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Diss Factsheets

Administrative data

Description of key information

A human insult patch test showed that the substance should not be considered as a primary irritant for skin. An in vitro Eye irritation study as well as an in vivo eye irritation performed with rabbit showed that the substance is not considered to be irritating for eyes.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No GLP study.
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was performed to determine the possibility of the test item to induce skin irritation.
50 caucasian Humans (25 males and 25 females ) were used to performed the experiment.
The test material was evaluated at a concentration of 10% in 3% methyl cellulose.
The series of 9 induction patches was applied .
Based on the incidence and severity of the reactions, the test material will be considered as irritant or not to Human skin.
GLP compliance:
no
Species:
other: Human
Strain:
other: Caucasian
Details on test animals or test system and environmental conditions:
- Age at study initiation: 21-38 for male (25) and 18-60 for female (25)
- Race: Caucasian
Type of coverage:
occlusive
Preparation of test site:
not specified
Vehicle:
other: 3% methylcellulose
Controls:
no
Amount / concentration applied:
0.03 mlof HT 939 was applied.
Duration of treatment / exposure:
A patch with HT 939 was applied on Monday, Wednesday and Thursday and allowed to contact the skin for 24 hours
Observation period:
72 hours
Number of animals:
50 caucasian Human (25 males and 25 females)
Details on study design:
Fifty human subjects were employed in the investigation.
A patch of HT 939 test material was applied on Monday, Wednesday and Thursday and allowed to contact the skin for 24 hours, after which time
it was removed and the skin site graded for irritation.


Skin application the test material was made using Readi-Band* "hypoallergenic nonirritating" clear plastic patches 1-1/2" x 1-1/2" square
with nonwoven Webril centers. Approximately 0.03 ml of the test materials was applied on the Webril center of the patch just prior to application.

SCORING SYSTEM:
Scoring Criteria for Skin Irritation Reactions
Erythema and Eschar Formation
- No reaction: 0
- Very slight erythema (barely perceptible): 1
- Mild, well-defined erythema: 2
- Moderate to severe erythema: 3
- Severe erythema (beet redness) to slight eschar formation (injuries in depth): 4

Total possible erythema score 4

Edema Formation
- No reaction: 0
- Very slight edema (barely perceptible): 1
- Slight edema (edge of area well -defined by definite raising: 2
- Moderate edema (area raised approximately 1 mm 3
- Severe edema (area raised more than 1 mm and extending beyond area of exposure): 4

Total possible edema score 4
Total possible irritation score 8
Remarks on result:
other: Patch test performed on 50 Humans (25 males and 25 females). Based on the incidence and severity of the reactions, the test material would not be considered a primary skin irritant under the exaggerated test conditions.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the incidence and severity of the reactions, the test material would not be considered a primary skin irritant under the exaggerated test
conditions .
Executive summary:

The study was performed to determine to possibility of HT 939 to induce skin irritation.

50 caucasian Humans (25 males and 25 females ) were used to performed the experiment.

The test material was evaluated at a concentration of 10% in 3% methyl cellulose.

The series of 9 induction patches was applied according to the following schedule. A patch of each test material was applied on Monday, Wednesday and Thursday and allowed to contact the skin for 24 hours, after which time it was removed and the skin site graded for irritation.

Based on the incidence and severity of the reactions, the test material would not be considered a primary skin irritant under the exaggerated test conditions.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
The study was conducted between 09 September 2014 and 18 September 2014.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Two New Zealand White (Hsdlf:NZW) strain rabbits were supplied by Harlan Laboratories UK Ltd., Leicestershire, UK. At the start of the study the animals weighed 2.54 or 2.97 kg and were twelve to twenty weeks old. After an acclimatization period of at least five days each animal was given a number unique within the study which was written with a black indelible marker pen on the inner surface of the ear and on the cage label.

The animals were individually housed in suspended cages. Free access to mains drinking water and food (2930C Teklad Global Rabbit diet supplied by Harlan Laboratories UK Ltd., Oxon, UK) was allowed throughout the study. The diet and drinking water were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

The temperature and relative humidity were set to achieve limits of 17 to 23 °C and 30 to 70% respectively. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

Justification
The rabbit is the preferred species of choice as historically used for irritation studies and is specified in the appropriate test guidelines. The number of animals used was the minimum required to achieve the objectives of the study. Testing was conducted in two animals and the response in those animals was such that exposure of a third animal would not affect classification of the test item, therefore, no further testing was needed.
Vehicle:
unchanged (no vehicle)
Controls:
other: The left eye remained untreated and was used for control purposes.
Amount / concentration applied:
A volume of 0.1 mL of the test item, which was found to weigh approximately 75 mg was used.
Duration of treatment / exposure:
The test substance was not removed from the test eye.
Observation period (in vivo):
Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment.
Number of animals or in vitro replicates:
Two
Details on study design:
Immediately before the start of the test, both eyes of the provisionally selected test rabbits were examined for evidence of ocular irritation or defect with the aid of a light source from a standard ophthalmoscope. Only animals free of ocular damage were used.

Initially, a single rabbit was treated. A subcutaneous injection of buprenorphine 0.01 mg/kg was administered 60 minutes prior to test item application to provide a therapeutic level of systemic analgesia. Five minutes prior to test item application, a pre dose anesthesia of ocular anesthetic (two drops of 0.5% tetracaine hydrochloride) was applied to each eye.

