7,7-dimethyl-3-oxa-6-azaoctan-1-ol

Endpoint summary

Description of key information

Acute oral toxicity, key study : Equivalent or similar to OECD Guideline 401 (Acute Oral Toxicity). The combined (male and female) acute rat oral LD50 was calculated to be 1467 mg/kg. Acute oral median lethal dose (NOAEL of <1000 mg/kg also estimated from study). Substance meets classification criteria for acute oral toxicity.
Acute dermal toxicity, key study : Equivalent or similar to OECD Guideline 402 (Acute Dermal Toxicity). The acute dermal LD50 in the New Zealand White rabbit was calculated to be >3160mg/kg. Acute dermal median lethal dose (NOAEL of 2000 mg/kg estimated from study). 

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:

Dosing initiated February 3 1982, Study termination 17 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Kingston, NY
- Age at study initiation: Approx. 12 weeks
- Weight at study initiation: Males: 302-380 g, Females: 205-265 g.
- Fasting period before study: All food was removed at approximately 4.00pm during the evening immediately prior to the day of administration of the test material. Food was withheld until completion of dosing the following morning.
- Housing: 5 animals per cage per sex. Suspended stainless steel.
- Diet (e.g. ad libitum): Purina Certified Rat Chow (ad libitum)
- Water (e.g. ad libitum): Automatic watering system (ad libitum)
- Acclimation period: 29 days.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Maintained range of 68 to 76 degrees Fahrenheit during study.
- Humidity (%): Maintained range of 40 to 70% RH during study.
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark by automatic timer.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE:
Not applicable.

DOSAGE PREPARATION (if unusual): The undiluted test material was administered by a single oral intubation via syringe and a No. 13 stainless steal, straight ball-tipped feeding needle.

Doses:

Seven dose levels: 1000 mg/kg, 1470 mg/kg, 2150 mg/kg, 3160 mg/kg, 4640 mg/kg, 6810 mg/kg, 10000 mg/kg

No. of animals per sex per dose:

5 per sex per dose.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made as to the nature onset, severity, and duration of toxicological signs at 1, 2, 4 and 6 hours immediately after dosing and once a day thereafter for a total of 14 days.
Bodyweights were recorded immediately before dosing and at Day 7, 14 and at death if before day 14.
- Necropsy of survivors performed: yes

Statistics:

The means and standard deviations of the body weights were calculated.

The estimated LD50 was calculated (using probit and low-dose values) using maximum likelihood estimates or the Litchfield-Wilcoxon Method. The dose-response curve slope, intercept and 95% confidence interval for the LD50 were calculated.

Sex:

male

Dose descriptor:

LD50

Effect level:

1 713.01 mg/kg bw

95% CL:

1 209.7 - 2 425.74

Sex:

female

Dose descriptor:

LD50

Effect level:

1 395.61 mg/kg bw

95% CL:

905.98 - 2 149.87

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 467.12 mg/kg bw

95% CL:

1 150.28 - 1 871.24

Mortality:

A total of 53 out of 70 animals succumbed during the study.
Animals died in every dose group.
Group 1 (1000 mg/kg): 3 animals died.
Group 2 (1470 mg/kg): 1 animal died.
Group 3 (2150 mg/kg): 9 animals died.
Group 4 (3160 mg/kg): 10 animals died.
Group 5 (1640 mg/kg): 10 animals died.
Group 6 (6810 mg/kg): 10 animals died.
Group 7 (10000 mg/kg): 10 animals died.

Clinical signs:

other: The most frequently observed toxicological signs were: dry rales, hypoactivity, oral discharge, and in Group 7, ataxia. Less frequent observations included nasal discharge, hypopnea, dyspnea, wet rales, ocular discharge, A/G staining, unthrifty coat, alo

Gross pathology:

There was a high incidence of internal abnormalities noted during necropsy, especially in the higher dose groups. The most frequent observation was reddening and/or distension of the gastro-intestinal tract, appearing in forty-one out of seventy animals. Twenty-one animals had distended stomachs containing either gas or fluid, and in sixteen animals the stomach was reddened. In seventeen animals the stomach fundus was dark red to black in colour, and in foureen animals it was thickened and reddened. The cecum appeared distended in six animals.

The brain was vascularized in twenty animals, the liver contained an accentuated lobular pattern in nine animals, four animlas had red fluid in the urinary bladder, and the thymus of seven animals contained foci. There was scattered foci and/or redness in the lungs of twenty-nine animals, however this observation could be a result of euthanizing with CO2.

Observations of less frequency included reddened megenteric lymph nodes in two animals, enlarged lymph nodes in one. Three animals had vascularized cecums.

There were two observations each of the following: thickened and congested liver, dilated renal pelvis of the kidneys, undescended testes, red material in the stomach, reddended acities of the abdominal cavity and dark red liver and kidneys, and reddened cervical lymph nodes.

There was one observation each of the following: enlarged testes, reddened mucosa in the jejunum, uterus diminished in size, yellow material in the stomach, reddened stomach mucosa, brown material in the cecum, red striations of the kidney cortex, vascularized testes, red fluid in the scrotal sac, reddened duodenum, and reddended abdominal muscles. It cannot be conclusively determined which of these observations were a result of treatment with the test substance or were part of the post-mortem antolysis observed in seventeen animals.

