5-methylheptan-3-one oxime

Endpoint summary

Description of key information

Over several studies, effects observed did not warrant classification as irritating to eyes or skin.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

not specified

GLP compliance:

not specified

Species:

guinea pig

Strain:

not specified

Type of coverage:

open

Preparation of test site:

clipped

Vehicle:

other: 10% ethanol

Controls:

yes

Amount / concentration applied:

concentrations of 30, 10, 3 and 1%

Duration of treatment / exposure:

There are 2 parts to this test, a single application and a 21-Day repeated application test.

Observation period:

In the single applicaiton test, thre was an observation period of 24 hours
In the repeated dos group, observations were recorded on days 7, 14 and 21

Number of animals:

6-8 animals were used in the single application test.
6 animals per dose (24 total) were used in the repeated application test

Details on study design:

Under the current OECD guidance, the repeated dose application test can not be used to assess clarification, only to aid irritant levels if a single application is only observed for 24 hours.

Irritation parameter:

other: Irritation

Basis:

other: 100% concentration

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

other: Slight Skin Irritation

Irritation parameter:

other: Irritation

Basis:

other: 30% concentration

Time point:

24 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

other: Slight Skin Irritation

Single application test

Slovent: ethanol

Lowest irritant concentration = 100%

Highest non irritant concentration = 30%

Repeated applications over 21 successive days

Concentration %	Skin irritation after days
	7	14	21
100	(+)	(+)	+
30	-	(+)	(+)
10	-	-	-
3	-	-	-

Degree of skin irritation:

– = none

+ = slight

++ = moderate

+++ = strong

Capacity to induce allergic sensitization

After daily applications over three weeks Concentration in %	Sensitisation rate Number of animals Positive/Total
	Day 21	Day 35
100	0/6	0/6
30	0/6	0/6
10	0/6	0/6
3	0/6	0/6

Results:

STEMONE is a well-tolerated preparation. The highest non-irritant solution after single application is 30%,after repeated applications 10% in ethanol. The 30% solution causes only very slight skin irritation beginning after one week's treatment. No sensitization occurs with STEMONE in the guinea pig under conditions of the OET.

Interpretation of results:

GHS criteria not met

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

After a single application, slight irritation was observed at a concentration of 100%.
Although no observations were taken at 48 and 72 hours, the data from the repeated dose study at 7, 14 and 21 days indicates that only slight irritation was observed.
Therefore, after a single application, no additional irritation would be expected which would lead to classification.

Executive summary:

Slight irritation observed after a single application which is insufficient for classification purposes.

This non-classification is based on the additional information after 21 days repeated dosing at 3%, 10%, 30% and 100% where after 7 days dosing at 100%, only slight irritation was observed.

Therefore after a single dose, it is extremely unlikely that oxyoctaline formate would be an irritant after 7 days and therefore would not be classifiable.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

24th January 1966 to 4th March 1966

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Qualifier:

no guideline available

Principles of method if other than guideline:

The technique employed in this study was that of the repeated insult method approyed by the Food and Drug Administration.

GLP compliance:

no

Species:

human

Strain:

not specified

Details on test animals or test system and environmental conditions:

The fifty-seven subjects were selected on a random basis in the order of their applying for participation in this study, except that no person was accepted who had active dermatologic conditions or other indicated illnesses. Previous sensitivities or a history of allergy were not considered to be reasons for rejection.
Out of the 57 volunteers who started this study, 53 completed all of the sensitivity tests and the challenge test series. The minimal loss of personnel in this full study resulted from personal reasons (two subjects developed upper respiratory infections during the study; one had a change in working hours and was unable to attend the tests; and one found it personally inconvenient).
Out of the 53 individuals who completed all of the tests, 50 were female and 3 male. Forty-seven of these subjects were between 18 and 32 years of age with the remaining six individuals being between 35 and 52 years of age.
The preponderance of female subjects increased the potentialities for sensitization and irritation responses.

Type of coverage:

occlusive

Preparation of test site:

not specified

Vehicle:

other: dimethyl phthalate

Controls:

no

Amount / concentration applied:

preparations were in 2% concentrations using dimethyl phthalate as the solvent.