A volume of 0.1 mL of the test item, which was found to weigh approximately 75 mg (as measured by gently compacting the required volume into an adapted syringe) was placed into the conjunctival sac of the right eye, formed by gently pulling the lower lid away from the eyeball. The upper and lower eyelids were held together for about one second immediately after treatment, to prevent loss of the test item, and then released. The left eye remained untreated and was used for control purposes. Immediately after administration of the test item, an assessment of the initial pain reaction was made.
Eight hours after test item application, a subcutaneous injection of post dose analgesia, buprenorphine 0.01 mg/kg and meloxicam 0.5 mg/kg, was administered to provide a continued therapeutic level of systemic analgesia. The treated animal was checked for signs of pain and suffering approximately 12 hours later. No further analgesia was required.

After consideration of the ocular responses produced in the first treated animal, a second animal was similarly treated.

Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment, according to the numerical evaluation (Draize, J.H, 1977).

Any other ocular effects were also noted. Examination of the eye was facilitated by the use of the light source from a standard ophthalmoscope.

Any clinical signs of toxicity, if present, were also recorded.

Individual body weights were recorded on Day 0 (the day of dosing) and at the end of the observation period.
Irritation parameter:
cornea opacity score
Remarks:
Male 74697
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Not applicable
Remarks on result:
other: Not classified
Irritation parameter:
cornea opacity score
Remarks:
Male 74710
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Not applicable
Remarks on result:
other: Not classified
Irritation parameter:
iris score
Remarks:
Male 74697
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: Not applicable
Remarks on result:
other: Not classified
Irritation parameter:
iris score
Remarks:
Male 74710
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: Not applicable
Irritation parameter:
conjunctivae score
Remarks:
Male 74697
Basis:
mean
Remarks:
Redness
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Not classified
Irritation parameter:
conjunctivae score
Remarks:
Male 74710
Basis:
mean
Remarks:
Redness
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Not classified
Irritation parameter:
chemosis score
Remarks:
Male 74697
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0.66
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Not classified
Irritation parameter:
chemosis score
Remarks:
Male 74710
Basis:
mean
Time point:
other: 24, 48 and 72 hours
Score:
0.66
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Not classified
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 1 hour
Score:
9
Max. score:
110
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 24 hours
Score:
8
Max. score:
110
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 48 hours
Score:
4
Max. score:
110
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Classed as a mild irritant according to a modified Kay and Calandra classification system; not classified according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures.
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 72 hours
Score:
0
Max. score:
110
Reversibility:
other: Not applicable
Irritant / corrosive response data:
No corneal or iridial effects were noted during the study.

Moderate conjunctival irritation was noted in both treated eyes 1 and 24 hours after treatment with minimal conjunctival irritation noted at the 48 Hour observation.

Both treated eyes appeared normal at the 72 Hour observation.
Other effects:
Body Weight
Both animals showed expected gain in body weight during the study.

Individual Scores and Individual Total Scores for Ocular Irritation

Rabbit Number and Sex

74697Male

74710Male

IPR= 0

IPR = 0

Time After Treatment

1
Hour

24
Hours

48
Hours

72
Hours

1
Hour

24
Hours

48
Hours

72
Hours

CORNEA

 

 

 

 

 

 

 

 

E = Degree of Opacity

0

0

0

0

0

0

0

0

F = Area of Cornea Involved

0

0

0

0

0

0

0

0

Score (E x F) x 5

0

0

0

0

0

0

0

0

IRIS

 

 

 

 

 

 

 

 

D

0

0

0

0

0

0

0

0

Score (D x 5)

0

0

0

0

0

0

0

0

CONJUNCTIVAE

 

 

 

 

 

 

 

 

A = Redness

2

2

1

0

2

2

1

0

B = Chemosis

2

1

1

0

1

1

1

0

C = Discharge

1

1

0

0

1

1

0

0

Score (A + B + C) x 2

10

8

4

0

8

8

4

0

Total Score

10

8

4

0

8

8

4

0

IPR=Initial pain reaction

Individual Total Scores and Group Mean Scores for Ocular Irritation

Rabbit Number

and Sex

Individual Total Scores At:

1 Hour

24 Hours

48 Hours

72 Hours

74697Male

10

8

4

0

74710Male

8

8

4

0

Group Total

18

16

8

0

Group Mean Score

9.0

8.0

4.0

0.0

 

Individual Body Weights and Body Weight Change

Rabbit Number
and Sex

Individual Body Weight (kg)

Body Weight Change (kg)

Day 0

Day 3

74697Male

2.54

2.61

0.07

74710Male

2.97

3.04

0.07

 

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test item produced a maximum group mean score of 9.0 and was classified as a mild irritant (Class 4 on a 1 to 8 scale) to the rabbit eye according to a modified Kay and Calandra classification system.
The test item does not meet the criteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures.
Executive summary:

Introduction

The study was performed to assess the irritancy potential of the test item to the eye of the New Zealand White rabbit.

 

Results

A single application of the test item to the non-irrigated eye of two rabbits produced moderate conjunctival irritation. Both treated eyes appeared normal at the 72‑Hour observation.

 

Conclusion

The test item produced a maximum group mean score of 9.0 and was classified as a mild irritant (Class4on a 1 to 8 scale) to the rabbit eye according to a modified Kay and Calandra classification system.

 

The test item does not meet the criteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for selection of skin irritation / corrosion endpoint:
only existing study

Justification for selection of eye irritation endpoint:
In vivo study

Justification for classification or non-classification

Based on the above stated assessment of the skin irritation potential, the substance does not have to be classified for skin irritation according to Council Directive 2001/59/EC and according to CLP (Regulation (EC) No 1272/2008 Of the European parliament and of the Council.

Base on the above assessment of the eye irritation potential, the substance does not have to be classified as for risk of serious damage to eyes according to Council Directive 2001/59/EC and according to CLP (Regulation (EC) No 1272/2008 Of the European parliament and of the Council.