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test substance is harmful based upon the LD50 results according the EU classification guidelines.

Executive summary:

The acute toxicity of the test substance was evaluated when administered by the oral route at seven different dose levels: 1000 mg/kg, 1470 mg/kg, 2150 mg/kg, 3160 mg/kg, 4640 mg/kg, 6810 mg/kg and 10000 mg/kg. The animals were fasted during the evening prior to administration of the test material. Observations for toxicological signs were made at 1, 2, 4, and 6 hours immediately after dosing and once each day for a total of 14 days. Body weights were recorded the day prior to dosing (pre-dose), on the day of dosing (fasted bodyweights), at Day 7, at Day 14, or whenever animals succumbed. Animals that did not succumb were sacrificed on Day 14.

The LD50 for males was calculated to be 1713.01 mg/kg with 95% confidence interval of 2425.74 - 1209.70 mg/kg; female LD50 was calculated to be 1395.61 with a 95% confidence interval of 2149.87 - 905.98; the combined (male and female) LD50 was calculated to be 1467.12 mg/kg with a 95% confidence interval of 1871.24 - 1150.28 mg/kg.

A total of fifty-three animals out of seventy succumbed during the course of the study. Animals died in every dose group. Group 4 (3160 mg/kg), Group 5 (1640 mg/kg), Group 6 (6810 mg/kg) and Group 7 (10000 mg/kg) each lost ten animals.

The most frequently observed toxicological signs were dry rales, hypoactivity, oral discharge, and in Group 7 ataxia. Also observed were: wet rales, dyspnea, hypopnea and nasal discharge.

Mean body weights at the end of the study showed an increase over the pre-dose mean weights for the animals that survived, those that succumbed had a loss in weight from the pre-dose mean.

The most frequently observed internal abnormalities at necropsy were reddening and/or distension of the gastro-intestinal tract (forty-one animals), distended stomachs containing either gas or fluid (twenty-one animals), reddened stomachs (sixteen animals), dark red to black stomach fundus (seventeen animals), and thickened and reddened stomach fundus (fourteen animals).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 467 mg/kg bw

Acute toxicity: via inhalation route

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:

experimental study

Adequacy of study:

key study

Study period:

February 4th 1982 to February 18th 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

not specified

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
Dutchland Laboratory Animals, Denver, PA

- Age at study initiation:
Approximately 12 weeks

- Weight at study initiation:
2.6 to 3.5 kg

- Fasting period before study:
- Housing:
Individual in suspended stainless steel caging

- Diet (e.g. ad libitum):
Purina Certified Rabbit Chow (pellets) ad libitum

- Water (e.g. ad libitum):
Automatic watering system ad libitum

- Acclimation period:
30 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C):
Monitored twice daily; maintained range of 65 to 71 degrees Fahrenheit

- Humidity (%):
Monitored once daily; maintained range of 40 to 70% relative humidity

- Photoperiod (hrs dark / hrs light):
12 hours light, 12 hours dark by automatic timer

IN-LIFE DATES: From: Day 1 To: Day 14

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure:
The dorsal surface from the shoulder to the lumber region (approximately 200 square centimeters)

- % coverage:
10%

- Type of wrap if used:
Covered with a gauze patch which was secured with tape. To retard evapouration, to prevent ingestion of the test material, and to keep the substance in contact with the skin, the gauze patches were secured to the trunk of the animals with tape and a plastic sleeve.

REMOVAL OF TEST SUBSTANCE
- Washing (if done):
The plastic sleeve, tape, and gauze patches were removed and the skin was wiped (but not washed) to remove any test material still remaining.

- Time after start of exposure:
After approximtely 24 hours

TEST MATERIAL
- Amount applied (volume or weight with unit):
3.16 g/kg

- Constant volume or concentration used: yes

Duration of exposure:

24 hours

Doses:

3160 mg/kg bw

No. of animals per sex per dose:

6 Male and 6 Female rabbits were abraded, 3 Male and 3 Female rabbits skin was left intact (but still exposed to the test material).

Control animals:

no

Details on study design:

- Duration of observation period following administration:
14 days

- Frequency of observations and weighing:
The animals were checked for viability once in the morning (before approximatel 10:30am) and once in the afternoon (after approximately 3:00pm).
The dermal responses were evaluated at approximately 24 hours after dosing (after removing the patched), and on Days 3, 7, 10 and 14 according to the Draize Method of Scoring.
Body weights were recorded the day of dosing and at death should an animal succumb prior to study termination.

- Necropsy of survivors performed:
yes

- Other examinations performed:
Clinical Observations were made for the nature, onset, severity, and duration of toxicological signs at 2 and 24 hours immediately after dosing, nd once a day thereafter for a total of 14 days.

Statistics:

The means and standard deviations of initial body weights are presented below.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 3 160 mg/kg bw

Mortality:

There was one spontaneous death during the study, Animal No. 349M, on Day 4 post-dosing (test day 5). The cause of death for this animal was not determined.

