Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC TR 110
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
BMCL10
Value:
18.7 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by inhalation. The recommended approach using oral data and assuming the same absorption for inhalation and oral route is used. For details, please refer to the discussion.
AF for dose response relationship:
1
Justification:
No assessment factor required, due to BMD approach
AF for differences in duration of exposure:
1
Justification:
No time extrapolation factor is needed since a chronic toxicity study is available.
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
1
Justification:
NTA and its salts are not metabolized and rapidly excreted. There is no evidence for species differences in the general mode of action or kinetics.
AF for intraspecies differences:
5
Justification:
Intraspecies differences of worker are considered to be fully covered by the selected factor.
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:
DNEL (Derived No Effect Level)
Value:
11.2 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
3
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
169.6 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC TR 110
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
BMDL10
Value:
848 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated dermal exposure. Since experimental investigations have shown that oral absorption is lower than 20 % and dermal absorption lower than 0,1 % DNEL is derived assuming 200 times lower absorption via the dermal route (end route) as compared to oral route (starting route).
AF for dose response relationship:
1
Justification:
No assessment factor required due to BMD approach.
AF for differences in duration of exposure:
1
Justification:
No time extrapolation factor is needed since a chronic toxicity study is available.
AF for interspecies differences (allometric scaling):
1
Justification:
No assessment factor for allometric scaling is used since experimental investigations have shown that absorption of the test item in humans is four times lower than in rat. For further details please refer to the discussion.
AF for other interspecies differences:
1
Justification:
NTA and its salts are not metabolized and rapidly excreted. There is no evidence for species differences in the general mode of action or kinetics.
AF for intraspecies differences:
5
Justification:
Intraspecies differences of worker are considered to be fully covered by the selected factor.
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
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

General

 

DNEL derivation for the substance is performed under consideration of the recommendations of ECHA REACH Guidance (2010) and ECETOC (2003). In view of the data used for evaluation, the "quality of whole database factors" is considered to amount to a value of 1, and is thus not shown in the calculations presented below. No assessment factor for exposure duration is needed since the dose descriptor of a chronic study is used for DNEL derivation.

 

Acute/short-term and long-term exposure - local effects

Skin irritation/corrosion and sensitization: The test item has no skin irritation potential in an acute skin irritation test available. Further, no skin sensitization potential could be observed in a Buehler test (BASF, 1997). Thus no DNEL for local effects was derived.

 

Eye irritation: The test item is classified for eye irritation according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP). However, based on the study, no DNEL can be derived as no dose-response curve is available. Thus, a qualitative risk assessment must be conducted.

 

Respiratory irritation: No effects on respiratory system were observed in a short-term inhalation study with the trisodium salt of the test item (TNO, 2007). Therefore, no DNEL for effects on respiratory system was derived.

Long-term exposure – systemic effects

Systemic toxicity after repeated exposure with the test item was assessed in a read-across approach to trisodium-NTA (CAS 5064-31-3). In an oral 2 -year chronic/carcinogenicity rat study (NCI, 1977) trisodium nitrilotriacetate was tested at diet concentrations of 0, 200, 2,000, and 20,000 ppm (approx. 0, 9, 92, 921 mg nitrilotriacetate/kg bw/d). Although a NOAEL for toxic lesions could be estimated to 2,000 ppm (92 mg/kg bw/d), at this dose preneoplastic lesions in rats were increased. Hyperplasias that were observed also at lower dose levels were interpreted as the relevant toxic effect and serve as basis for the assessment of repeated dose toxicity. In this regard it was preferred to use a BMD value, calculated for the increase of hyperplasias (benchmark response), rather than using the NOAEL/LOAEL approach. According to the Risk Assessment for trisodium nitriloacetate of the Federal Institute for Occupational Safety and Health (2008),abenchmark dose was calculated using the U.S.EPA BMD software (Version 1.3.2). Data fitted best when the Gamma Multi-Hit model was applied (AIC criterium 46.7).The benchmark dose lower bound (BMDL) where a treatment-related increase in response of 10% could not be expected within the 95% confidence interval on the BMD for trisodium nitriloacetate was 5.7 mg/kg bw/d. It was proposed to use this value as starting point for quantitative risk characterisation.

