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Description of key information

The result for skin sensitisation is a read across from the ammonium salt (CAS 34274-28-7). The substance was not found to be sensitising to the skin of guinea pigs in a high reliability, guideline study (Safepharm Laboratories, 1995; rel 1).

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
27.03.1995 to 05.05.1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
The study is a read across from the ammonium salt (CAS 34274-28-7).
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
GLP compliance:
yes (incl. certificate)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
An LLNA study was not performed because there is an existing reliable study for skin sensitisation using the Guinea Pig Maximisation test method.
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: David Hall Limited, Staffordshire, UK.
- Age at study initiation:8-12 weeks
- Weight at study initiation: 334-430 g
- Housing: Singly or in pairs in solid-floor polypropylene cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Minimum five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-28
- Humidity (%): 51-68
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 27.03.1995 To 05.05.1995
Route:
intradermal and epicutaneous
Vehicle:
water
Concentration / amount:
Intradermal induction: 10% w/v in distilled water; 10% w/v in a mixture of FCA plus distilled water (1:1).
Topical induction: undiluted.
Topical challenge: 100% and 75% v/v in distilled water.
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
water
Concentration / amount:
Intradermal induction: 10% w/v in distilled water; 10% w/v in a mixture of FCA plus distilled water (1:1).
Topical induction: undiluted.
Topical challenge: 100% and 75% v/v in distilled water.
No. of animals per dose:
20 test and 10 control used for the main study.
Details on study design:
RANGE FINDING TESTS: Four concentrations of test substance were investigated (1, 5, 10 and 25% w/v in distilled water). A total of four guinea pigs were used, each animal received four 0.1 ml injections of only one concentration of the test substance. The degree of erythema at the injection sites was assessed approximately 24, 48 and 72 hours and seven days after the injection according to the Draize scale. Oedema was not assessed. Evidence of systemic toxicity was recorded. The highest concentration that caused only mild to moderate skin irritation, and which was well tolerated systemically, was selected for the intradermal induction stage of the main study.
Two guinea pigs (intradermally injected with Freund's Complete Adjuvant 15 days earlier) were treated with the undiluted test substance and three preparations of the test substance (75, 50 and 25%) v/v in distilled water). Applications were made to the clipped flanks under occlusive dressings for an exposure period of 48 hours.The degree of erythema and oedema was evaluated approximately 1, 24 and 48 hours after dressing removal. The highest concentration producing only mild to moderate dermal irritation was selected for the topical induction stage of the main study.
The undiluted test substance and three preparations of the test substance (75, 50 and 25% v/v in distilled water) were applied to the clipped flanks of two guinea pigs under occlusive dressings for 24 hours. The animals did not form part of the main study, but had been treated identically to the controls of the main study up to Day 14. The degree of erythema and oedema was evaluated approximately 1, 24 and 48 hours after dressing removal. The highest non-irritant concentration of test substance and one lower concentration were selected for the topical challenge stage of the main study.
MAIN STUDY
A. INDUCTION EXPOSURE
Shortly before treatment on Day 0 the hair was removed from an area on the shoulder region of each animal. A row of three injections (0.1ml) each was made on each side of the mid-line. The injections were: a) FCA plus distilled water (1:1); b) a 10% w/v formulation of the test substance in distilled water; c) a 10% w/v formulation of the test substance in a 1:1 preparation of FCA plus distilled water. Approximately 24 and 48 hours after the intradermal injection, the degree of erythema at the injection sites was evaluated. One week later (Day 7), the same area on the shoulder region was clipped again and treated with a topical application of the undiluted test substance (under an occlusive dressing for 48 hours). The degree of erythema and oedema was quantified at one and 24 hours following removal of the patches.
Induction of the control animals used an identical procedure as the test animals, except the injections were: a) FCA plus distilled water in the ratio 1:1; b) distilled water; c) 50% w/v formulation of distilled water in a 1:1 mixture of FCA/distilled water. The topical applications followed the same procedure as for the test animals, but nothing was applied to the patch. Skin reactions were quantified.

B. CHALLENGE EXPOSURE
Shortly before treatment on Day 21, an area of skin on both flanks of each animal was clipped free of hair. A square filter paper patch saturated with the undiluted test substance was applied to the shorn right flank of each animal and was held in place with a strip of surgical adhesive tape. To ensure that the maximum non-irritant concentration was used at challenge, the test substance at a concentration of 75% v/v in distilled water was similarly applied to a skin site on the left shorn flank. The patches were covered with an occlusive dressing. After 24 hours the dressing was removed. The challenge sites were swabbed with cotton wool soaked in distilled water to remove residual material. Prior to the observation period, the flanks were clipped to remove regrown hair.
Approximately 24 and 48 hours after challenge dressing removal, the degree of erythema and oedema was quantified, and any other reactions recorded. The percentage of test animals that showed a more severe reaction at the test substance challenge site than the most severe reaction observed in the control animals, was compared using the scale: 0% = non-sensitiser; >0-8% = weak sensitiser; >8-28 = mild sensitiser; >28-64% = moderate sensitiser; >64-80% = strong sensitiser; >80-100% = extreme sensitiser.
Challenge controls:
Negative controls only.
Positive control substance(s):
no
Positive control results:
No positive control.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
75 and 100%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
75 and 100%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
distilled water
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
distilled water
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Group:
positive control
Remarks on result:
other: not used in the study

Body weights of the guinea pigs in the test group between Day 0 and 24, were comparable to those observed in the control groups over the same period.

Interpretation of results:
GHS criteria not met
Conclusions:
In a GLP, skin sensitisation study (reliability score 1) conducted to OECD 406 (maximisation test), ammonium salt of ATMP was not sensitising to the skin of guinea pigs. The result is a read across from the ammonium salt (CAS 34274-28-7).
Executive summary:

In a GLP, skin sensitisation study (reliability score 1) conducted to OECD 406 (maximisation test), ammonium salt of ATMP was not sensitising to the skin of guinea pigs.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

The result for skin sensitisation is a read across from the ammonium salt (CAS 34274-28-7). The substance was not found to be sensitising to the skin of guinea pigs in a high reliability, guideline study (Safepharm Laboratories, 1995; rel 1).

The use of read-across data between members of the category is in accordance with the rationale outlined in the Toxicological information endpoint summary of the IUCLID section 7.1 and Section 1.4 of the CSR. Studies are available for the acid and the ammonium salt and the results of these studies are in agreement, indicating that the ammonium ion does not influence sensitisation. In several in vivo toxicity studies, at a defined pH, a salt will behave no differently to the parent acid, at identical concentration of the particular speciated form present, and will be fully dissociated to yield ATMP anion and the relevant counterion(s). Hence properties for a salt (in contact with water or in aqueous media) can be directly read across (with suitable mass correction) to the parent acid andvice versa.Therefore, read-across within the ATMP category is considered appropriate. Ammonia and ammonium ions have been extensively studied and reported in the public literature and are discussed fully in respect of each endpoint. 

 

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available data, no classification is required for ammonium salt, [nitrilotris(methylene)]trisphosphonic acid, sodium salt for skin sensitisation in accordance with Regulation (EC) No 1272/2008.