AF: 1

In conclusion, long term local dermal DNEL, workers = 140 µg/cm2

Hazard to the eye-local effects (worker)

The test item is not classified for eye damage according to Regulation (EC) No 1272/2008 (CLP).

 

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016

The MAK Collection for Occupational Health and Safety 2018, Vol 3, No 2, WILEY-VCH Verlag GmbH & Co. KGaA, Triethanolamine [102-71-6]

CoRAP-Substance Evaluation Report, 2,2’,2”-NITRILOTRIETHANOL (TEA), CAS 102-71-6, August 2015

Bruening et al 2014, Sensory irritation as basis for setting occupational exposure limits, Arch Toxicol (2014) 88:1855-1879

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
repeated dose toxicity
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:
0.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
36
Dose descriptor:
BMCL05
Value:
14.1 mg/m³
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
A progression of adverse effects was observed between day 5 (Dose-Range finding study) and day 28 (main study) showing that the duration of exposure plays a role in the development of observed effects. In this case, an assessment factor of 6 was chosen for extrapolation from subacute to chronic.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling should not be applied because in humans inhalation rate is 4-fold lower compared to rats according to the slower metabolic rate and thereby the allometric species difference is already implicitly taken into account.
AF for other interspecies differences:
3
Justification:
A sub-acute repeated dose toxicity study for inhalation according to OECD 412 is available for DNEL derivation. The appropriate assessment factors were set based on the publication of Bruening et al (2014). In this publication the sensory irritation pathway in humans was compared to the tissue irritation pathway in animals. Experimental exposure studies with human volunteers provided the empirical basis for effects along the sensory irritation pathway and thus, sensory NOAEChuman was derived. In contrast, inhalation studies with rodents investigated the second pathway that yielded an irritative NOAECanimal. The comparison of the sensory NOAEChuman with the irritative NOAECanimal (chronic) resulted in an interspecies assessment factor of 3 for extrapolating animal data concerning local sensory irritating effects.
AF for intraspecies differences:
2
Justification:
An additional assessment factor is used for consideration of differences in susceptibility of general population.
AF for the quality of the whole database:
1
Justification:
The repeated dose inhalation toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
2.66 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
125 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
266 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Please refer to "Additional information".

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
1
Justification:
The default extrapolation factor for chronic exposure duration is used.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
The default value for interspecies differences is used.
AF for intraspecies differences:
10
Justification:
The default value for the more heterogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
70 µg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor:
other: NOAEL = 125 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. However, a correction for exposure duration is not appropiate as exposure duration does not increase the incidence or severity of adverse effect
AF for interspecies differences (allometric scaling):
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Allometric scaling should not be applied if the effects are not dependent on metabolic rate or systemic absorption, e.g. in the case of local effects.
AF for other interspecies differences:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: 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) 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. In this case the effects are not dependent on metabolic rate or systemic absorption and no further kinetic considerations apply. Therefore, the default factor for remaining uncertainties of 2.5 could be reduced to 1.
AF for intraspecies differences:
10
Justification:
The default value for the more heterogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
3.3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
LOAEL
Value:
333 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
1
Justification:
The default extrapolation factor for chronic exposure duration is used.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
The default value for interspecies differences is used.
AF for intraspecies differences:
10
Justification:
The default value for the more heterogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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

General

DNEL derivation for TEA is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Long term, systemic DNEL – exposure via inhalation (General population)

An inhalation study performed with Triethanolamine (TEA, CAS 102-71-6) is available. No signs of systemic toxicity were observed in the available 28-day inhalation study at the highest concentration level of 500 mg/m3, while a NOAEC of 20 mg/m3 was established for local effects. Therefore, local effects are considered to be more critical and the derived DNEL for local effects by inhalation exposure is considered to be sufficient to protect against possible systemic effects.

Acute, systemic DNEL- exposure via inhalation (General population)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, "a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute inhalation toxicity. Therefore, a DNEL is not required.

Long term, local DNEL- exposure via inhalation (General population)

A 28- inhalation toxicity study was performed according to OECD guideline 412 and GLP (BASF SE, 1993). Wistar rats (10/sex/dose) were exposed head/nose only to 0, 0.02, 0.1 or 0.5 mg/L TEA for 6 hours/day and 5 days/week. No mortality was observed. No statistically significant differences between groups were observed in body weight, haematology and clinical chemistry. Differences in grip strength were judged not substance-related because of a lack of concentration- or time-related effect. No other abnormalities were observed during neurofunctional testing. A significant difference in red blood cells was observed in males of the mid-dose group compared to controls, but since this deviation was marginal, not observed in females, and not dose-related, this finding was considered of no toxicological significance. Local effects were characterized histopathologically by focal inflammatory changes in the submucosa of the larynx, with a concentration-dependent tendency in incidence and severity. No such effects were observed in females of the low dose, whereas minimal to slight effects were seen in males at this dose.