 

M (trisodium salt) = 257.13 g/mol

M (test item) = 191.14 g/mol

Factor: 1.35

 

Corrected BMDL10 for the test item

= 5.7 mg/kg bw/d / 1.35

= 4.24 mg/kg bw/d

 

Inhalation exposure:

Considering the appropriate modification and assessment factors, the worker DNEL (long-term, inhalation exposure) is calculated as follows:

 

- Modification of the starting point

Relevant dose descriptor (BMDL10): 4.24 mg/kg bw/ day

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/day

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 50% / 20%

Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

 

Corrected inhalatory BMCL for workers

= 4.24 mg/kg bw/day × (1 / 0.38 m³/kg bw/day) × 50% / 20% × (6.7 m³/10 m³)

= 18.68 mg/m³

 

- Calculation of the worker DNEL

Corrected inhalatory BMCL10 for workers: 18.68 mg/m³

 

Assessment factor for intraspecies differences (worker): 5

 

Worker DNEL (long-term inhalation exposure)

= 18.68 mg/m³ / 5

= 3.74 mg/m³

 

Dermal exposure:

In order to derive the worker DNEL (long-term dermal exposure), a read-across approach to trisodium-NTA (CAS 5064-31-3) was used. The BMDL10 was calculated as described above from the 2 year repeated dose oral toxicity study (NCI, 1977) and was identified as the relevant dose descriptor. Experimental investigations have shown that oral absorption in humans is about 20 % (Budny & Arnold, 1973). Additionally, an in vitro study revealed a dermal absorption of the test item lower than <0.1% (BASF, 2008). Thus, dermal absorption is 200 times lower than oral absorption and the BMDL10 was multiplied with a factor of 200. No AF for allometric scaling was used as experimental investigations have shown that oral absorption in humans is 4 times lower than in the rat (Budny & Arnold, 1973). Considering the appropriate modification and assessment factors, the worker DNEL (long-term dermal exposure) is calculated as follows:

 

- Modification of the dose descriptor:

Dose descriptor of relevant study: 4.24 mg/kg bw/d (BMDL10)

Ratio between oral and dermal absorption: 200

= 4.24 mg/kg bw/d × 200 = 848 mg/kg bw/day

 

Relevant dose descriptor (BMDL10): 848 mg/kg bw/day

 

Assessment factor for intraspecies differences (worker): 5

 

Worker DNEL (long-term dermal exposure)

= 848 mg/kg bw/day / 5

= 169.6 mg/kg bw/day

 

Short-term exposure- systemic effects:

The key effects of the test item are focal cytotoxicity in renal tubular cells and bladder epithelium which may be observed even after single exposure and therefore have a meaning also for the acute DNEL.

 

Inhalation exposure:

The derivation of the worker DNEL (short-term, inhalation exposure) was based on the worker DNEL (long-term, inhalation exposure) which was modified as follows:

 

Worker DNEL (long-term, inhalation exposure): 3.74 mg/m3

Default value for extrapolation from long-term to short-term DNEL: 3

 

Worker DNEL (short-term, inhalation exposure):

= 3.74 mg/m3× 3

= 11.2 mg/m3

 

 

References

(not included as endpoint study record)

 

- ECHA (2010). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health.Version 2. ECHA-2010 -G-19 –EN.

 

- ECETOC (2010). Technical Report 110. Guidance on assessment factors to derive a DNEL.

 

