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

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Dosing inititated: January 24 1983

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.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1983

Report date:

1983

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Deviations:

not specified

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

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

EC Number:

400-390-6

EC Name:

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

Cas Number:

87787-67-5

Molecular formula:

Hill formula: C8 H19 N O2 CAS formula: C8 H19 N O2

IUPAC Name:

2-[2-(tert-butylamino)ethoxy]ethan-1-ol

Details on test material:

Material identification: MRD-82-178
Description: Amber liquid

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dutchland Laboratories, Incorporated, Denver, PA
- Age at study initiation: Approx 16 weeks
- Weight at study initiation: 2.98 - 4.06 kg
- Housing: Individual stainless steel cage
- Diet (e.g. ad libitum): Purina Certified Rabbit Chow (pellets), ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 Days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 65 to 71 degrees Fahrenheit
- Humidity (%): 40 to 70%
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark

Administration / exposure

Type of coverage:

not specified

Vehicle:

water

Details on exposure:

TEST SITE
- Area of exposure: 10 x 20 cm
- Type of wrap if used: surgical tape and guaze.
- Time intervals for shavings or clipplings: Twice per week.



TEST MATERIAL
Test dilutions were prepared weekly by diluting the appropriate amounts of substance with distilled water. The volume of dosing solution applied to each animal was 2 ml/kg.




USE OF RESTRAINERS FOR PREVENTING INGESTION: Elizabethan-type collars.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

5 days per week for at least 4 weeks. Male rabbits received a total of 21 applications and females 22 applications.

Frequency of treatment:

The test material was applied directly to the gauze 5 days per week.

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0% (w/v)
Basis:
other: control group

Doses / concentrations 2

Remarks:

Doses / Concentrations:
1.0% (w/v)
Basis:
analytical per unit area

Doses / concentrations 3

Remarks:

Doses / Concentrations:
5.0% (w/v)
Basis:
analytical per unit area

No. of animals per sex per dose:

10 males and 10 females per group.
Dose group I = 0%
Dose group II = 1.0%
Dose group III = 5.0%

Control animals:

yes, concurrent vehicle

Details on study design:

Doses determined by preliminary study.

Animals determined to be unsutiable for inclusion on this study because of poor health, outlying body weights or other abnormalities were excluded from selection.

Positive control:

No.

Examinations

Observations and examinations performed and frequency:

Each animal was observed daily during the 4 week dosing period for dermal and systemic toxicological responses. Clinical laboratory studies were conducted on blood samples collected pretest and at termination.

Sacrifice and pathology:

Gross necropsies were performed and specific organs retained.

Statistics:

The following parameters were statistically analyzed for significant differences.
- mean terminal hematology parameters.
- mean terminal clinical chemistry parameters.
- mean organ weights.
- mean organ to body weight ratio's.
- mean body weights, by weighing period.
- mean food consumption.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Dermal irritation:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Dermal irritation: The incidence and severity of dermal irritation increased with dose. Mild dermal irritation was observed in many of the low dose group animals. Irritation was more severe in the high dose groups.

Supplemental dermal observations of desquamation, necrosis and eschar were noted in several animals of the high dose group.

In-life observations: Four animals died prior to termination of the study. One Group I male was sacrificed for humane reasons on Day 21, and 1 female of group I was found dead on Day 29. 2 Group III males were found dead on Day 5 and on Day 28 respectively.

Food consumption: There were no treatment related effects on food consumption patterns.

Body weights: Mean body weights for all groups increased over the course of the study.

Hematology parameters: There were statistically significant differences from control in the Group III male MCH, Group II female platelet and Group II female MCHC values. It is unlikely that these differences are biologically significant.

Clinical Chemistry parameters: There were statistically significant differences from control noted in Group II male and female total blirubin, Group III female alkaline phosphatase, Group III male chloride and Group III female calcium values. The decreased calcium mean is attritutable to 1 abnormally low female value; the other mean values fall within the normal biological range for these parameters.

Necropsy Observations: The most common findings observed during gross postmortem examination were renel and pulmonary discolourations. The incidence of these findings was similar in all 3 groups and not considered treatment related.

Organ weights: A statistically elevation in mean adrenal gland weight and mean adrenal to body weight ratio was noted in Group II and III males.

Effect levels

Dose descriptor:

dose level: 5.0% w/v

Effect level:

1 - 5 other: % w/v dose of substance causing dermal irritation.

Sex:

male/female

Basis for effect level:

other: By study termination, 5.0% test substance had elicited moderate to severe irritation in the females but only mild irritation in the majority of males.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

With the exception of primary dermal irritation, topical adminstration of the test substance at 2 concentrations to male and female rabbits for a period of approximately 4 weeks did not appear to produce toxicological change in the parameters and organs examined, which could unequivocally be related to treatment.

Executive summary:

The objective of this study was to evaluate the dermal irritation potential and systemic toxicity of 2 concentrations of test material MRD-82 -178 following repeated topical application. The material was applied to the dorsal surface of rabbits 5 days per week for at least 4 weeks. 60 New Zealand White rabbits were divided into 3 groups of 10 males and 10 females each. Group I was used as a control. Groups II and III received 2 ml/kg administrations of 1.0 and 5.0% (w/v) test substance. Each animal was observed daily for dermal and systemic toxicological responses. Clinical laboratory studies were conducted on blood samples collected pre-test and at termination. Gross necropsies were performed and specific organs retained.

Four animals died prior to study termination: 1 male and 1 female in the control group and 2 males in the high dose group.

The incidence and severity of dermal irritation increased with dose. By study termination, 5.0% test substance had elicited moderate to severe irritation in the females but only mild irritation in the majority of males.

There was an overall low incidence of in-life observations noted in all 3 groups, with none appearing to be treatment related. There were no treatment related effects on food consumption patterns. Mean body weights for all groups increased over the course of the study.

Statistically significant differences were noted in a small number of mean terminal hematology and clinical chemistry values. It is unlikely that any of these differences are biologically significant.

A review of the in-life, clinical laboratory and gross necropsy findings did not reveal any significant signs of toxicity, other than primary irritation, which could be directly attributed to the administration of MRD-82 -178.