Therefore, 0.02 mg/L (20 mg/m3) was considered to be the LOAEC for local effects with a BMDL05 of 14mg/m3.

Step 1: PoD: BMDL05 (local): = 14.1 mg/m3

Step 2: Overall AF= 36

Interspecies: AF: 1

Local effects are independent of the basal metabolic rate, allometric scaling should not be applied.

Interspecies AF, remaining differences: 1

There is no evidence for species differences in the general mode of action or kinetics.

Intraspecies AF: 3

According to Bruening et al., 2014, an interspecies extrapolation factor of 3 should be applied for local sensory irritants without reliable human data.

Dose response relationship AF: 1

Exposure duration AF: 6

A progression of adverse effects was observed between day 5 (Dose-Range finding study) and day 28 (main study) showing that the duration of exposure plays a role in the development of observed effects. In this case, an assessment factor of 6 was chosen for extrapolation from subacute to chronic.

Intraspecies differences: 2

An additional assessment factor is used for consideration of differences in susceptibility of general population.

Whole database AF: 1

The repeated dose inhalation toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

In conclusion, long term local inhalation DNEL for general population was determined to be 0.4 mg/m3

Short term, local DNEL- exposure via inhalation (general population)

A DNEL short term - local effects is not established because the substance is not classified dangerous for skin/eye irritation/corrosion and skin sensitisation according to Regulation EC No 1272/2008.

Long term, systemic DNEL- dermal exposure (general population)

In a dermal carcinogenicity study in rats performed to a similar method as OECD guideline 451 and under GLP, Fischer rats (60/sex/dose) were dermally exposed to 0, 32, 63, or 125 mg/kg bw/day (males) and 0, 63, 125, or 250 mg/kg bw/day (females) TEA in acetone, 5 days/week for 103 weeks (NTP, 1999).The survival rate of females in the 250 mg/kg bw group was slightly less than that of the vehicle controls. The mean body weight of females administered 250 mg/kg bw ranged from 9% to 12% less than that of the vehicle controls between weeks 73 and 93. Male and female rats receiving triethanolamine had irritated skin at the site of application; in dosed females, the site of application also had a crusty appearance. The number of animals in which these findings were observed increased with increasing dose. At the 15-month interim evaluation, the absolute left and right kidney weights and relative right kidney weight of females administered 250 mg/kg bw were significantly greater than those of the vehicle controls.

The incidence of acanthosis at the site of application in males administered 125 mg/kg bw and the incidences of acanthosis, inflammation, and ulceration in dosed females were greater than in the vehicle controls at the 15-month interim evaluation and at the end of the 2-year study. Males in the 125 mg/kg bw group also had greater incidences of inflammation and ulceration than the vehicle controls, and females receiving 125 or 250 mg/kg bw had greater incidences of epidermal erosion than the vehicle controls at 2 years. There were no skin neoplasms at or away from the site of application that were considered related to treatment with triethanolamine. At the end of the study, renal tubule adenomas were observed in seven dosed males and in one vehicle control female and one female in the 63 mg/kg group. One male in the 125 mg/kg bw group and one female in the 250 mg/kg bw group had renal tubule hyperplasia. Extended (step-section) evaluation of the kidneys of all male rats revealed additional renal tubule adenomas in one vehicle control male, one male in the 32 mg/kg bw group, two males in the 63 mg/kg bw group, and three males in the 125 mg/kg bw group (including one male from the 15-month interim evaluation). An oncocytoma was also identified in one male in the 32 mg/kg bw group. Hyperplasia was identified in eight additional vehicle control males and in 19 additional dosed males. The total incidences (combined standard and extended evaluations) of renal tubule adenoma in dosed male rats were slightly greater than the vehicle control incidence (vehicle control, 1/50; 32 mg/kg bw, 2/50; 63 mg/kg bw, 6/49; 125 mg/kg bw, 4/50). The total incidence of hyperplasia in dosed and vehicle control males was similar (9/50, 8/50, 7/49, 6/50). The severity of hyperplasia in males in the 32 and 125 mg/kg bw groups was greater than that in the vehicle controls.

