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

Endpoint summary

Description of key information

In a study conducted using a method equivalent to OECD Guideline 406 (Skin Sensitisation), the result was negative indicating that the substance is not classified as a skin sensitiser.

The substance was found to show no adverse effects (not sensitising) in a study conducted using a method equivalent to OECD 406 Trimmer (1987).

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Dosing initiated: August 26 1986, Study termination (in vivo phase): September 26, 1986

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 406 (Skin Sensitisation)

Version / remarks:

similar to that described by B. Magnusson and A. Kligman in: "The Identification of Contact Allergens by Animal Assay. The Guinea Pig Maximization Test"

Deviations:

no

GLP compliance:

no

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

The first Test Guideline (TG) for the determination of skin sensitisation in the mouse, the Local Lymph Node Assay (LLNA; TG 429) was adopted in 2002. The OECD 406 study summarised for this skin sensitisation in vivo endpoint pre-dates the OECD 429 (the study report was produced in 1987).
Furthermore, in ECHA document Chapter R7a: Endpoint specific guidance (v6.0; July 2017); Section 7.2.3:
It is observed that for existing animal data, the use of methods other than those specified in the Annex to the EU Test Methods Regulation, or corresponding OECD methods may be accepted on a case-by-case basis - specifically including skin sensitisation test EU B.6/OECD TG 406 (as is the scenario with this substance).

Species:

guinea pig

Strain:

Hartley

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source:
Charles River Breeding Laboratories, Kingston Facility, Stone Ridge, New York

- Age at study initiation:
Approximately 5 weeks

- Weight at study initiation:
306 - 376 grams

- Housing:
Individual, in suspended stainless steel.

- Diet (e.g. ad libitum):
Purina Certified Guinea Pig Chow ad libitum.

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

- Acclimation period:
14 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):
Approximately 12 hours light and 12 hours dark by automatic timer.

IN-LIFE DATES: From: August 26th 1986 (Day 0) To: termination September 26th 1986

Route:

intradermal

Vehicle:

other: Primol 185 (white oil)

Concentration / amount:

Day 0:
Site 1: 0.1 ml (FCA/water)
Site 2: 0.1 ml (1.0% MRD-85-707 in vehicle)
Site 3: 0.1 ml (1.0% MRD-85-707 in vehicle)

Day 7: 0.5 ml (25% MRD-85-707 in vehicle)

Day 21: 0.5ml (1.0% MRD-85-707 in vehicle)

Day 28: 0.5 ml (1.0% MRD-85-707 in vehicle)

Route:

epicutaneous, open

Vehicle:

other: Primol 185 (white oil)

Concentration / amount:

Day 0:
Site 1: 0.1 ml (FCA/water)
Site 2: 0.1 ml (1.0% MRD-85-707 in vehicle)
Site 3: 0.1 ml (1.0% MRD-85-707 in vehicle)

Day 7: 0.5 ml (25% MRD-85-707 in vehicle)

Day 21: 0.5ml (1.0% MRD-85-707 in vehicle)

Day 28: 0.5 ml (1.0% MRD-85-707 in vehicle)

No. of animals per dose:

Total of 30 animals, 15 in treatment group, 15 as a control group.

Details on study design:

RANGE FINDING TESTS:
Not recorded

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures:
3

- Exposure period:
21 Days

- Test groups:
1 Treatment group of 15 animals.

- Control group:
1 control group of 15 animals.

- Site:
An area measuring approximately 4 x 6 cm, near the scapula in the mid-dorsal region of all animals was clipped on the day prior to intradermal injection of the test material and/or vehicle. All animals were clipped using Oster A-2 Small Animal Clippers equipped with size 40 blades.
Solutions for Site 1 and Site 2 were injected close together and near the first thoracic vertebra; the solution for Site 3 was injected more caudally.

- Frequency of applications:
every 7 days until day 28

- Duration:
21 Days

- Concentrations:
Day 0:
Site 1: 0.1 ml (FCA/water)
Site 2: 0.1 ml (1.0% MRD-85-707 in vehicle)
Site 3: 0.1 ml (1.0% MRD-85-707 in vehicle)

Day 7:
0.5 ml (25% MRD-85-707 in vehicle)

B. CHALLENGE EXPOSURE
- No. of exposures:
2

- Day(s) of challenge:
Day 21 and Day 28

- Exposure period:
24 hours

- Test groups:
1 Treatment group of 15 animals.

- Control group:
1 Treatment group of 15 animals.

- Site: The fur in an area measuring approximately 5 x 5 cm on the right flank in the abdominal region was clipped approximately 4 hours prior to challenge dosing of the test material.
For rechallenge, the same area on the left flank was clipped prior to dosing.

- Concentrations:
Day 21: 0.5ml (1.0% MRD-85-707 in vehicle)

Day 28: 0.5 ml (1.0% MRD-85-707 in vehicle)

- Evaluation (hr after challenge):
Evaluation of sensitisation potential was based on a comparison of treated and irritation control group dermal responses. Since sensitisation to any material requires multiple exposures, control group responses were used to distinguish true sensitisation from local irritation produced by a single exposure to the same concentration of test material.

