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

Endpoint summary

Description of key information

LD 50 (oral, rats, 24 h): >2000 mg/kg bw

LD 50 (dermal, rabbits, 24 h): >5000 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from April 4, 1996 to June 20, 1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

not specified

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test system: Rat, Hanlbm: WIST (SPF)
Rationale: Recognized by the international guidelines as a recommended test system.
Source: 8RL, Biological Research Laboratories Ltd. Wolferstrasse 4, 4414 Fullinsdorf / Switzerland
Number of animals per group: 5 males, 5 females
Age when treated: males: 8weeks females: 10 weeks
Body weight range when treated: males: 201 - 205 g females: 172 - 182 g
Identification: By unique cage number and corresponding color-coded spots on the tail.
Randomization: Randomly selected at the time of delivery into groups of five.
Acclimatization: One week under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.
HUSBANDRY
Room No.: E 16 / RCC
Conditions:
Standard Laboratory Conditions.
Air-conditioned with XO-15 air changes per hour and continuously monitored environment with target ranges for temperatures of 20 ±3 degrees centigrade, and for relative humidity between 40 - 70 % (values above 70% during cleaning process possible), 12 hours artificial fluorescent light/12 hours dark, music during the light period.
Accommodation:
Groups of five in Makrolon type-4 cages with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz).
Diet: Pelleted standard Kliba 343, Batch no. 72/96 rat maintenance diet (Kliba Muhlen AG, CH-4303 Kaiseraugst) available ad libitum (except for the overnight fasting period prior to application). Results of analyses for contaminants are included in the report.
Water: Community tap water from Itingen, available ad libitum. Results of bacteriological, chemical and contaminant analyses are included in the report.

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

test article preparation:
The test article was placed into a glass beaker on a tared Mettler PM 460 balance, and the vehicle (bi-distilled water) was added. A weight by volume dilution was prepared. A homogenizer (Ultra-Turrax, Janke & Kunkelr 0-79219 Staufen) was used to ensure homogeneous distribution of the test article in vehicle.
Homogeneity of the test article in the vehicle was maintained during treatment using a magnetic stirrer (Janke & Kunkel, D-79219 Staufen) .
The preparation was made shortly before dosing.
Treatment:
The animals received a single dose of the test article on a mg/kg body weight basis by oral gavage following fasting for approximately 16 hours, but with free access to water. Food was provided again approximately 3 hours after dosing.
Dose/kg body weight: 2000 mg
Application Volume/ kg body weight: 10 ml
Rationale: Oral administration was used as this is one possible route of human exposure during manufacture, handling and use of the test article.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 per sex per dose

Control animals:

no

Details on study design:

test article was administered by single oral gavage to rats, followed by an observation period of 14 days.
observation:
Mortality / Viability: Four times during test day 1 and once daily during days 2 - 15.
Body Weights: On test day 1 (pre-administration), 8 and 15.
Clinical Signs: Each animal was examined for changes in appearance and behaviour four times during day 1 and once daily during days 2 - 15.

Statistics:

The LOGIT-Model could not be used as no deaths occurred.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: There were no deaths as a result of treatment with the test article. No adverse effect was observed in the clinical sign, body weight and macroscopic findings.

Mortality:

There were no deaths as a result of treatment with the test article.

Clinical signs:

other: No clinical signs of toxicity were observed during the observation period.

Gross pathology:

No macroscopic findings were observed at necropsy.

Interpretation of results:

not classified

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The mean lethal dose of test article after single oral administration to rats of both sexes, observed over a period of 14 days, could not be estimated, because no mortality occured and the LD50 was found greater than 2000 mg/kg.

Executive summary:

The test article was administered to a group of 5 male and 5 female rats by oral gavage, at a single dose of 2000 mg test article/kg body weight. A weight by volume dilution was prepared with bi-distilled water as vehicle. There were no deaths as a result of treatment with the test article. No clinical signs of toxicity were observed during the observation period. The body weight of the animals was within the normal range for rats of this strain and age. No macroscopic findings were observed at necropsy.

Therefore, it is concluded that test article is not subject to classification for acute oral toxicity according to CLP (Regulation EC No. 1272/2008).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The acute dermal LD50 (dermal, rabbits) in either sex upon exposure to N,N,N',N'-tetrakis(2-hydroxyethyl) hexanediamide is greater than 5000 mg/kg bw, being representative also for N,N,N',N'-tetrakis(2-hydroxypropyl) hexanediamide.

Executive summary:

The dermal toxicity of the test substance N,N,N',N'-tetrakis(2-hydroxyethyl) hexanediamide, a structurally similar surrogate for N,N,N',N'-tetrakis(2-hydroxypropyl) hexanediamide was assessed by applying the test article to the clipped intact skin of six male and six female New Zealand White rabbits at a dose of 5.0 g/kg body weight. The application sites were covered with impervious cuffs for a period of 24 hr, after which the cuffs were removed and the sites were wiped with water-soaked paper towels. There were no mortalities or treatment-related clinical signs over the 14 -day observation period. Erythema appeared on the application sites on Day 1, and test substance adhered to application sites throughout the observation period. There were no treatment-related body-weight effects. Necropsy revealed no gross changes. The acute dermal LD50 in male and female rabbits was greater than 5.0 g/kg. According to CLP (Regulation EC No. 1272/2008), the test substance is not to be classified for acute dermal toxicity. Thus, liewise absence of toxicity can be assumed for N,N,N',N'-tetrakis(2-hydroxypropyl) hexanediamide.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Additional information

As the proportion of test item having an inhalable particles size of less than 100 µm was determined to be 7.32%, and an oral and dermal study both being available, it is reasonable to expect that the inhalation route will not be a significant exposure route to the test material. Thus, there is no additional test requirement for this endpoint.

An acute toxicity study (Dr. H. Schmid, 1996) for target substance was conducted by oral application following OECD guideline 401. Upon oral administration and a 14 day post-treatment observation period, the LD50 determined for test substance is greater than 2000 mg/kg bw. The test article was administered to a group of 5 male and 5 female rats by oral gavage, at a single dose of 2000 mg test article/kg body weight. A weight by volume dilution was prepared with bi-distilled water as vehicle. There were no deaths as a result of treatment with the test article. No clinical signs of toxicity were observed during the observation period. The body weight of the animals was within the normal range for rats of this strain and age. No macroscopic findings were observed at necropsy.

Thus, it can be concluded that test substance exerts no toxic influence in rats of either sex at levels up to 2000 mg/kg bw.

The present study for N, N, N', N'-Tetrakis (2-hydroxyethyl) hexanediamide via dermal application is used for read across to avoid duplicate tests. This substance is structurally very similar to the target substance being the hydroxypropyl derivative.

A GLP dermal test (K.R.Lampe, 1988) following OECD guideline 402 showed that no signs of toxicity was observed following a single, 24 hours, occluded application of the test material to intact New Zealand White strain rabbits' skin at a dose level of 5000 mg/kg body weight. The acute dermal median lethal dose (LD50) of the test material in the New Zealand White rabbits was found to be greater than 5000 mg/kg bw.

Justification for classification or non-classification

Based on the existing animal data, the test substance is not to be classified in accordance with CLP (Regulation EC No.1272/2008) for acute toxicity endpoints.