1,1',1''-nitrilotripropan-2-ol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

86 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor starting point:

NOAEL

Value:

272 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

863 mg/m³

Explanation for the modification of the dose descriptor starting point:

Starting point is a NOAEL of 272 mg/kg bw. A factor 0.9 (90/100) is applied for route to route extrapolation, oral to inhalation. An 8h respiratory volume of 0.19 m3/kg bw for dogs is used for conversion (calculated according to AIT recommended method (Alexander et al. (2008), Inhal Toxicol 20, 1179 -1189), default bodyweight values were used). Correction for activity driven difference of respiratory volumes in workers compared to workers in rest are used.

272 mg/kg * (90/100) * (1/0.19) * (6.7/10) = 863.0 mg/m3

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEC, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker 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. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-chronic toxicity study is available, default assessment factor of 2 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, as long as route-to-route extrapolation is not needed, allometric scaling should not be applied in cases where doses in experimental animal studies are expressed as concentrations (e.g. in mg/m3 air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate. In this case the NOAEC is expressed as concentration (mg/m3), therefore a factor for allometric scaling is not needed.

AF for other interspecies differences:

1

Justification:

TIPA is known to be rapidly absorbed and excreted primarily unmetabolized in the urine. Therefore, metabolic rate and systemic absorption are minimal factors for a potential adverse systemic effect. Besides, after repeated oral exposure of high doses of TIPA in the dog and the rat either no observed effects or adaptive effects were observed.
Following ECHA guidance R.8: Characterisation of dose [concentration]-response for human health from 2012, exclusion of tissue metabolism driving the ultimate toxic response, enables to reduce remaining uncertainties for toxicokinetic and toxicodynamic from 2.5 to 1.

AF for intraspecies differences:

5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. This results in recommended default assessment factor of 10 for the general population. As the worker population is more homogeneous (i.e. younger, healthier, protected from exposures), a default assessment factor of 5 is recommended.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

There are no remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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:

50 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):

60

Dose descriptor starting point:

NOAEL

Value:

3 000 mg/kg bw/day

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

3

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker 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. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available a correction factor needs to be used. Since the material is soluble and unlikely to accumulate (Log Pow = -0.015) the sub-acute to sub-chronic assessment factor is considered 1.5 rather than the default 3 (Bitsch et al. (2006), Regul Toxicol Pharmacol 46, 202-210). Combination with with the default sub-chronic to chronic factor 2 leads to a correction factor of 3.

AF for interspecies differences (allometric scaling):

4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results a default allometric scaling factor for the rats when compared with humans, namely 4. In ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a similar approach is followed. Toxicokinetic differences can be explained by basal metabolic rate which can be accounted for by allometric scaling. The underlying principle is that due to the faster metabolic rate of small animals, humans would less effectively detoxify and/or excrete xenobiotics than laboratory animals and thus are more vulnerable. The allometric scaling factor for the rats versus humans is 4.

AF for other interspecies differences:

1

Justification:

TIPA is known to be rapidly absorbed and excreted primarily unmetabolized in the urine. Therefore, metabolic rate and systemic absorption are minimal factors for a potential adverse systemic effect. Besides, after repeated dermal exposure of high doses of TIPA in the rat no effects were observed.
Following ECHA guidance R.8: Characterisation of dose [concentration]-response for human health from 2012, exclusion of tissue metabolism driving the ultimate toxic response, enables to reduce remaining uncertainties for toxicokinetic and toxicodynamic from 2.5 to 1.

AF for intraspecies differences:

5

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. This results in recommended default assessment factor of 10 for the general population. As the worker population is more homogeneous (i.e. younger, healthier, protected from exposures), a default assessment factor of 5 is recommended.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

There are no remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

According to the REACH “Guidance on information requirements and chemical safety assessment”, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

 

Kinetics (absorption figures for oral, dermal and inhalation route of exposure)

No data on inhalation absorption are available. Therefore for the DNEL derivation the default as reported in the REACH guidance will be used, i.e. 100%.