OTHER:

Challenge controls:

Irritation control group - 1.0% MRD-85-707 in vehicle at 21 days, No treatment at 28 days.

Positive control substance(s):

yes

Remarks:

Formalin

Positive control results:

Please see Appendix C attached for details on results.

Reading:

rechallenge

Hours after challenge:

48

Group:

test chemical

Dose level:

1.0%

No. with + reactions:

10

Total no. in group:

15

Clinical observations:

Exhibited slight to well-defined etythema. No edema was noted following rechallenge.

Remarks on result:

other: see Remark

Remarks:

Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 1.0%. No with. + reactions: 10.0. Total no. in groups: 15.0. Clinical observations: Exhibited slight to well-defined etythema. No edema was noted following rechallenge..

Reading:

rechallenge

Hours after challenge:

72

Group:

test chemical

Dose level:

1.0%

No. with + reactions:

12

Total no. in group:

15

Clinical observations:

Exhibited slight to well-defined etythema. No edema was noted following rechallenge.

Remarks on result:

other: see Remark

Remarks:

Reading: rechallenge. . Hours after challenge: 72.0. Group: test group. Dose level: 1.0%. No with. + reactions: 12.0. Total no. in groups: 15.0. Clinical observations: Exhibited slight to well-defined etythema. No edema was noted following rechallenge..

Reading:

rechallenge

Hours after challenge:

216

Group:

test chemical

Dose level:

1.0%

No. with + reactions:

10

Total no. in group:

13

Clinical observations:

Exhibited slight to well-defined erythema. No edema was noted following rechallenge. 2 animals found dead at Day 30.

Remarks on result:

other: see Remark

Remarks:

Reading: rechallenge. . Hours after challenge: 216.0. Group: test group. Dose level: 1.0%. No with. + reactions: 10.0. Total no. in groups: 13.0. Clinical observations: Exhibited slight to well-defined etythema. No edema was noted following rechallenge. 2 animals found dead at Day 30..

Reading:

rechallenge

Hours after challenge:

240

Group:

test chemical

Dose level:

1.0%

No. with + reactions:

8

Total no. in group:

13

Clinical observations:

Exhibited slight to well-defined etythema. No edema was noted following rechallenge. 2 animals found dead at Day 30.

Remarks on result:

other: see Remark

Remarks:

Reading: rechallenge. . Hours after challenge: 240.0. Group: test group. Dose level: 1.0%. No with. + reactions: 8.0. Total no. in groups: 13.0. Clinical observations: Exhibited slight to well-defined etythema. No edema was noted following rechallenge. 2 animals found dead at Day 30..

Reading:

rechallenge

Hours after challenge:

48

Group:

negative control

Dose level:

1%

No. with + reactions:

9

Total no. in group:

15

Clinical observations:

Exhibited slight to well-defined etythema. No edema was noted following rechallenge. 1 animal found day on Day 23.

Remarks on result:

other: see Remark

Remarks:

Reading: rechallenge. . Hours after challenge: 48.0. Group: negative control. Dose level: 1%. No with. + reactions: 9.0. Total no. in groups: 15.0. Clinical observations: Exhibited slight to well-defined etythema. No edema was noted following rechallenge. 1 animal found day on Day 23..

Reading:

rechallenge

Hours after challenge:

72

Group:

negative control

Dose level:

Untreated

No. with + reactions:

8

Total no. in group:

15

Clinical observations:

Exhibited slight to well-defined etythema. No edema was noted following rechallenge. 1 animal found day on Day 23.

Remarks on result:

other: see Remark

Remarks:

Reading: rechallenge. . Hours after challenge: 72.0. Group: negative control. Dose level: Untreated. No with. + reactions: 8.0. Total no. in groups: 15.0. Clinical observations: Exhibited slight to well-defined etythema. No edema was noted following rechallenge. 1 animal found day on Day 23..

Reading:

rechallenge

Hours after challenge:

552

Group:

positive control

Dose level:

0.1 mL

No. with + reactions:

15

Total no. in group:

15

- Irritation Control:

One irritation control animal died prior to study termination. Of the surviving animals one animal displayed a weight loss when compared to their initial values. All remaining animals displayed an increase in body weight over the initial values.

Following topical challenge with 1.0% MRD-85-707, very slight to well-defined erythema was noted for nine irritation control animals on Day 23 and for each animals on Day 24.

Gross postmortem examination of the animal which succumbed prior to study termination revealed:

JDE929F

A/G Area: Slight amount of brown material on fur

Stomach: Empty, slight amount of mucous like material

Cecum: One half normal size, slight amount of green-brown thickened material

Small Intestine: Slight amount of frothy amber material

Gall Bladder: Slight amount of green, grainy material in the clear amber liquid

Individual challenge dermal irritation scored for all animals are presented in Table 1 (attached). The incidence of challenge dermal irritation scores for each group is presented in Table 2 (attached) The incidence of in-life observations is presented in Table 3 (attached). Individual animal body weights by weighing period and dose, including the means and standard deviations, are presented in Table 4.

