Registration Dossier

Administrative data

Description of key information

In a skin irritation study (reliability score 1) conducted to OECD 404 and GLP, ATMP-H (50% active acid) was not irritating to the skin of rabbits (Safepharm Laboratories, 1982). 3 out of 3 test animals showed Grade 1 erythema 1 hour post-exposure, persisting to 24 hours in 2 animals. All skin reactions were fully resolved by the 48 hour observation. A further study was performed using a sample of the pure powder and a 25% aqueous formulation, with a 24 hour treatment under occlusion (Younger Laboratories, 1967). Although the powder was non-irritating, there were signs of irritation with the aqueous formulation; moderate erythema with defined oedema were reported in 3 of 3 test animals 24 hours post-exposure, reducing in severity at 48 and 72 hours. All skin reactions were fully resolved within 7 days. This study, although pre-GLP, is considered acceptable for assessment.

In a summary of an eye irritation study (Younger Laboratories, 1967) conducted prior to the adoption of OECD test guidelines and GLP, finely ground powder of ATMP-H caused moderately severe irritation to rabbit eyes. In supporting studies, solutions of ATMP-H were found to be irritating to 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:
27.07.1982 to 30.07.1982
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
undiluted
Duration of treatment / exposure:
4 hour(s)
Observation period:
1, 24, 48 and 72 hours
Number of animals:
Three
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
24/48/72 h
Score:
0.4
Reversibility:
fully reversible
Remarks on result:
other: No edema observed in any animal. 3/3 animals had grade 1 erythema after one hour, 2/3 had grade 1 erythema after 24 hours. There was no erythema in any animal by 48 hours.
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Other effects:
None reported.
Interpretation of results:
GHS criteria not met
Conclusions:
In a skin irritation study (reliability score 1) conducted to OECD 404 and GLP, ATMP was not irritating to the skin of rabbits.
Executive summary:

In a skin irritation study (reliability score 1) conducted to OECD 404 and GLP, ATMP was not irritating to the skin of rabbits.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (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:
No data
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 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
No details on test substance, animals and environmental conditions.
Principles of method if other than guideline:
Method: other: Insufficient detail to fully assess comparability with OECD guideline.
GLP compliance:
no
Species:
rabbit
Strain:
not specified
Details on test animals or tissues and environmental conditions:
No data
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
100 mg of a finely ground powder placed into the conjunctival sac of the right eye.
Duration of treatment / exposure:
24 hour(s)
Observation period (in vivo):
Seven days
Number of animals or in vitro replicates:
Three
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes, with warm isotonic saline solution.
- Time after start of exposure: 24 hours.

SCORING SYSTEM: Draize

TOOL USED TO ASSESS SCORE: No data
Irritation parameter:
other: Average maximum score
Basis:
mean
Time point:
other: 24 hours
Score:
53.6
Max. score:
110
Reversibility:
not fully reversible within: Seven days
Remarks on result:
other: Results given as one overall score per animal, not broken down into effects on cornea/iris/conjunctivae.
Irritant / corrosive response data:
Oedema with the lids about half closed, copious discharge, moderate redness of the conjunctivae and mild corneal cloudiness were recorded by one hour after instillation. The lids were nearly closed overnight and there was moderate iris conjunction (24 hours). Improvement followed irrigation so that within five days iris clarity was nearly normal in two animals. Also, discharge had ceased and oedema had reduced considerably.
Other effects:
Signs of discomfort or pain were pawing at the eyes.

Table 1 Summary of eye irritation scores

 Animal Number                 Numerical Evaluation* at the end of:
   1 hour  24 hours  48 hours  72 hours  120 hours  168 hours
 1 - Male  32  57  48  39  19  8
 2 - Female  25  49  41  31  10  2
 3 - Male  27  55  44  29  8  2
 Average  28.0  53.6  44.3  33.0  12.3  4.0

*Results given as one overall score per animal, not broken down into effects on cornea/iris/conjunctivae.

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
In a summary of an eye irritation study (reliability score 2) conducted prior to the adoption of OECD test guidelines and GLP, finely ground powder of ATMP-H (Dequest 2000) caused moderately severe eye irritation to rabbit eyes.
Executive summary:

In an eye irritation study conducted prior to the adoption of OECD test guidelines and GLP, 100 mg of a finely ground powder of ATMP-H was placed in the conjunctival sac of the right eye of each of three albino rabbits. The eyes were rinsed with warm isotonic saline solution after 24 hours. The eyes were then observed and reactions scored for seven days. Following instillation, animals showed signs of discomfort/pain. Oedema with the lids about half closed, copious discharge, moderate redness of the conjunctivae and mild corneal cloudiness were recorded by one hour after instillation. The lids were nearly closed overnight and there was moderate iris conjection (24 hours). Improvement followed irrigation so that within five days iris clarity was nearly normal in two animals. Also, discharge had ceased and oedema had reduced considerably. The average maximum score was 53.6 out of a possible 110, at 24 hours post-exposure (individual scores for cornea, iris and conjunctivae not given in study report). It was concluded that ATMP-H is a moderately severe eye irritant.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The most reliable studies were selected as the key studies.

For skin irritation, the differences between responses for the two studies on the formulations may be due to the different exposure times and/or may reflect compositional differences as the formulations were produced by different suppliers. However, neither study resulted in skin reactions that were sufficient to trigger classification according to current EC guidelines.


Justification for classification or non-classification

Low pH (<2) predicts that ATMP acid should be severely irritating or corrosive to skin and eyes. However, for skin irritation, 4 studies on several different formulations produced by different manufacturers, including a guideline key study of reliability 1, consistently demonstrate no corrosive effects and insufficient irritation for classification as irritating to skin.

For eye irritation, one study on the acid as a pure powder and two on the undiluted commercial product demonstrate moderate irritation. Two of the studies examined eyes only up to 7 days post exposure, at which time slight effects still persisted. In the study which examined eyes up to 14 days, all irritant effects had resolved. From the low degree of irritant effects still present but reducing in severity at 7 days, it can be predicted that all effects would have resolved had examination continued to 21 days. None of these studies therefore indicate a requirement to classify for irreversible eye effects in Category 1. The classification indicated from the study data is Category 2.

According to the tiered approach in Regulation 1272/2008 for classification for skin irritation under EU GHS, existing human/animal data are to be considered first if available, and classification should be based on these data. A default classification derived from pH alone is only required if no reliable test data are available.

It is concluded that classification for skin irritation or corrosion is not required for ATMP acid. ATMP acid should be classified for eye irritation in Category 2 in accordance with EC regulation 1272/2008.