N,N,N',N'-tetramethyl-2,2'-oxybis(ethylamine)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

A key, reliable prenatal development study (K2, equivalent to OECD guideline 414; BRRC, 1985) is available. Therefore, no screening reproduction/developmental toxicity study is performed, according to the REACH Regulation column 2, annex IX, section 8.7.2.

A test proposal for an extended one-generation reproductive toxicity study is included in the dossier. This study will be performed according to OECD guideline 443, with a basic study design (rat, oral gavage, no additional cohorts).

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no adverse effect observed

Additional information

Data from repeated dose toxicity studies

No significant effects on reproductive organs were observed in a 90 -day (13 week) repeated dose dermal study nor in a 14 -week vapor inhalation study. In addition no data indicating developmental toxicity at doses that did not cause maternal toxicity were reported in a pre-natal development toxicity study as described below.

In the 90-day dermal repeated dose study, conducted using protocols equivalent to OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study) NZW rabbits were dosed with 0%, 0.2%, 0.7% or 2% [equivalent to 0, 0.74, 2.8 or 8 mg/kg bw/day, respectively] for 6 hrs/day, 5 days/wk for 13 weeks (90 days). No treatment-related effects were seen in any reproductive organs in either males or females at any dose level. Some signs of irritation were observed at the site of contact but no systemic toxicity was reported. The NOAEL was >=8 mg/kg bw/day.

 

In a vapor inhalation study, Sprague-Dawley rats were exposed to 0, 0.23, 1.25, or 5.8 ppm [0, 1.51, 8.2, or 38.0 mg/m3, respectively] via whole body exposure for 6 hours/day, 5 days/week for 14 weeks. No significant treatment-related effects were seen in any reproductive organs in either males or females at any dose level. Exposure-related increases in relative organ weights were observed for the adrenals and testes of males from the 38.0 mg/m3 group at the 14-week time point, but not after the 6-week recovery period and these organs showed no histologic abnormalities. The NOAEL was 8.2 mg/m3 based on non-systemic toxicity observed at 38.0 mg/m3. Local toxicity was reported at 1.51 mg/m3 including eye and respiratory tract irritation.

 

Prenatal developmental toxicity study

In addition to the repeated dose studies described above, a dermal Prenatal Developmental Toxicity Study was carried out in NZW rabbits conducted using protocols equivalent to OECD Guideline 414. Rabbits were exposed to 0, 1, 5 and 10 % [ca 2.4, 12 and 24 mg/kg bw/day], resepectively for 6 hrs per day on gestatation day 6-18. Histopathological changes in the kidney with vacuolar swelling of the collecting ducts were reported at 12 and 24 mg/kg bw/day in maternal animals and a significant decrease in body weight gain occurred at 24 mg/kg bw/day. The NOAEL for maternal toxicity was >= 2.4 - 12 mg/kg bw/day. In the foetus, a significant decrease in mean litter weight and female fetal body weight per litter was observed at 24 mg/kg bw/day. Male fetal body weights were also decreased although did not reach statistical significance. The NOAEl for fetotoxicity was >= 12 - 24 mg/kg bw/day. In terms of teratogenicity, no treatment-related effects on number of ovarian corpora lutea of pregnancy, total implantations, viable or non-viable implantations per litter, percent pre-implantation loss, percent live fetuses per litter, or on sex ratio (% males) were observed at any dose group studied. The NOAEL for embryotoxicity was >=24 mg/kg bw/day. These data suggest that any fetal effects that occur do so at doses that also cause maternal toxicity hence may not be a direct chemical effect.

Results from the pre-natal development toxicity study indicated no treatment-related effects on number of ovarian corpora lutea of pregnancy, total implantations, viable or non-viable implantations per litter, percent pre-implantation loss, percent live fetuses per litter, or on sex ratio (% males). In addition, no significant treatment-related effects on reproductive organs in males or females were observed in a 14-week vapor inhalation study in rats or in a 90-day dermal study in rabbits.

Extended one-generation reproductive toxicity study

A test proposal for an extended one-generation reproductive toxicity study is included in the dossier. This study will be performed according to OECD guideline 443, with a basic study design (rat, oral gavage, no additional cohorts).

Effects on developmental toxicity

Description of key information

A key, reliable prenatal development study (K2, equivalent to OECD guideline 414; BRRC, 1985) is available. Therefore, no screening reproduction/developmental toxicity study is performed, accordign to the REACH Regulation column 2, Annex IX, section 8.7.2.

Administration of the test substance by dermal application to timed-pregnant New Zealand white rabbits during organogenesis (gestation days 6 -18) resulted in maternal toxicity at 10% and 5%, i.e., transient reduced weight gain during exposure at 10%, renal lesions at 5 and 10% and elevated kidney weight at 10%. There was no maternal toxicity at 1% except for transient irritation at the application site. Toxicity to the fetus (reduced fetal body weight per litter) was observed unaccompanied by any indication of reduced fetal ossification, only at 10%, a dose which also produced signs of maternal toxicity. There was no evidence for embryotoxicity or teratogenicity at any dose level employed.

A test proposal for a prenatal developmental toxicity study in a second species (the rat) is included to the dossier. This study will be performed according to OECD guideline 414.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

12 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Quality of whole database:

A single non GLP study is available following a protocol that is equivalent to OECD Guidelines (excepting that animals were only treated from gestation days 6-18). The study was well documented, sufficient number of animals and doses were employed, and a vehicle and untreated control group were included.

Additional information

A well documented study following a protocol equivalent to OECD Guideline 414 is available. Administration of the test item by dermal application to timed-pregnant New Zealand white rabbits during organogenesis (gestation days 6-18) resulted in maternal toxicity at 10% (ca. 24 mg/kg bw) and 5% (ca. 12 mg/kg bw), i.e., transient reduced weight gain during exposure at 10%, renal lesions at 5 and 10% and elevated relative kidney weight at 10%. There was no maternal toxicity at 1% (ca. 2.4 mg/kg bw) except for transient irritation at the application site. Toxicity to the fetus (reduced fetal body weight per litter) was observed unaccompanied by any indication of reduced fetal ossification, only at 10%, a dose which also produced signs of maternal toxicity. There was no evidence for embryotoxicity or teratogenicity at any dose level employed.

A test proposal for a prenatal developmental toxicity study in a second species (the rat) is included in the dossier. The study will be performed according to OECD guideline 414.

Justification for classification or non-classification

Based on the results, the test subtance does not meet the criteria for classification as reproductive or developmental toxicant according to CLP Regulation 1272/2008.