Triethylamine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.4 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.6 mg/m³

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.4 mg/m³

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.6 mg/m³

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.1 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

24

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

Additional information - workers

For TEA, DNELs are needed for acute and chronic exposures by the inhalation and dermal exposure routes. Since TEA is classified as corrosive to skin and eyes, a DNEL_short-term for local effects has also been derived. The calculation of the DNELs is performed in accordance with the principles given in ECHA (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”

Available dose descriptors:

From all available data for the different human health endpoints it is clear that TEA exerts its effect by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint.DNELs are derived from the available toxicity data of TEA, reflecting the routes, duration and frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment.There are following annotations for each endpoint:

o  DNELs for acute toxicity are established because TEA may represent an acute hazard by all routes of exposure (classified accordingly). For dermal and inhalation acute effects (systemic and local), a LOAEC from an acute inhalation study in rats (International Research and Development Corporation, 1995) was identified and used as a dose descriptor starting point. 1 -hour LC50 value (converted into a 4 -hou value) was used also as the starting point.

o  A qualitative approach for the derivation of DNELs of eye irritation/corrosion and skin sensitization is used because no dose descriptors are available on these endpoints.

o  A quantitative approach for the derivation of DNELs of skin irritation/corrosion is used because TEA classified as corrosive to skin.

o  For the non-threshold endpoints (mutagenicity and carcinogenicity) no DNELs can be derived because a No-Effect Level could not be established from the relevant studies. Hence, the hazard characterization is based on a qualitative approach.

o  There is no animal data on repeated oral and dermal exposures. To cover these endpoints, data from an inhalation sub-chronic study in rats (Lynch et al., 1990) have been used.

First of all, available dose descriptors were converted into a correct starting point to take into account differences in routes of exposure between experimental animals and humans and differences in human and animal exposure conditions. Consecutively, the assessment factors have been applied to the correct starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.

The assessment factors are applied in accordance with ECETOC Technical Report No 86, referenced in Table R.8-19 of ECHA guidance document.

Modification of the relevant dose descriptors to the correct starting point:

Bioavailability (absorption)

TEA is readily absorbed via all exposure routes. Bioavailability for experimental animals and humans for all exposure routes was assumed to be the same because of the absence of information. 100% dermal absorption is assumed, based on the criteria set out in Annex IV-B of the EU Technical Guidance Document on Risk Assessment (TGD; 2003, Part I).

Route-to-route extrapolation:

o Inhalation-to-dermal extrapolation is performed to assess acute and long-term dermal effects in humans.

Exposure conditions:

o  Exposure times differed in the acute inhalation and repeated dose inhalation studies. The dose descriptors were corrected as described in the Appendix R.8-2.

o  Haber’s law was used to calculate the 15 -min starting point from 1 -hour LC50 value.

o The 1 -hour LC50 value was divided by a factor of 2 to obtain a 4 -hour LC50 value.

Respiratory volumes:

o  Differences in the respiratory volumes between experimental animals and humans were used when an inhalation NOAEC from a rat study was used to assess dermal and oral exposure in humans.

o  Differences in the respiratory volumes in humans under normal conditions and by light activity (6.7 m³ and 10 m³, respectively) were taken into account when calculating inhalatory DNELs in case of inhalation route of exposure in treated animals.

Applying of assessment factors:

Interspecies differences:

o  The species-specific default assessment factors of 2.4 for allometric scaling for rabbits was applied in case of calculation of a dermal DNEL from LD50 established in the acute dermal study in rabbits.

o  The species-specific default assessment factors of 4 for allometric scaling for rats was applied in case of inhalation-to-dermal extrapolation. The calculation of dermal DNELs for both acute (short-term) and long-term exposure was perfomed using inhalative LC50 or NOAEC, respectively, established in the inhalation studies .

o  No allometric scaling factor is applied in case of inhalation exposure routes in animals and in humans.

o  No additional assessment factors are applied for remaining interspecies differences.

 

Intraspecies differences: 

o  Assessment factors of 3 and 5 are applied for workers and for general population, respectively, for all endpoints and all exposure routes.