Clinical signs:

other: Clinical observations included: nasal discharge, respiratory rate increase, ocular discharge, activity decrease, fine tremors, respiratory rate decrease, no stool, emaciation, food consumption decrease, soft stool, labored breathing, urinary staining, ora

Gross pathology:

Necropsy observations included:
skin of dosing site thickened, with red exudate, dark red to black, some with scabbing, surface hard or soft, all animals exept Animal No. 349M which died on Test Day 5.
In addition to the observations noted for the dorsal skin, Animal No. 327M showed ocular discharge, red lungs, and an accessory lobe on the left adrenal; Animal No. 351M showed nasal and ocular discharge, alopecia, a cavernous subcutaneous skin region filled with red fluid, vascularity of the subcutaneous skin, enlarged submaxillary gland with scattered fluid-filled areas, hair ball in stomach, and a general condition of emaciation; Naimal No. 361M showed tan and dark red mottling of the right apical lobe of the lung; Animal No, 363M showed a small gall bladder; Animal No. 367M showed surfaces on the ventral abdomen that were extremely thickened, releaseing fluid on incision, and moderate reddening of the duodenum and descending colon, and hair balls in stomach; Animal No. 328F showed hair matted in stomach, and grey foci on all lobes and surfaces of lungs; Animal No. 334F showed scattered hair balls in the stomach and modorate dark red foci on all lobes and surfaces of the lungs; Animal 350F showed ocular and nasal discharge, red foci and general bright redness of lungs, and a small hair ball in stomach; Animal No. 354F showed scattered lesions on ventral abdomen, and hair ball in stomach; Animal No. 366F showed hair in stomach contents, scattered dark red and grey foci on lungs; Animal No. 368F had moderate to extreme pitting on both kidney surfaces.

Other findings:

Not applicable.

Necropsy observations of Animal 349M:

The dorsal skin of this animal showed moderate to extreme reddened areas, slightly raised and filled with a clear, viscous tan fluid. This animal also showed extreme reddening of colon, rectum, G.I tract, and fecal, urinary staining, nasal discharge.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute dermal toxicity of MRD-82 -10 was evaluated following administration by the dermal route at 3160 mg/kg body weight to 6 male and 6 femal rabbits and was found to be >3160 mg/kg.

Executive summary:

The acute dermal toxicity of MRD-82 -10 was evaluated following administration by the dermal route at 3160 mg/kg body weight to 6 male and 6 femal rabbits. The animals' backs were clipped, the skin was left intact for 6 animals, and each rabbit was fitted with an Elizabethan-type collar during the day prior to administration of the test material.

Immediately prior to dosing, the exposed skin of the remaining six animals was abraded longitudinally every two to three centimeters. The abrasions were deep enough to penetrate the stratum corneum, but not so deep as to disturb the dermis or produce bleeding. The test material was held in place with a gauze patch which was secured with tape. After approximately twenty-four hours of exposure, the gauze patches were removed and the amount of the excess material remaining was noted and gently wiped from the skin. Observations for toxicological signs were made at 2 and 24 hours immediately after dosing, and once each day for a total of 14 days. Dermal responses were evaluated at approximately 24 hours post exposure (after removal of the gauze patches), and on Days 3, 7, 10 and 14 days after test material administration. Body weights were recorded the day of dosing, or at death if an animal died spontaneously. Animals that did not succumb were sacrificed at Day 14.

There was one spontaneous death during the study, Animal No. 349M on Day 4 post-dosing (Test Day 5). The cause of death for this animal was not determined.

Necrosis was observed in all animals from the 24 -hour observation through study termination. Other findings included: atonia, leathery skin, fissurins, desquamation, eschar and exfoliation. There was no lessening of the severity of irritation over time.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 160 mg/kg bw

Additional information

Acute Oral, Key Study:

A total of fifty-three animals out of seventy succumbed during the course of the study. Animals died in every dose group. The most frequently observed toxicological signs were dry rales, hypoactivity, oral discharge, and ataxia (in the highest dose group).

The combined (male and female) LD50 was calculated to be 1467 mg/kg.

The test substance meets the CLP/GHS and DSD/DPD classification criteria for acute oral toxicity.

Acute Dermal, key study:

The acute dermal toxicity was evaluated following administration by the dermal route at 3160 mg/kg body weight to 6 male and 6 female rabbits, and was found to be > 3160 mg/kg bw (>2000 mg/kg for classification purposes).

There was one spontaneous death during the study. The cause of death for this animal was not determined.

Necrosis was observed in all animals from the 24 -hour observation through study termination. Other findings included: atonia, leathery skin, fissuring, desquamation, eschar and exfoliation. There was no lessening of the severity of irritation over time.

Acute Inhalation:

No study was conducted.

Justification for selection of acute toxicity – oral endpoint
Key study for endpoint.

Justification for selection of acute toxicity – dermal endpoint
Key study for endpoint.

Justification for classification or non-classification

Based on the results the substance meets the classification criteria for acute oral toxicity.