1,1'-[[3-(dimethylamino)propyl]imino]bispropan-2-ol

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

A combined repeated dose toxicity study with reproduction/developmental toxicity screening test in rats according to OECD guideline 422 was performed (GLP; Martell, 2013). A NOAEL of > 500 mg/kg bw/day for male systemic toxicity, maternal systemic toxicity and embryo-fetal toxicity was derived.

Link to relevant study records

Reference

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Type of information:

experimental study planned

Study period:

to be determined by ECHA

Justification for type of information:

TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: 1,1'-[[3-(dimethylamino)propyl]imino]bispropan-2-ol

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- Available GLP studies:
Genetic toxicity:
Three in vitro genetic toxicity studies, performed according to GLP regulation are available. In a key bacterial reverse mutation assay (Ames), the test substance is not mutagenic with and without metabolic activation (according to OECD471; Dakoulas, 2012). In a key, chromosome aberration test in Chinese hamster lung fibroblasts, the test substance did not induce chromosome aberrations (according to OECD473; Suzuki, 2016). In a CHO/HGPRT mutation assay, the test substance was concluded to be negative with and without metabolic activation (according to OECD476; Clarke, 2012).
In an in vivo micronucleus test in male or female ICR mice, a single oral administration of the test item up to 2000 mg/kg did not trigger effects, and the test substance was concluded to be negative (according to OECD474; Krsmanovic and Divi, 2011).
Repeated dose toxicity (oral):
In a key, K1, 90-day oral repeated dose toxicity study in rats, an NOAEL for systemic toxicity of 150 mg/kg body weight/day was derived (according to OECD408; Maleshappa, 2021). The changes observed at 450 mg/kg body weight/day were related to haematology, clinical chemistry, organ weight (liver) and histopathology (liver, lungs, spleen). No adverse, test item-related effects were observed in thyroid hormone analysis or behavior (functional findings). No adverse effects to reproductive organs were observed.
Toxicity to reproduction:
In the combined repeated dose toxicity with reproduction/developmental screening test in rats, an NOAEL of > 500 mg/kg body weight/day was established for male and maternal systemic toxicity and embryo-fetal toxicity (according to OECD422; Martell, 2013). No test item-related adverse effects were observed in any of the mating or gestation parameters included, number of live or dead pups, (pup) mortality, gross pathology.
A prenatal development toxicity study in rats via oral gavage was performed according to OECD414 (Latha, 2021). An NOAEL of 500 mg/kg body weight/day was derived for maternal toxicity, developmental toxicity and teratogenicity. There were no effects of test item treatment on mortality, clinical signs, body weight, food consumption, maternal and litter parameters, gross pathology or external, visceral and skeletal examinations.
- Available non-GLP studies:
Acute toxicity (oral): In a key, K2 study, the LD50 for male and female rats was estimated to be 2200 mg/kg body weight (equivalent to OECD401; Auletta, 1979a).
Acute toxicity (dermal): In a key, K2 study , the dermal LD50 for male and female rabbits was estimated to be 3300 mg/kg body weight (equivalent to OECD402; Auletta, 1979b).
Skin irritation/corrosion: Two rabbit studies (K2-scored) are available (equivalent to OECD404; Moreno, 1979 and according to 49 CFR 172.240; Moreno, 1979), demonstrating that the substance is corrosive to the skin and classified as corrosive category 1C.
Eye irritation: In a key, K2 study in rabbit (equivalent to OECD405), the substance is demonstrated to be corrosive to the eye (Moreno, 1979)
- Historical human/control data: No data is available
- (Q)SAR: No (Q)SAR data can be used in a stand-alone approach to assess the reproductive toxicity potential. According to ECHA guidance document R.7a (Dec 2016), QSAR approaches are currently not fitted-for-purpose for reproductive toxicity and not all necessary aspects can be covered by a QSAR prediction
- In vitro methods: No in vitro methods have been developed; however, according to ECHA Guidance document R.7a (Dec 2016) these in vitro methods have not reached regulatory acceptance and do not provide equivalent information.
- Weight of evidence: No data is available which would allow a weight of evidence approach
- Grouping and read-across: No chemical grouping or read-across approach was identified
- Substance-tailored exposure driven testing [if applicable]: not applicable
- Approaches in addition to above [if applicable] : not applicable
- Other reasons [if applicable]: not applicable

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- This test proposal is fully compliant with the ECHA guidance document R.7a (Dec 2016). It is not possible to waive the study based on column 2 adaptations of the REACH Regulation.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed
Selected species: rat
Pre-mating period: 2 weeks is proposed, as there were effects observed in available studies
No triggers of the extension of cohort 1B are identified: the substance demonstrated no concern in toxicity data, information on endocrine function, genotoxicity or toxicokinetic evaluation
No triggers of DNT and DIT cohorts: no particular concerns on neurotoxicity or immunotoxicity are identified

Qualifier:

according to guideline

Guideline:

OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)

Justification for study design:

SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION TOXICITY STUDY WITH JUSTIFICATIONS :
An EOGRTS with basic design (cohort 1A, and 1B without extension) is proposed. There are no triggers in the available studies towards neurotoxicity or immunotoxicity.
- Premating exposure duration for parental (P0) animals: a pre-mating exposure period of 2 weeks is proposed
- Basis for dose level selection: No adverse effects were observedin the OECD422 and OECD414 study at 500 mg/kg bw/day (highest doe tested). Increase of the highest dose can be considered, based on a dose range finder study
- Inclusion/exclusion of extension of Cohort 1B: no trigger identified
- Termination time for F2: not applicable
- Inclusion/exclusion of developmental neurotoxicity Cohorts 2A and 2B: no trigger identified
- Inclusion/exclusion of developmental immunotoxicity Cohort 3: no trigger identified
- Route of administration: oral gavage
- Other considerations, e.g. on choice of species, strain, vehicle and number of animals [if applicable]: not applicable

Species:

rat

Route of administration:

oral: gavage

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subacute

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

Toxicity to reproduction:

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was performed in rats, in which male and female rats were exposed to 0 (vehicle), 10, 100, 500 mg/kg bw/d via gavage (Betancourt Martell, 2013). The study was performed according to OECD 422 guideline. The vehicle used was water and the test solutions were prepared daily and administered within 2 hours after preparation.

 

The test substance did not cause mortality (treatment-related) during the study; however, male and female rats exposed to 500 mg/kg/day presented respiratory clinical signs between treatment days 6 to 44. Also, during the functional observational battery, in one male and one female rat at the same dose level, dyspnea and respiratory sounds were observed.

Although these clinical signs were moderate in magnitude, they were sporadically observed throughout the dosing period in the test animals and were transitory in nature. Due to the extremely corrosive nature of the test substance to animal tissues and the dosing volumes used in the dosing of the high dose animals, it is likely that these respiratory observations were artefacts from the gavage dosing procedure. While these observations could be considered test item-related, they are not considered to be toxicologically relevant and are of low concern in the absence of other findings related to male systemic toxicity, maternal systemic toxicity, and embryo-fetal toxicity.

None of the mating or gestation parameters was considered to be affected by treatment with the test item. No differences were found between the numbers of live or dead pups from treated and control dams. No test-item related pup mortality occurred. No treatment-related macroscopic findings were observed at necropsy in the offspring.

Based on the abovementioned considerations, the NOAEL was considered to be > 500 mg/kg bw/day (nominal dose received) for male and systemic toxicity and maternal systemic toxicity, and greater than 500 mg/kg bw/day for embryo-fetal toxicity.

 

A testing proposal for an extended one-generation reproductive toxicity study according to OECD guideline 443 is included in this dossier.

Effects on developmental toxicity

Description of key information

A prenatal development toxicity study in rats (K1) was performed according to OECD guideline 414 (Latha, 2021) via oral gavage. A NOAEL of 500 mg/kg/day was derived for maternal toxicity, developmental toxicity and teratogenicity.

In addition, Martell (2013) performed a combined repeated dose toxicity study with reproduction/developmental toxicity screening test in rats according to OECD guideline 422 (GLP).
A NOAEL of > 500 mg/kg bw/day for male systemic toxicity, maternal systemic toxicity and embryo-fetal toxicity was derived.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study planned

Study period:

to be determined by ECHA

Justification for type of information:

TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: 1,1'-[[3-(dimethylamino)propyl]imino]bispropan-2-ol

