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

Endpoint summary

Description of key information

Acute toxicity - Oral:  A Klimisch 1-rated oral (gavage) acute toxicity study performed in accordance with OECD Guideline 401 reported a LD50 value of 677 mg/kg bw in rats.  This study is supported by three other Klimisch 2-rated studies in rats reporting LD50 values ranging from 571 – 1045 mg/kg bw.
Acute toxicity - Inhalation:   A Klimisch 1 -rated 4 -hr vapour inhalation LC50 study in rats performed in accordance with OECD Guideline 403 reported a LC50 value of > 2.204 mg/L.  All animals survived until the scheduled necropsy on Day 15, the exception of one male animal that was found moribund in its housing cage on Test Day 5.  This study is supported by three additional Klimisch 2 -rated studies in rats reporting LC50 values of 4 mg/L (4 -hr exposure, aerosol), >3.2 mg/L (3 -hr exposure, vapour) and 1.088 mg/L (6-hr exposure, vapour).  
Acute toxicity - Dermal:  The key study is a well-documented study following methods equivalent to OECD Guideline 402 (Acute Dermal Toxicity).  New Zealand White rabbits (5/sex/dose) were exposed dermally under occluded conditions for 24-hours to varying doses of undiluted test substance. The LD50 in males was reported to be 0.373 mL/kg bw and in females was 0.367 mL/kg bw.  Using the density of the test substance of 0.848 g/mL (OECD Guideline 109) to convert to mg/kg bw resulted in LD50s of 316 mg/kg bw and 311 mg/kg bw in males and females, respectively.  The value used for the CSR was 314 mg/kg bw, the average of the LD50 in males and females.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

677 mg/kg bw

Quality of whole database:

Oral (gavage) LD50 values from four reliable studies on the test substance are availble with results ranging from 571 - 1045 mg/kg bw (male and female rats) [OECD 401]. Clinical findings in the moribund animals included various staining/material/matting, rales, abnormal excretion, ataxia piloerection, dyspnea, abnormal stance/gait and hypoactivity. At necropsy, gastrointestinal abnormalities (distended stomach, red fluid and/or dark red contents, reddened mucosa, dark red area(s) in the intestine and/or stomach) were reported in three of these studies in the moribund animals and one study also reported edema and extensive hyperemia in the lungs and congestive hyperemia (centrilobular edema, peripheral-lobular fatty degeneration) in the liver of the moribund animals. The weight of evidence supports the use of the LD50 value of 677 mg/kg bw provided in the Klimisch 1 study chosen as the key study.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

2 204 mg/m³ air

Quality of whole database:

In a reliable, well-conducted study conducted according to OECD 403 (identified as the key study), the four hour vapour inhalation LC50 for BDMAEE with male and female rats is > 2.204 mg/L. This is supported by three additional studies reporting a 4-hour aerosol inhalation LC50 of 4 mg/L, a 6 hour vapour inhalation LC50 in male and female rats of 1.088 mg/L and a 3-hour vapour LC0 (limit test, male and female rats) of >3.2 mg/L.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

314 mg/kg bw

Quality of whole database:

Reliable data are available for three acute dermal toxicity studies (according to or similiar to OECD 402) - all studies were conducted under occluded conditions. In the key study, the dermal LD50 for rabbits was ca. 314 mg/kg bw (24 hour exposure). In the second (supporting) study, the dermal LD50 for rabbits was >400 mg/kg bw (24 hour exposure, limit test) and in the third study, the dermal LD50 for rabbits was 750 mg/kg bw (24 hour exposure). Severe skin necrosis was noted at the site of application. Other effects following dermal contact included hypoactivity, altered gate/posture and, in males in one study, dyspnea.

