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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

one-generation reproductive toxicity

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

Species:

rat

Dose descriptor:

NOAEL

Effect level:

20 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

20 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Reproductive effects observed:

not specified

Conclusions:

No treatment related reproductive toxicity was observed when rats were exposed to the test article N,N,N',N'-tetrakis(2-hydroxyethyl) hexanediamide in the diet at concentrations up to and including 20,000 ppm (>1000 mg/kg/day). These results are considered adequate also for the structurally similar substance N,N,N',N'-tetrakis(2-hydroxypropyl) hexanediamide.

Executive summary:

The purpose of this study was to investigate the effects of N,N,N',N'-tetrakis(2-hydroxyethyl) hexanediamide on growth, development and reproductive performance in male and female rats through production of one generation of offspring.

Based on the results of a preliminary range-finding study in male rats, a limit concentration of 20’000 ppm (target dose of 1’000 mg/kg) test article was selected as the high dose level for the reproductive study. Rats were exposed to test article in the diet at concentrations of 0, 1’000, 4’500 and 20’000 ppm beginning at approximately six weeks of age. Animals were mated after eleven weeks of exposure; treatment continued throughout gestation, lactation, and until terminal necropsy. No treatment-related effects on mortality, body weight or feed consumption were observed in either sex.

There were no treatment-related effects on any reproductive endpoints including number of litters produced, gestation length, mating and fertility indices (in both sexes), and gestation index. There were no treatment-related effects on number of live born or stillborn pups per litter, postnatal survival viability and lactation indices or growth. No treatment-related gross findings were observed in the parental animals or offspring at any dose. In addition, no treatment-related microscopic changes were observed in the organs examined from parental animals treated with 20’000 ppm. At 20’000 ppm, indications of toxicity were limited to soft and/or irregular feces in both sexes. Based on the available data, it is concluded that reproductive toxicity was not observed at doses up to and including 20’000 ppm.

Considering the structural similarity and comparable purity/impurity profile as well as phys-chem and tox data to N,N,N',N'-tetrakis(2-hydroxypropyl) hexanediamide, it is justified to read-across same finding to this target substance.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

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

 

The test substance N,N,N',N'-tetrakis(2-hydroxyethyl) hexanediamide is accepted as the structural analogue of target substance N,N,N',N'-tetrakis(2-hydroxypropyl) hexanediamide. A one-generation study (D.L Shuey, 1994) was available for read-across to investigate the effects of the test substance N,N,N',N'-tetrakis(2-hydroxyethyl) hexanediamide on growth, development and reproductive performance in male and female rats through production of one generation of offspring.

 

Based on the results of a preliminary range-finding study in male rats, a limit concentration of 20’000 ppm (target dose of 1’000 mg/kg) test article was selected as the high dose level for reproductive study. Rats were exposed to the test article in the diet at concentrations of 0, 1’000,4’500 and 20’000 ppm beginning at approximately six weeks of age. Animals were mated after eleven weeks of exposure; treatment continued throughout gestation, lactation, and until terminal necropsy. No treatment-related effects on mortality, body weight or feed consumption were observed in either sex.

There were no treatment-related effects on any reproductive endpoints including number of litters produced, gestation length, mating and fertility indices (in both sexes), and gestation index. There were no treatment-related effects on number of live born or stillborn pups per litter, postnatal survival viability and lactation indices) or growth. No treatment-related gross findings were observed in the parental animals or offspring at any dose. In addition, no treatment-related microscopic changes were observed in the organs examined from parental animals treated with 20’000 ppm. At 20’000 ppm, indications of toxicity were limited to soft and/or irregular feces in both sexes. Based on the available data, it is concluded that reproductive toxicity was not observed at doses up to and including 20’000 ppm. Therefore, it is concluded that the NOAEL of target article for the reproductive toxicity is 1’000 mg/kg bw/day resulting from this one-generation reproductive toxicity study.

 

Short description of key information:

No treatment related reproductive toxicity was observed when rats were exposed to test article in the diet at concentrations up to and including 20’000 ppm (1’000mg/kg bw/day).

Effects on developmental toxicity

Description of key information

There was no evidence on developmental toxicity at dosage levels up to 1’000 mg/kg bw/day from the one-generation reproductive toxicity study.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available (further information necessary)

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Developmental toxicity information was present from the one-generation toxicity study.

In this study, there were no treatment-related effects on any reproductive endpoints including number of litters produced, gestation length, mating and fertility indices (in both sexes), and gestation index. There were no treatment-related effects on number of live born or stillborn pups per litter, postnatal survival viability and lactation indices) or growth. No treatment-related gross findings were observed in the parental animals or offspring at any dose. In addition, no treatment-related microscopic changes were observed in the organs examined from parental animals treated with 20’000 ppm. At 20’000 ppm, indications of toxicity were limited to soft and/or irregular feces in both sexes. Based on the available data given in one-generation toxicity study, it is concluded that there was no evidence of developmental toxicity observed at doses up to and including 20’000 ppm under this experimental conditions.

Justification for classification or non-classification

In absence of reproductive toxicity effects, no classification of the substance according to CLP (Regulation 1272/2008) is required.