Duration of treatment / exposure:

repeated 48-72h exposures in two rotating areas over 24 days

Observation period:

after the last exposure period a 2 week rest period was allowed prior to the challenge test series, following this a further 48h and 72 hour observation was taken.
Start date: 24-January-1966
End date: 04-March-1966

Number of animals:

Out of the 57 volunteers who started this study, 53 completed all of the sensitivity tests and the challenge test series. The minimal loss of personnel in this full study resulted from personal reasons (two subjects developed upper respiratory infections during the study; one had a change in working hours and was unable to attend the tests; and one found it personally inconvenient).
Out of the 53 individuals who completed all of the tests, 50 were female and 3 male. Forty-seven of these subjects were between 18 and 32 years of age with the remaining six individuals being between 35 and 52 years of age.
The preponderance of female subjects increased the potentialities for sensitization and irritation responses.

Details on study design:

In order to assure the completion of both the sensitizing and challenge test series by a minimum of fifty individuals, fifty-seven were inducted into the study for the first sensitization test application. The expanded number of volunteers accepted in order to assure the completion of the study by at least fifty individuals, takes into consideration the anticipated loss of individuals because of adhesive tape irritations and personal reasons which generally occur during the course of a study of this length of time.
The fifty-seven subjects were selected on a random basis in the order of their applying for participation in this study, except that no person was accepted who had active dermatologic conditions or other indicated illnesses. Previous sensitivities or a history of allergy were not considered to be reasons for rejection.
The technique employed in this study was that of the repeated insult method approved by the Food and Drug Administration. This procedure consists in the repeated applications of closed patch tests with 0.5 cc. of each solution being applied to individual absorbent patches, one material to each specific patch. These patches are applied to the area to be tested in a rotational sequence, identical at each testing. These patches are then secured by means of overlying strips of impervious adhesive tape which are then further sealed completely with additional overlying strips of similar tape. These patches are allowed to remain in situ for 48 hours and then removed, at which time readings are recorded. Following the removal of these tests, identical, similarly prepared patches in the identical sequence with the identical occlusive precautions –are then applied to the next area. The exception to this 48 hour contact is over the weekends when applications remain in situ for 72 hours until the following Monday. This prolonged contact offered a greater opportunity for irritation and sensitization and would, if such potentialities existed in these materials, add to the opportunities for their elicitation.
The initial site of application of these patch tests was the inner surface of the right deltoid area. When these were removed 48 hours after application, the next application was made to the inner surface of the left deltoid area. The third application was made to the original site of the first application, the inner surface of the right deltoid area, and the fourth application was made to the site of the second application on the medial surface of the left deltoid area. Thus, the cycle of rotation of the sites of application was alternately between the inner surfaces of the right and left deltoid areas.
This cycle of rotation of sites was continued through the series of ten identical sensitization test applications of the coded seven preparations on the following dates:
January 24, 26, 28, 31
February 2, 4, 7, 9, 11, 14, 16, 1966
The tenth patch test series which was applied on February 14 was removed and recorded on the eleventh visit, February 16, 1966.
This completed the sensitization series.
 
There then followed a two week rest period after which the challenge test series was applied on March 1, 1966. These applications were removed and a 48 hour reading -was recorded on March 3, 1966. The patches were not re-applied. Instead, a loosely applied cover of plain sterile gauze was made to cover the test site area to prevent washing, scratching or other interference with the development of any delayed reactions, if any were to develop. Twenty-four hours later, a 72 hour, or delayed reading was taken on March 4, 1966, to complete the study. The 48 hour contact of the material confined by the closed patches is considered a stringent test permitting maximum opportunity for elicitation of any sensitization or irritation reactions. The alternation of test sites is to permit an opportunity for involution of any irritative, traumatic or sensitizing responses which might occur from the materials being tested, or from the adhesive tape used to secure the test patches.
In addition to these test studies, there was performed the routine precautionary measure of checking on the primary irritative potentialities of the materials by applying them in the same manner as described above on a pilot group of seven subjects prior to the institution of these tests on the full group. Therefore, on Friday, January 21, 1966, these seven preparations were applied in closed patches in the same manner as described above' to the inner surface of the left deltoid areas of the seven subjects .selected for this pilot study. When, 24 hours later there were no complaints of itching, burning or other paresthesias from these seven volunteers, the patches were left in situ over the remainder of the weekend to be removed early on January 24. When all of the results were determined to be negative, it was considered safe to initiate this study on the full group of subjects as described above and the full study was initiated imIl1ediately on the full complement of individuals. These seven volunteers then became part of the full complement of fifty-seven subjects so that at the end of this sensitization series, they had eleven such sensitizing test applications as compared to the remaining fifty individuals who were to have ten such series of tests.
All of the preparations in the 2% solution were clear liquids at room temperature. Preparation DCIC, at room temperature, was a viscous jelly which upon warming, became a solution more suitable for application to the test patch.