- Budny JA, Arnold FD. Nitrilotriacetate (NTA): human metabolism and its importance in the total safety evaluation program. Toxicology and applied pharmacology, 1973, 15:48-53. - Risk Assessment for trisodium nitriloacetate of the Federal Institute for Occupational Safety and Health (BAuA, 2008)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
BMCL10
Value:
9.2 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by inhalation. The recommended approach using oral data and assuming the same absorption for inhalation and oral route is used. For details, please refer to the discussion.
AF for dose response relationship:
1
Justification:
No assessment factor required due to BMD approach.
AF for differences in duration of exposure:
1
Justification:
No time extrapolation factor is needed since a chronic toxicity study is available.
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
1
Justification:
NTA and its salts are not metabolized and rapidly excreted. There is no evidence for species differences in the general mode of action or kinetics.
AF for intraspecies differences:
10
Justification:
Intraspecies differences of general population are considered to be fully covered by the selected factor.
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:
DNEL (Derived No Effect Level)
Value:
2.7 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
3
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
84.8 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
BMDL10
Value:
848 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated dermal exposure. Since experimental investigations have shown that oral absorption is lower than 20 % and dermal absorption lower than 0,1 % DNEL is derived assuming 200 times lower absorption via the dermal route (end route) as compared to oral route (starting route).
AF for dose response relationship:
1
Justification:
No assessment factor required due to BMD approach.
AF for differences in duration of exposure:
1
Justification:
No time extrapolation factor is needed since a chronic toxicity study is available.
AF for interspecies differences (allometric scaling):
1
Justification:
No assessment factor for allometric scaling is used since experimental investigations have shown that absorption of the test item in humans is four times lower than in rat. For further details please refer to the discussion.
AF for other interspecies differences:
1
Justification:
NTA and its salts are not metabolized and rapidly excreted. There is no evidence for species differences in the general mode of action or kinetics.
AF for intraspecies differences:
10
Justification:
Intraspecies differences of general population are considered to be fully covered by the selected factor.
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:
DNEL (Derived No Effect Level)
Value:
254.4 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
0.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
BMDL10
Value:
4.2 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is necessary since a repeated dose oral toxicity study is available.
AF for dose response relationship:
1
Justification:
No assessment factor required due to BMD approach.
AF for differences in duration of exposure:
1
Justification:
No time extrapolation factor is needed since a chronic toxicity study is available.
AF for interspecies differences (allometric scaling):
1
Justification:
No assessment factor for allometric scaling is used since experimental investigations have shown that absorption of the test item in humans is four times lower than in rat. For further details please refer to the discussion.
AF for other interspecies differences:
1
Justification:
NTA and its salts is not metabolized and rapidly excreted. There is no evidence for species differences in the general mode of action or kinetics.
AF for intraspecies differences:
10
Justification:
Intraspecies differences of general population are considered to be fully covered by the selected factor.
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
Most sensitive endpoint:
acute toxicity
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 the substance is performed under consideration of the recommendations of ECHA REACH guidance (2010) and ECETOC (2003). In view of the data used for evaluation, the "quality of whole database factors" is considered to amount to a value of 1, and is thus not shown in the calculations presented below. No assessment factor for exposure duration is needed since the dose descriptor of a chronic study is used for DNEL derivation.

Acute/short-term and long-term exposure - local effects

Eye irritation: The test item is classified for eye irritation according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP). However, as the concentration of the test item is limited to 5 % in consumer products and articles no adverse effect for the eyes is expected.

 

Long-term exposure – systemic effects

Systemic toxicity after repeated exposure with the test item was assessed in a read-across approach to trisodium-NTA (CAS 5064-31-3). In an oral 2 -year chronic/carcinogenicity rat study (NCI, 1977) trisodium nitrilotriacetate was tested at diet concentrations of 0, 200, 2,000, and 20,000 ppm (approx. 0, 9, 92, 921 mg nitrilotriacetate/kg bw/d). Although a NOAEL for toxic lesions could be estimated to 2,000 ppm (92 mg/kg bw/d), at this dose preneoplastic lesions in rats were increased. Hyperplasias that were observed also at lower dose levels were interpreted as the relevant toxic effect and serve as basis for the assessment of repeated dose toxicity. In this regard it was preferred to use a BMD value, calculated for the increase of hyperplasias (benchmark response), rather than using the NOAEL/LOAEL approach. According to the Risk Assessment for trisodium nitriloacetate of the Federal Institute for Occupational Safety and Health (2008), a benchmark dose was calculated using the U.S.EPA BMD software (Version 1.3.2). Data fitted best when the Gamma Multi-Hit model was applied (AIC criterium 46.7). The benchmark dose lower bound (BMDL) where a treatment-related increase in response of 10% could not be expected within the 95% confidence interval on the BMD for trisodium nitriloacetate was 5.7 mg/kg bw/d. It was proposed to use this value as starting point for quantitative risk characterisation.

