N,N,N',N'-tetrakis(2-hydroxypropyl)adipamide

Endpoint summary

Description of key information

Under the experimental conditions, the NOAEL of specific target organ toxicity is concluded to be 1000 mg/kg bw/day from 28-day toxicity study in rats.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

A deduction from Klimisch 1 (reliable without restrictions) to Klimisch 2 (reliable with restrictions) was made to appreciate read-across uncertainties.

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The source substance N,N,N',N'-tetrakis(2-hydroxyethyl) hexanediamide (EC 405-370-0) used for read-across and the target substance N,N,N',N'-tetrakis(2-hydroxypropyl) hexanediamide (EC 260-982-3) do share a common functional group (two bis 2-hydroxyalkylamide functions) and both are manufactured by reacting a hexanedioic acid through an amidation reaction with either bis-2-hydroxyethyl amine or bis-2-hydroxypropyl amine to a N,N,N',N'-tetrakis(2-hydroxyalkyl) hexanediamide (see also attached file "Comparison_Hydroxypropyl_Hydroxyethyl_20221121.pdf").

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Data derived with the source substance N,N,N',N'-tetrakis(2-hydroxyethyl) hexanediamide (EC 405-370-0) are used for read-across to the target substance N,N,N',N'-tetrakis(2-hydroxypropyl) hexanediamide (EC 260-982-3) as outlined and justified in the attached file "Comparison_Hydroxypropyl_Hydroxyethyl_20221121.pdf". Purity and impurity profile of source and target substance are absolutely comparable.

3. ANALOGUE APPROACH JUSTIFICATION
Please see attached file "Comparison_Hydroxypropyl_Hydroxyethyl_20221121.pdf"

4. DATA MATRIX
Please see attached file "Comparison_Hydroxypropyl_Hydroxyethyl_20221121.pdf"

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

not specified

Conclusions:

In conclusion from three repeated dose studies by oral exposure, applying dose levels of up to 1000 mg N,N,N',N'-tetrakis(2-hydroxyethyl) hexanediamide /kg bw/d the results indicate consistently that the no-observed-adverse-effect level (NOAEL) of the test article is 1000 mg/kg bw/d and above for males and females and this result can be carried forward being representative also for N,N,N',N'-tetrakis(2-hydroxypropyl) hexanediamide.

Executive summary:

The purpose of the existing studies with the source substance N,N,N',N'-tetrakis(2-hydroxyethyl) hexanediamide was to characterize the potential toxic effects due to repeated oral administration of test article to Sprague-Dawley rats of both sexes for repeated exposure at dose levels of 0, 10, 100 and 1000 as well as of 0, 8, 40, 200 and 1000 mg/kg by/d to assess the toxicity of the test substance. Also, reproductive effects were investigated in a one-generation reproductive toxicity stud with 11 weeks pre-mating period (total exposure time 21 weeks for males and females).

Clinical observation, body weight, food consumption, haematological tests, blood chemistry tests, urinalysis, organ weight, necropsy and histopathologic examination revealed no changes attributable to the administration of the test substance. Thus, it can be concluded that test article does not cause significant adverse effects by oral application to the rats and no systemic toxicity was seen to any organs. Thus, the NOAEL in all three studies was set at the high dose level of 1000 mg/kg bw/d.

Hence, it can be reasonably assumed, as justified, to assume likewise absence of systemic toxicity to exposure to N,N,N',N'-tetrakis(2-hydroxypropyl) hexanediamide.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

As the proportion of test item having an inhalable particles size of less than 100 µm was determined to be 7.32%, it is reasonable to expect that the inhalation route will not be a significant exposure route to the test material. Moreover, since oral route is considered to be the most likely exposure, there is no safety assessment concern for the inhalation and dermal route.

The 28-day oral toxicity study (Kashima Laboratory, 1998) was performed to assess the toxicity potential of test article, structural analogue of target article due to repeated oral administration of test article to Sprague-Dawley rats of both sexes for 28 days at dose levels of 0, 8, 40, 200 and 1000 mg/kg bw/d. In this study, clinical observation, body weight, food consumption, haematological tests, urinalysis, organ weight, necropsy and histopathologic examination revealed no changes attributable to the administration of the test substance. Thus, it was concluded that test article did not cause significant adverse effects by oral application to the rats for 28 days. Another study (James A. Edwards, et al. 1990) supported the results as above. The NOAEL of specific target organ toxicity (STOT) was also determined to be 1000 mg/kg/day.

Therefore, it is concluded that the NOAEL for STOT is considered to be 1000 mg/kg bw/day.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

As the proportion of test item having an inhalable particles size of less than 100 µm was determined to be 7.32%, it is reasonable to expect that the inhalation route will not be a significant exposure route to the test material. Thus, there is no safety assessment concern for this route.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:

As the proportion of test item having an inhalable particles size of less than 100 µm was determined to be 7.32%, it is reasonable to expect that the inhalation route will not be a significant exposure route to the test material. Thus, there is no safety assessment concern for this route.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

Since oral route is considered to be the most likely exposure, there is no safety assessment concern for this route.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:

Since oral route is considered to be the most likely exposure, there is no safety assessment concern for this route.

Justification for classification or non-classification

Based on the available data, test article failed to cause adverse toxicity at doses up to 1000 mg/kg bw/day during sub-acute test period. Thus, target article is not to be classified for the specific target organ toxicity according to CLP (Regulation EC No. 1272/2008).