63 mg/kg bw/day was established to be the NOAEL for local effects in males, and the LOAEL in females, based on acanthosis and chronic active inflammation at the application site. A NOAEL of 125 mg/kg bw/day was established for systemic effects due to increased relative kidney weights observed in females.

Step 1:PoD: NOAEL = 125 mg/kg bw/day

An absorption, distribution, metabolism, and excretion study by the NTP (2004) found that after 72 hours of exposure, only 20% to 30% of the applied dermal dose of TEA (68 or 276 mg/kg) was absorbed in rats. In addition to animal studies, human skin penetration of TEA was tested in vitro using diffusion cell techniques (Kraeling, 2003). Oil-in-water emulsions containing 1% or 5%14C-TEA were added to the stratum corneum side of 200-300 µm thick human skin sections and penetration of radioactivity into and through the skin (into a receptor fluid, sampled up to 24 hours after application) was determined. At pH 8.0, 1.1 and 1.2% of the dose was absorbed into the receptor fluid with a total penetration of 22.0 and 16.5% for 1 and 5% TEA, respectively. At pH 7.0, 0.43 and 0.28% was absorbed into the receptor fluid with a total penetration of 9.8 and 5.8% after 24 hours for 1 and 5% TEA, respectively. After 48 hours at pH 7.0, 0.68 and 0.60% was absorbed into the receptor fluid with a total penetration of 9.6 and 6.9%, for 1 and 5% TEA respectively. This pH-related difference reflects the higher percentage of non-ionised test material at pH 8.0. A dermal absorption value of 10% was used for humans.

Step 2:Corrected NOAEL

Correction for difference between human and experimental exposure conditions: 5 d, 24 h rat/7 d, 24 h general population

= dermal NOAEL x (ABS derm-rat/ABS derm-human) x 0.71

= 125 mg/kg bw/day x (30/10) x 0.71

= 266 mg/kg bw/day

Step 2: Overall AF= 100

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF: 1

In conclusion, long term systemic dermal DNEL, general population = 2.66 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (general population)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute dermal toxicity. Therefore, a DNEL is not required.

Long term & acute, local DNEL- dermal exposure (general population)

The substance is not classified dangerous for skin/eye irritation/corrosion and skin sensitisation according to Regulation EC No 1272/2008. However, local skin effects were apparent in the mice and rat 90-day dermal repeated-dose studies (Battelle 1987). A NOAEL of 125 mg/kg/d for local effects was established from the rat study.

Step 1: PoD: NOAEL local = 125 mg/kg bw/day

Step 2: Corrected NOAEL

The modification from NOAEL in mg/kg of bw to NOAEL in mg/cm2/day is:

125 mg/kg x (0.25 kg/44.5 cm2) = 0.7 mg/cm2= 700 μg/cm2

Step 3: Overall AF= 10

Interspecies AF, remaining differences: 1 (for effects on skin via simple destruction of membranes)

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF: 1

In conclusion, long term local dermal DNEL, workers = 70 µg/cm2

Long term, systemic DNEL – exposure by oral route (general population)

In an oral carcinogenicity study in rats, Fischer rats (50/sex/dose) were daily exposed to 0, 1, or 2% TEA via the drinking water (corresponding to a dose of approximately 667 and 1333 mg/kg bw/day) for 2 years (Maekawa et al, 1986). In week 69, dose levels in females were reduced to 0.5 and 1% (corresponding to ca. 333 and 667 mg/kg bw/day), because of associated nephrotoxicity. A variety of tumours developed in all groups, but no statistically significant differences were observed to control levels. A positive trend towards increased occurrence of hepatic tumours in males and of uterine endometrial sarcomas and renal-cell adenomas in females was judged as not related to the treatment. It was concluded that TEA is not carcinogenic under these conditions in the Fischer rat, but is toxic to the kidneys.

Step 1: Relevant dose descriptor (LOAEL): 333 mg/kg bw/day

Step 2: Overall AF= 100

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF: 1

In conclusion, long term systemic oral DNEL, general population= 3.3 mg/kg bw/day

Acute, systemic DNEL- exposure by oral route (general population)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute dermal toxicity. Therefore, a DNEL is not required.

Hazard to the eye-local effects (General population)

The test item is not classified for eye damage according to Regulation (EC) No 1272/2008 (CLP).

 

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016

Bruening et al 2014, Sensory irritation as basis for setting occupational exposure limits, Arch Toxicol (2014) 88:1855-1879

CoRAP-Substance Evaluation Report, 2,2’,2”-NITRILOTRIETHANOL (TEA), CAS 102-71-6, August 2015