Orally administered TIPA was rapidly and extensively absorbed by the rat. The principle route of excretion was urine, which contained 81-85% of the total dose, 3-5% was eliminated as14CO2 and <2% was recovered in the tissues/carcass and final cage wash. The amount of 14C in the traps for volatile organics was negligible. Therefore, an oral absorption percentage of 90% is assumed for TIPA (feces contained 4-7%).

For dermal absorption, the specific DIPA figure will be used (20%). This is considered a worst case scenario since DIPA is a smaller molecule and therefore expected to penetrate the skin more readily than the larger TIPA molecule.

Long-term, systemic effects, inhalation   

The derivation of a POD for the most sensitive effect for the inhalation route is based on the results of the highest dose from a repeated dose toxicity study in dogs due to its most sentive derived no exposure limit (DNEL).

Besides, no adverse effects were observed in the reproductive toxicity study, according to US FDA guidelines.

For comparison, the NOAEL from the developmental toxicity study in rabbits, according to OECD 414, is used as to derive a an inhalatory DNEL:

Considering the NOEAL from the key reproduction oral toxicity study in rabbits as relevant dose descriptor and taking the starting point modification and assessment factors into account, the worker DNEL can be calculated as follows:

(following the ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health)

Relevant dose descriptor (NOAEL): 440 mg/kg bw/d

Modification for the absorption differences: experimentally derived oral absorption 90% / inhalatory conservative absorption 100%

Modification of respiratory volume: 1/0.23 (6.7 m3/person/8h human / 70 kg * allometric scaling rabbit = 0.0957*2.4)

Modification for light activity at work: 0.67 (human resting respiratory volume / human light activity respiratory volume = 6.7 m3/kg bw/8h / 10 m3/kg bw/8h)

NOAEC = 440 mg/kg * (90/100) * (1/0.23) * (6.7/10) = 1153 mg/m3

Intrapecies factor (rabbit-to-worker): 5

Intrerspecies factor: 1 (The AF has already been handled within the correction of the modification of the dose descriptor. Therefore, no additional factor has to be applied. Besides, allometric scaling should not be applied in cases where doses in experimental animal studies are expressed as concentrations (e.g. in mg/m3 air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate.)

Exposure duration factor: 1 (no time extrapolation is required for developmental toxicity as increasing exposure duration does not increase the incidence or severity of adverse effects)

Extrapolation factor (NOAEC): 1

Quality of database factor: 2 (POD is based on a read across approach

worker DNEL (long-term inhalation exposure) = 1153 mg/m3 /(2 × 5) = 115 mg/m3

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

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:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

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:

9.7 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):

28

Dose descriptor starting point:

NOAEL

Value:

272 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

272 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A modification of the POD (NOAEL) is not essential as no route-to-route extrapolation is performed.

AF for dose response relationship:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose…) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

2

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker 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. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-chronic toxicity study is available, default assessment factor of 2 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

1.4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results a default allometric scaling factor for the dog when compared with humans, namely 1.4. In ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a similar approach is followed. Toxicokinetic differences can be explained by basal metabolic rate which can be accounted for by allometric scaling. The underlying principle is that due to the faster metabolic rate of small animals, humans would less effectively detoxify and/or excrete xenobiotics than laboratory animals and thus are more vulnerable. The allometric scaling factor for the dog versus humans is 1.4.

AF for other interspecies differences:

1

Justification:

TIPA is known to be rapidly absorbed and excreted primarily unmetabolized in the urine. Therefore, metabolic rate and systemic absorption are minimal factors for a potential adverse systemic effect. Besides, after repeated oral exposure of high doses of TIPA in the dog and the rat either no observed effects or adaptive effects were observed.
Following ECHA guidance R.8: Characterisation of dose [concentration]-response for human health from 2012, exclusion of tissue metabolism driving the ultimate toxic response, enables to reduce remaining uncertainties for toxicokinetic and toxicodynamic from 2.5 to 1.

AF for intraspecies differences:

10

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. This results in recommended default assessment factor of 10 for the general population.

AF for the quality of the whole database:

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.

AF for remaining uncertainties:

1

Justification:

There are no remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

Although there are no consumer uses for TIPA, CAS 122-20-3, the systemic long-term oral DNEL for the general population is necessary for the assessment of indirect exposure of humans via the environment (ECHA GD R.16, v 3.0, Feb 2016).