Irritation parameter:

other: irritative or allergenic reactions

Time point:

72 h

Remarks on result:

no indication of irritation

The study was conducted according to the schedule and procedures as discussed in the preceding section of this report. There were no complications and no alterations in the planned procedure were necessary.

Out of the 57 volunteers who started this study, 53 completed all of the sensitivity tests and the challenge test series. The minimal loss of personnel in this full study resulted from personal reasons (two subjects developed upper respiratory infections during the study; one had a change in working hours and was unable to attend the tests; and one found it personally inconvenient).

Out of the 53 individuals who completed all of the tests, 50 were female and 3 male. Forty-seven of these subjects were between 18 and 32 years of age with the remaining six individuals being between 35 and 52 years of age.

The preponderance of female subjects increased the potentialities for sensitization and irritation responses.

There were no reactions either irritative or allergenic at any time either during the sensitization series or as a result of the challenge tests.

Because of the large number of tests which were applied and the necessary adhesive materials to keep these tests in place, there were at different times twenty-two reactions of irritation to the adhesive tape. In four of these subjects the reactions were becoming discomforting toward the end of the sensitization series. In the remainder of the individuals who reacted to the tape, the responses were primarily redness and puffiness which had disappeared by the time it was necessary to repeat the tests in the same sites.

Interpretation of results:

GHS criteria not met

Conclusions:

Fifty-seven volunteers were inducted into this sensitization and challenge test study in accordance with the schedule and technique described in the Procedure. Fifty-three of these subjects completed the entire test series.
There were no reactions either irritative or allergenic to any of the preparations employed in this study.

Executive summary:

An investigation was conducted to ascertain the irritative and sensitizing potentialities of the titled seven coded preparations. Preparation DCIC was prepared in a 5% concentration, while the remaining six preparations were in 2% concentrations using dimethyl phthalate as the solvent.

Fifty-seven volunteers were inducted into this sensitization and challenge test study in accordance with the schedule and technique described in the Procedure. Fifty-three of these subjects completed the entire test series.

There were no reactions either irritative or allergenic to any of the preparations employed in this study.

Reference 3

Endpoint:

skin irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Abstract only

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

not specified

Principles of method if other than guideline:

The method of procedure is that suggested by Dr. Draize and described in "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics", published by the Association of Food and Drug Officials of the United States.

GLP compliance:

no

Species:

rabbit

Strain:

other: study refers to "albino rabbits" which implies that new zealand whites were used, but this cannot be confirmed.

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Vehicle:

other: 80% Propylene Glycol

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Concentration (if solution): reported as 2.0% solution MHO in 80% Propylene Glycol

VEHICLE
- Concentration (if solution): 80% Propylene Glycol
- Purity: no data

Duration of treatment / exposure:

7 days (no wash)

Observation period (in vivo):

Both the treated and control eyes were examined every 24 for four days and then again on the seventh day.

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no washing was carried out
- Time after start of exposure: n/a