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION [please address all points below]:
- Available GLP studies
Genetic toxicity:
Three in vitro genetic toxicity studies, performed according to GLP regulation are available. In a key bacterial reverse mutation assay (Ames), the test substance is not mutagenic with and without metabolic activation (according to OECD471; Dakoulas, 2012). In a key, chromosome aberration test in Chinese hamster lung fibroblasts, the test substance did not induce chromosome aberrations (according to OECD473; Suzuki, 2016). In a CHO/HGPRT mutation assay, the test substance was concluded to be negative with and without metabolic activation (according to OECD476; Clarke, 2012).
In an in vivo micronucleus test in male or female ICR mice, a single oral administration of the test item up to 2000 mg/kg did not trigger effects, and the test substance was concluded to be negative (according to OECD474; Krsmanovic and Divi, 2011).
Repeated dose toxicity (oral):
In a combined repeated dose toxicity study with reproduction/developmental toxicity screening test in rats, an NOAEL > 500 mg/kg body weight/day was derived for male systemic and maternal systemic toxicity (according to OECD422; Martell, 2013). In a key, K1, 90-day oral repeated dose toxicity study in rats, an NOAEL for systemic toxicity of 150 mg/kg body weight/day was derived (according to OECD408; Maleshappa, 2021). The changes observed at 450 mg/kg body weight/day were related to haematology, clinical chemistry, organ weight (liver) and histopathology (liver, lungs, spleen). No adverse, test item-related effects were observed in thyroid hormone analysis or behavior (functional findings). No adverse effects were observed to reproductive organs.
Toxicity to reproduction:
In the combined repeated dose toxicity with reproduction/developmental screening test in rats, an NOAEL of > 500 mg/kg body weight/day was established for male and maternal systemic toxicity and embryo-fetal toxicity (according to OECD422; Martell, 2013). No test item-related adverse effects were observed in any of the mating or gestation parameters included, number of live or dead pups, (pup) mortality, gross pathology.
A prenatal development toxicity study in rats via oral gavage was performed according to OECD414 (Latha, 2021). An NOAEL of 500 mg/kg body weight/day was derived for maternal toxicity, developmental toxicity and teratogenicity. There were no effects of test item treatment on mortality, clinical signs, body weight, food consumption, maternal and litter parameters, gross pathology or external, visceral and skeletal examinations.
- Available non-GLP studies:
Acute toxicity (oral): In a key, K2 study, the LD50 for male and female rats was estimated to be 2200 mg/kg body weight (equivalent to OECD401; Auletta, 1979a).
Acute toxicity (dermal): In a key, K2 study , the dermal LD50 for male and female rabbits was estimated to be 3300 mg/kg body weight (equivalent to OECD402; Auletta, 1979b).
Skin irritation/corrosion: Two rabbit studies (K2-scored) are available (equivalent to OECD404; Moreno, 1979 and according to 49 CFR 172.240; Moreno, 1979), demonstrating that the substance is corrosive to the skin and classified as corrosive category 1C.
Eye irritation: In a key, K2 study in rabbit (equivalent to OECD405), the substance is demonstrated to be corrosive to the eye (Moreno, 1979)
- Historical human/control data: No data is available
- (Q)SAR: No (Q)SAR data can be used in a stand-alone approach to assess the reproductive toxicity potential. According to ECHA guidance document R.7a (Dec 2016), QSAR approaches are currently not fitted-for-purpose for reproductive toxicity and not all necessary aspects can be covered by a QSAR prediction
- In vitro methods: No in vitro methods have been developed; however, according to ECHA Guidance document R.7a (Dec 2016) these in vitro methods have not reached regulatory acceptance and do not provide equivalent information.
- Weight of evidence: No data is available which would allow a weight of evidence approach
- Grouping and read-across: No chemical grouping or read-across approach was identified
- Substance-tailored exposure driven testing [if applicable]: not applicable
- Approaches in addition to above [if applicable] : not applicable
- Other reasons [if applicable]: not applicable

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- This test proposal is fully compliant with the ECHA guidance document R.7a (Dec 2016). It is not possible to waive the study based on column 2 adaptations of the REACH Regulation.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed: no further details

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Species:

rabbit

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subacute

Species:

rat

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:

A prenatal developmental toxicity study was performed (K1, OECD 414; Latha, 2021) in rats, in which female rats were exposed to 0 (vehicle), 125, 350, 500 mg/kg bw/d via oral gavage. The test item was administered to pregnant rats from gestation day (GD) 6 to 19. The vehicle used was Milli-Q® water. Dose formulations were prepared fresh daily before dosing and used within the established stability period. 

There were no mortalities and clinical signs observed in dams at any of the doses tested. Maternal body weight, food consumption and the maternal and litter parameters were not affected at all the doses tested. There were no gross pathological changes in any dam at any dose level. External, visceral, and skeletal examinations of fetuses revealed no signs of teratogenicity.
Based on the above findings, under the test conditions and doses employed in this study, it is concluded that the No- Observed- Adverse- Effect- Level (NOAEL) for Maternal toxicity and developmental toxicity is 500 mg/kg/day as the maternal and litter parameters were not affected up to 500 mg/kg/day. The No-Observed-Adverse-Effect-Level (NOAEL) for teratogenicity is 500 mg/kg/day as fetal external, visceral and skeletal examinations revealed no signs of teratogenicity in any of the tested dose levels up to high dose of 500 mg/kg/day.

 

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was performed in rats, in which male and female rats were exposed to 0 (vehicle), 10, 100, 500 mg/kg bw/d via gavage (Betancourt Martell, 2013). The study was performed according to OECD 422 guideline. The vehicle used was water and the test solutions were prepared daily and administered within 2 hours after preparation. No differences were found between the numbers of live or dead pups from treated and control dams. No test-item related pup mortality occurred. No treatment-related macroscopic findings were observed at necropsy in the offspring. Based on the abovementioned considerations, the NOAEL was considered to be > 500 mg/kg bw/day (nominal dose received) for male and systemic toxicity and maternal systemic toxicity, and greater than 500 mg/kg bw/day for embryo-fetal toxicity.

A testing proposal for a prenatal development study in a second species according to OECD guideline 414 is included in this dossier.

Toxicity to reproduction: other studies

Description of key information

no other study available

Justification for classification or non-classification

Based on the available data and according to the CLP criteria, the test substance should not be classified as toxic to reproduction.