Gross postmortem examination of the animals which succumbed prior to study termination revealed:

Test treatment group

JDE934F

A/G Area: Slight amount of brown staining on fur

Gall Bladder: Small approximately 0.6 cm diameter

Cecum: Filled with liquid-like ingesta

JDF031F

A/G Area: Moderate amount of brown staining on fur

Stomach: Slight amount of dark brown tar-like material. Moderate number of dark brown-black foci over the surface of the inner mucosa

Cecem: Empty, one third normal size

Validation:

Environmental Deviation:

On September 26th 1986 normal power was out for a total of 3 hours, 40 minutes due to a Public Service Electric power failure. Emergency power was on for a total of 4 hours, 10 minutes. The animal room temperature and humidity were checked and were within the required tolerance during this period.

Protocol Deviation:

On Day 7, a 25% (w/v) mixture was administered to the treated group animals instead of a 75% (w/v) mixture. The deviation was caused by a calculation and verification error on the test material preparation sheet. The effect of this deviation is undetermined since the 25% mixture was a slightly irritating concentration.

Interpretation of results:

not sensitising

Remarks:

Migrated information

Conclusions:

Following topical challenge with 1.0% MRD-85 -707, the incidence and severity of dermal irritation was similar for both the treated and control groups. Following rechallenge, the treated animals displayed a slightly lower severity and incidence of dermal irritation.

Based on these findings, it appears that MRD-85 -707 should be classified as a non-sensitiser.

Executive summary:

The allergic contact sensitisation potential of MRD-85 -707 was evaluated in 15 female Hartley albino guinea pigs following intradermal injection and 3 topical occlusive exposures. An irritation control group of 15 female guinea pigs received only a single topical exposure to the test material. The technique employed was similar to that described by B. Magnusson and A. Kligman in: "The Identification of Contact Allergens by Animal Assay. The Guinea Pig Maximisation Test", Journal of Investigate Dermatology, Vol. 52: 268 -276, 1969. Evaluation of sensitisation potential was based on a comparison of treated and control group dermal scores. A known sensitiser (positive control) was tested concurrently for purposes of comparison.

Dermal responses were evaluated approximately 24 hours after each of the induction exposures, and 24 and 48 hours after the removal of the challenge patch, and 24 and 48 hours after removal of the re-challenge patch for treated group animals only, according to the Draize Method of scoring. Observations were made as to the nature, on-set, severity and duration of toxicological signs immediately after dosing on Day 0 and on Days 7, 14, 21 and prior to terminal sacrifice. Observations were also made on Day 28 for treated group animals only. Body weights were recorded at initiation of dosing and on Day 7, 14, 21 and at sacrifice. Body weights were also recorded on Day 28 for animals of the treated group. After the final clinical in-life observations and weighings, all animals were sacrificed by carbon dioxide asphyxiation and discarded without further examination. Animals dying prior to study termination were subjected to a gross postmortem examination.

One irritation control and two treated group animals died prior to study termination. These animals exhibited gastro-intestinal tract abnormalities on gross postmortem examination.

One animal in each group displayed a weight loss when compared to the initial values. The remaining animals displayed an increase in body weight over the initial values.

Clinical in-life observations noted during the study were minimal with the majority of the animals exhibiting no observable abnormalities.

Treated group animals received 1.0% and 25.0% MRD-85 -707 during the intradermal and topical induction phases respectively. Following topical challenge with 1.0% MRD-85 -707, the incidence and severity of dermal irritation was similar for both the treated and control groups. Following rechallenge, the treated animals displayed a slightly lower severity and incidence of dermal irritation.

Based on these findings, it appears that MRD-85 -707 should be classified as a non-sensitiser.

Reference 2

Endpoint:

skin sensitisation: in vitro

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
The need for an in vitro skin sensitisation study is waived. An in vivo non-LLNA study (Trimmer, 1986) was performed on the test item.
As per Regulation (EC) 1907/2006, Annex VII, Part 8.31, Column 2:
The test(s) [skin sensitisation in vitro/in chemico] do not need to be conducted if an in vivo study according to point 8.3.2 is available.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

In a study conducted using a method equivalent to OECD Guideline 406 (Skin Sensitisation), the result was negative indicating that the substance is not classified as a skin sensitiser.

The substance was found to show no adverse effects (not sensitising) in a study conducted using a method equivalent to OECD 406 Trimmer (1987).

Justification for selection of skin sensitisation endpoint:
Key study for endpoint.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information:

No data available on respiratory sensitisation.

Justification for classification or non-classification

The results of the key study for sensitisation indicate that the substance is not classified as a sensitiser.