Extrapolation of duration: an assessment factor of 2 was applied in case of sub-chronic to chronic extrapolation.

 

Quality of whole data base:

 

o The assessment factor for uncertainties to the quality of the data base is regarded to be 1.

 

Issues related to dose response:

In case of LOAEC(L) to NOAEC(L) extrapolation, an assessment factor of 3 was applied.

Additional assessment factors:

Acute toxicity:

o  An uncertainty factor of 100 was applied to LC50 value to cover all possible effects by the acute exposures.

Calculation of endpoint-specific DNELs for workers

Acute/short-term exposure - systemic effects (dermal)

The available data on acute toxicity dermal (Meyers and Ballantyne, 1997) allows calculating a DNEL, which would be uncertain because of application of a large assessment factor of 100 for severity of effects to LD 50 value. (LD50 is 580 mg/kg bw, applying assessment factors of 720 (2.4 inter-(for rabbits), 3 -intraspecies and 100 for severity of effects), DNEL would be 0.80 mg/kg bw. This acute DNEL is lower than the long-term DNEL of 12.1 mg/kg bw for systemic dermal effects. Therefore, as an alternative to calculate an acute dermal DNEL, an acute LOAEC was identified in the acute inhalation study (International Research and Development Corporation, 1995). The LOAEC of 10,290 mg/m³ was the lowest concentration tested (based on 1ppm = 4.2 mg/m³). At this concentration, no mortalities, increased salivation, labored breathing in all animals and tremors in 1 of 5 males and in 1of 5 females were observed. Then using route-to-route extrapolation, a DNEL for acute dermal effects is calculated as follows:

1. The animals were exposed to TEA by inhalation during 1 hour. Therefore, the LOAEC is corrected to a dose descriptor representing 15 minutes exposure using the modified Haber's law (Gaylor, 2000):

in case of extrapolation from longer to shorter durations of exposure (C³ x t) = (C')³ x t', giving C' = C x (t/t')E0.333. C' is sought concentration. C' = 10,290 x (1h/0.25h)^0.333 = 16,334.4 mg/m³

2. Inhalation-to dermal extrapolation: 16,344.4 x 0.012 m³/kg bw = 196 mg/kg bw, where 0.012 is the respiratory volume of rats during 15 min.

3. DNEL = 196 mg/kg bw/(4 x 3 x 3) = 5.44 mg/kg bw. AFs are: 4 - inter (for rats), 3 - intraspecies, 3 - LOAEC to NOAEC. Such a DNEL is also uncertain because of extrapolation procedure and could be covered by a long-term DNEL (see below).

Acute/short-term exposure - systemic effects (inhalation)

An EU Indicative Occupational Exposure Limit (IOEL) of 3 ppm (12.6 mg/m³) currently exists. This value is for a short 15 min exposures. A scientific justification is required according to the REACh-guidance and understood as prerequisite to use such a value. The underlying health effect observed is corrosivity.

It is proposed to use the existing IOEL value of 3 ppm for the inhalation DNEL on the basis of the following:

A DNEL_short-termfor inhalation derived using LC₅₀value from the acute inhalation study in rats (International Research and Development Corporation, 1995) is similar to the existing OEL.

The conversion of the inhalatory rat LC50 into a corrected inhalatory LC50

was performed taken into account differences between experimental and human exposure conditions (rats were exposed 1 h to TEA and using Haber's law inhalation exposure was adjusted to 15 min, as described above) and differences in respiratory volumes of humans under standard conditions and under conditions of light activity: 1. LC50 = 3496 ppm = 14,439.2 mg/m³; C' = 14,439.2 x (1/0.25)^0.333 = 22,815.1; 2. Corrected LC50: 22,815.1 x 6.7/10 = 15,286.1 mg/m³;

3. DNEL = 15,286.1/(3 x 100) = 50.95 mg/m³. AFs are: 3 (intraspecies) x 100 (severity of effects). No allometric scaling factor is applied (inhalation-to-inhalation). This DNEL is much higher than the IOEL value established for TEA.