 

M (trisodium salt) = 257.13 g/mol

M (test item) = 191.14 g/mol

Factor: 1.35

Corrected BMDL10 for the test item

= 5.7 mg/kg bw/d / 1.35

= 4.24 mg/kg bw/d

 

Inhalation exposure:

Considering the appropriate modification and assessment factors, the general population DNEL (long-term, inhalation exposure) is calculated as follows:

 

- Modification of the starting point

Relevant dose descriptor (BMDL10): 4.24 mg/kg bw/ d

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m³/kg bw/day

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 50% / 20%

 

Corrected inhalatory BMCL10 for general population

= 4.24 mg/kg bw/day × (1 / 1.15 m³/kg bw/day) × 50% / 20%

= 9.22 mg/m³

 

- Calculation of the general population DNEL

Corrected inhalatory BMCL10 for general population: 9.22 mg/m³

Assessment factor for intraspecies differences (general population): 10

 

General population DNEL (long-term inhalation exposure)

= 9.22 mg/m³ / 10

= 0.9 mg/m³

 

Dermal exposure:

In order to derive the worker DNEL (long-term dermal exposure), a read-across approach to trisodium-NTA (CAS 5064-31-3) was used. The BMDL10 was calculated as described above from the 2 year repeated dose oral toxicity study (NCI, 1977) and was identified as the relevant dose descriptor. Experimental investigations have shown that oral absorption in humans is about 20 % (Budny & Arnold, 1973). Additionally, an in vitro study revealed a dermal absorption of the test item lower than <0.1% (BASF, 2008). Thus, dermal absorption is 200 times lower than oral absorption and the BMDL10 was multiplied with a factor of 200. No AF for allometric scaling was used as experimental investigations have shown that oral absorption in humans is 4 times lower than in the rat (Budny & Arnold, 1973) Considering the appropriate modification and assessment factors, the general population DNEL (long-term dermal exposure) is calculated as follows:

 

- Modification of the dose descriptor:

Dose descriptor of relevant study: 4.24 mg/kg bw/d (BMDL10)

Ratio between oral and dermal absorption: 200

= 4.24 mg/kg bw/d × 200 = 848 mg/kg bw/day

 

Relevant dose descriptor (BMDL10): 848 mg/kg bw/day

Assessment factor for intraspecies differences (general population): 10

 

General population DNEL (long-term dermal exposure)

= 848 mg/kg bw/d / 10

= 84.8 mg/kg bw/day

Oral exposure:

In order to derive the general population DNEL (long-term, oral), the BMDL10 that was calculated from a 2 year repeated dose oral toxicity study with trisodium nitriloacetate as described above (NCI, 1977) is identified as the relevant dose descriptor. Since experimental investigations have shown that absorption of the test item in humans is 4 times lower than that of rat, the AF for allometric scaling was considered to be negligible (Budney & Arnold 1973). The general population DNEL (long-term oral exposure) is calculated as follows:

 

Relevant dose descriptor (BMDL10): 4.24 mg/kg bw/day

 

Assessment factor for intraspecies differences (general population): 10

 

General population DNEL (long-term oral exposure)

= 4.24 mg/kg bw/day / 10

= 0.42 mg/kg bw/day

 

Short-term exposure – systemic effects

The key effects of the test item are focal cytotoxicity in renal tubular cells and bladder epithelium which may be observed even after single exposure and therefore have a meaning also for the acute DNEL.

Inhalation exposure:

The inhalation exposure is assumed to be relevant for the general population only for occasional consumer exposure scenarios. The derivation of the general population DNEL (short-term, inhalation exposure) was based on the general population DNEL (long-term, inhalation exposure) which was modified as follows:

 

General population DNEL (long-term, inhalation exposure): 0.9 mg/m3

Default value for extrapolation from long-term to short-term DNEL: 3

 

General population DNEL (short-term, inhalation exposure):

= 0.9 mg/m3× 3

= 2.7 mg/m3

 

Dermal exposure:

The dermal exposure is assumed to be relevant for the general population only for occasional consumer exposure scenarios. The derivation of the general population DNEL (short-term, dermal exposure) was based on the general population DNEL (long-term, dermal exposure) which was modified as follows:

 

General population DNEL (long-term, dermal exposure): 84.8 mg/kg bw/day

Default value for extrapolation from long-term to short-term DNEL: 3

 

General population DNEL (short-term, dermal exposure):

= 84.8 mg/kg bw/day × 3

= 254.4 mg/kg bw/day

 References

(not included as endpoint study record)

 

- ECHA (2010). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2. ECHA-2010 -G-19 –EN.

 

- ECETOC (2010). Technical Report 110. Guidance on assessment factors to derive a DNEL.

 

- Budny JA, Arnold FD. Nitrilotriacetate (NTA): human metabolism and its importance in

the total safety evaluation program. Toxicology and applied pharmacology, 1973, 15:48-53.

 

-  Risk Assessment for trisodium nitriloacetate of theFederal Institute for Occupational Safety and Health (BAuA, 2008)