Additional information

Acute toxicity - oral:
An oral acute toxicity study in Crl:CD(SD)BR rats was performed in accordance with OECD 401 without deviations and GLP-compliant and thus was chosen as the key study (K1; WIL, 1997). All report elements required by the guideline were present. Five male and five female rats per dose group (500, 720 and 1037 mg/kg bw) were dosed via oral gavage. The rats were observed over a 14-day period. LD50 results were reported to be 708 mg/kg bw in males (95% CL 652 – 769 mg/kg bw); 603 mg/kg bw in females (95% CL 527 – 689 mg/kg bw); and 677 mg/kg bw in males/females (95% CL 636 – 722 mg/kg bw). Clinical findings were noted in all dose groups. Wet and/or dried red, yellow and/or clear staining/matting/material (around the nose, mouth, eye(s), forepaw(s) and/or urogenital area) was noted for 23 rats. Nineteen animals were hypoactive. Rales and abnormal excretion (decreased defecation, decreased urination, soft stool, mucoid feces) were observed for 7 and 6 rats, respectively. Ataxia and pale extremities were noted for 5 and 4 rats, respectively, that died. Findings documented in one or two animals that were found dead included hypothermia (body cool to touch), clear ocular discharge, emaciation, prostration, gasping and eyes matted shut. There were no other clinical findings. All animals appeared normal by day 11 or earlier and throughout the remainder of the study. Of the animals found dead, 17/18 animals had gastrointestinal abnormalities (a distended stomach, red fluid and/or dark red contents, reddened mucosa, dark red area(s) in the intestine and/or stomach). Small seminal vesicles, a hemorrhagic thymus gland and dilated renal pelvis were noted for one male rat each. Seven animals had various external matting (yellow, red and/or brown matting around the eyes, nose, mouth, urogenital and/or anogenital area). There were no other gross necropsy findings for all other animals found dead. There were no findings for animals which survived to the scheduled necropsy.

Three reliable, K2 studies were available to support this conclusion.

Acute toxicity - inhalation:
The key study was chosen due to it being a recent, Klimisch 1-rated study conducted according to OECD 403 (RCC, 2006). In this study, HanRcc:WIST(SPF) rats (5/sex/dose) were exposed nose only to a 2.204 mg/L vapour concentration of the test substance for four hours. The rats were observed for 15 days post-exposure. Salivation, decreased spontaneous activity, rales, labored respiration, ruffled fur, and scabbed wounds to the nose were reported in all treated animals. All animals survived until the scheduled necropsy on Day 15, with the exception of one male animal that was found moribund in its housing cage on Test Day 5. No gross pathology findings were noted following necropsy. The four hour vapour inhalation LC50 for the test substance in male and female rats was reported to be > 2.204 mg/L.

Three reliable, K2 studies were available to support this conclusion.

Acute toxicity - dermal:
The key study is a well-documented study following methods equivalent to OECD Guideline 402 (Acute Dermal Toxicity; BRRC, 1985). New Zealand White rabbits (5/sex/dose) were exposed dermally under occluded conditions for 24-hours to varying doses of undiluted test substance. Clinical signs included severe irritation of the skin consisting of erythema, edema, necrosis, scabs and ulcerations as well as sluggishness, unsteady gait and prostration. At necropsy, lungs were mottled and red, a few stomachs had multiple black surface foci and a few animals had subcutaneous edema. There were also instances of enlarged kidneys and one spleen with adhesions. The LD50 in males was reported to be 0.373 mL/kg bw and in females was 0.367 mL/kg bw. Using the density of the test substance of 0.848 g/mL (OECD Guideline 109) to convert to mg/kg bw resulted in LD50s of 316 mg/kg bw and 311mg/kg bw in males and females, respectively. The value used for the CSR was 314 mg/kg bw, the average of the LD50 in males and females.

Three supporting studies are available for this endpoint (2 Klimisch score 2, and 1 Klimisch score 4).

Justification for classification or non-classification

Based on the results of acute toxicity studies, the suggested classification for the test substance according to EU Regulation 1272/2008 is oral category 4 (Harmful if swallowed), dermal category 3 (Toxic in contact with skin), and inhalation category 4 (Harmful if inhaled).