Using another approach of extrapolation 1 -hour LC50 value to a 4 -hour value outlined in the Guidance on the Application of Regulation (EC) No. 1272/2008, 1 -hour LC50 of 3496 ppm should be divided by a factor of 2 resulting in 1748 ppm (7220 mg/m³). In this case the corrected LC50 would be: 7220 mg/m³ x 6.7/10 = 4,837.4 mg/m³. Herefrom the resulting DNEL = 4,837.4 mg/m³/(3 x 100) = 16.12 mg/m³. This DNEL is very similar to the IOEL value of 12.6 mg/m³. Taken into account uncertainties originated from the use of a high factor of 100 and considering a high priority of IOEL value compared to a calculated value, the IOEL value of 12.6 mg/m³ is considered to be a DNEL for short-term exposures. 

Acute/short-term exposure - local effects (dermal)

TEA is classified as a corrosive substance, therefore a separate DNEL for acute local effects is needed. An irritation specific DNEL for the local effects could be derived from dermal acute, sub-acute or sub-chronic studies in animals (Appendix R.8-9). However, in the available acute dermal studies on TEA, a poor dose-response information is available. A LD50 value is close to the lowest concentration tested (Meyers and Ballantyne, 1997). There is no repeated dose dermal toxicity data on TEA from that a non-irritant dose/concentration could be derived. A qualitative approach to assessing and controlling the risks is more appropriate in this case.

Acute/short-term exposure - local effects (inhalation)

The LOAEC of 2450 ppm (10,290 mg/m³) from the acute inhalation study (International Research and Development Corporation, 1995) was taken as a dose descriptor starting point for setting of a DNEL for local effects. The LOAEC was modified only for differences in respiratory volumes in case of working humans (6.7/10) as suggested in AppenixR.8 -9:

DNEL = 10,290 x (6.7/10) / (3 x 10) = 230 mg/m³. AFs are: 3 (intraspecies) x 10 (LOAEC to NOAEC). IOEL value for short-term acute effects is about twenty-fold lower than the calculated value and is more appropriate to ensure of controlling risk. Therefore, the IOEL value is taken as a DNEL to cover this endpoint.

Long-term exposure - systemic effects (dermal)

NOAEC of 1020 mg/m³ from the repeated dose toxicity inhalation study in rats (Lynch et al., 1990) was taken for the DNEL derivation:

1. Corrected NOAEL = NOAEC x 0.38 m³/kg bw/day x (6h/8h) = 1020 mg/m³ x 0.38 x 0.75 = 290.7 mg/kg bw/day;

2. DNEL = 290.7/(4 x 3 x 2) = 12.1 mg/kg bw/day.

Long-term exposure - systemic effects (inhalation)

Repeated dose toxicity inhalation study in rats (Lynch et al., 1990) was taken for the DNEL derivation:

1. Corrected NOAEC = NOAEC x (6h/8h) x (6.7/10) = 1020 x 0.75 x 0.67 = 512.6 mg/m³

2. DNEL = 512.6/ (3 x 2) = 85.4 mg/m³. The IOEL value of 8.4 mg/m³ also exists for long-term exposures by inhalation. This value is ten-fold lower as the calculated value and ensures rather controlling of risk.

Long-term exposure - local effects (dermal)

There is no route specific information on this endpoint. A qualitative risk characterization would be more appropriate.

Long-term exposure - local effects (inhalation)

Repeated dose toxicity inhalation study in rats (Lynch et al., 1990) was taken for the DNEL derivation:

1. Corrected NOAEC = 1020 mg/m³ x 0.67 = 683.4 mg/m³. No further modifications of the starting point were performed (as suggested in the Appendix R.8 -9);

2. DNEL = 683.4/3 = 227.8 mg/m³. AF is 3 for intraspecies (workers).

As in case of long-term systemic effects, the IOEL value would be cover sufficient this endpoint and ensure that no effects on respiratory tract will occur.

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure

DNEL related information

Additional information - General Population

DNELs for general population/consumers are not relevant since no consumer use is intended.