SCORING SYSTEM:
__________________________________
Cornea
A. Opacity-Degree of Density (area which is most dense is taken for reading)
Scattered or diffuse area-details of iris clearly visible = 1
Easily discernible translucent areas, details of iris slightly obscured = 2
Opalescent aress, no details of iris visible, size of pupil barely discernible = 3
Opaque, iris invisible = 4
B. Area of Cornea Involved
One quarter (or less) hut not zero = 1
Greater than one quarter-less than one-half = 2
Greater than one-haH less than three quarters = 3
Greater than three quarters up to whole area = 4
Score equals A x B x 5 Total maximum = 80
__________________________________
lris
A. Values
Folds ahove normal, congestion, swelling, circumcorneal injection (anyone or all of these or combination of any thereof), iris still reacting to light (sluggish reaction if positive) = 1
No reaction to light, hemorrhage; gross destruction (anyone or all of these) = 2
Score equals A x 5 Total possible maximum
__________________________________
Conjunctivae
A. Redness (refers to palpebral conjunctivae only)
Vessels definitely injected above normal = 1
More diffuse, deeper crimson red, individual vessels not easily discernible = 2
Diffuse beefy red = 3
B. Chemosis
Any swelling above normal (includes nictitating membrane) = 1
Obvious swelling with partial eversion of the lids = 2
Swelling with lids about half closed = 3
Swelling with lids about half closed to completely closed = 4
C. Discharge
Any amount different from normal (does not include small amount observed in inner canthus of normal animals) = 1
Discharge with moistening of the lids and hairs just adjacent to the lids = 2
Discharge with moistening of the lids and considerable area around the eye = 3
Score (A + B + C) x 2 Total maximum = 20
__________________________________

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24 h

Score:

0

Max. score:

20

Reversibility:

not specified

Irritation parameter:

iris score

Basis:

mean

Time point:

24 h

Score:

0

Max. score:

10

Reversibility:

not specified

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24 h

Score:

2

Max. score:

20

Reversibility:

fully reversible

Irritant / corrosive response data:

Instillation of the test material into rabbits' eyes, in the manner described, produced a very slight irritation only to the conjunctivae. On the second day of observation the treated eyes were normal.

Obervations:

Rabbit #1	day 1	day 2	day 3	day 4	day 7
Cornea-A-Opacity	0	0	0	0	0
Cornea-B-Area	0	0	0	0	0
Score = A x B x 5	0 x 0 x 5 = 0
Iris-A-Values	0	0	0	0	0
Score = A x 5	0 x 5 =0
Conjunctivae-A-Redness	1	0	0	0	0
Conjunctivae-B-Chemosis	0	0	0	0	0
Conjunctivae-C-Discharge	0	0	0	0	0
Score = (A+B+C)x2	(1 + 0 + 0) x 2 = 2

Rabbit #2	day 1	day 2	day 3	day 4	day 7
Cornea-A-Opacity	0	0	0	0	0
Cornea-B-Area	0	0	0	0	0
Score = A x B x 5	0 x 0 x 5 = 0
Iris-A-Values	0	0	0	0	0
Score = A x 5	0 x 5 =0
Conjunctivae-A-Redness	1	0	0	0	0
Conjunctivae-B-Chemosis	0	0	0	0	0
Conjunctivae-C-Discharge	0	0	0	0	0
Score = (A+B+C)x2	(1 + 0 + 0) x 2 = 2

Rabbit #3	day 1	day 2	day 3	day 4	day 7
Cornea-A-Opacity	0	0	0	0	0
Cornea-B-Area	0	0	0	0	0
Score = A x B x 5	0 x 0 x 5 = 0
Iris-A-Values	0	0	0	0	0
Score = A x 5	0 x 5 =0
Conjunctivae-A-Redness	1	0	0	0	0
Conjunctivae-B-Chemosis	0	0	0	0	0
Conjunctivae-C-Discharge	0	0	0	0	0
Score = (A+B+C)x2	(1 + 0 + 0) x 2 = 2

Interpretation of results:

GHS criteria not met

Conclusions:

According to Regulation EC 1272/2008, CLP, a substance should be considered for calssification as Eye irrit. 2 - H319 where a conjunctival redness and/or conjunctival oedema (Chemosis) score of ≥2 is observed. Since this is not the case for according to this data (only a redness score of 1 was observed in each observation, diminishing after 24h)

Executive summary:

Three healthy albino rabbits had 0.1 ml. of a 2% solution of Stemone in 80% Propylene glycol, instilled into the right eye with no further treatment. The untreated left eye of each animal served as its own control. Both the treated and control eyes were examined every twenty-four hours for four days and then again on the seventh day. The recorded observations, based on the the Draize scale for scoring ocular lesions, indicated that, according to the classification recommendations described in regulation EC 1272/2008 (CLP), the substance should not be considered irritating to the eyes based on the results of this study.

Reference 2

Endpoint:

eye irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)