Disodium 1-amino-4-[[3-[(5-chloro-2,6-difluoro-4-pyrimidinyl)amino]-2-methyl-5-sulphonatophenyl]amino]-9,10-dihydro-9,10-dioxoanthracene-2-sulphonate

Respiratory sensitisation

Administrative data

Endpoint:

respiratory sensitisation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1990-09-10 to 1991-02-26

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The study is equivalent to following methods:
- according KAROL et al. 1995; KAROL et al. 1978; DeCEAURRIZ et al. 1987; BARROW et al, '1977, BOTHAM et al., 1988; BOTHAM et al., 1989
- exposition technical criteria according OECD 403 and corresponding EG-guideline as relevant so far for this study type
- Measuring according to general recommendations of ASTM E 981-84; ALARIE, 1973

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Disodium 1-amino-4-[[3-[(5-chloro-2,6-difluoro-4-pyrimidinyl)amino]-2-methyl-5-sulphonatophenyl]amino]-9,10-dihydro-9,10-dioxoanthracene-2-sulphonate

EC Number:

276-374-6

EC Name:

Disodium 1-amino-4-[[3-[(5-chloro-2,6-difluoro-4-pyrimidinyl)amino]-2-methyl-5-sulphonatophenyl]amino]-9,10-dihydro-9,10-dioxoanthracene-2-sulphonate

Cas Number:

72139-17-4

Molecular formula:

C25H16ClF2N5O8S2.2Na

IUPAC Name:

disodium 1-amino-4-({3-[(5-chloro-2,6-difluoropyrimidin-4-yl)amino]-2-methyl-5-sulfophenyl}amino)-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate

Test material form:

solid

Test animals

Species:

guinea pig

Strain:

Pirbright-Hartley

Remarks:

White - Dunkin

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Versuchstierzucht Winkelmann, Borchen
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 1-2 months
- Weight at study initiation: 284 ± 20 g
- Housing: Makrolon-cages type IV (4 animals per cage); cages were cleaned once a week and disinfected with Zephirol (10%), Litter: wooden granular (Typ S 8/15; Ssniff - Spezialdiaten GmbH, D 4770 Soest)
- Diet (e.g. ad libitum): ad libitum; fixed formula standard diet “Altromin 3022 – Haltungsdiät für Meerschweinchen from Altromin GmbH, Lage)
- Water (e.g. ad libitum): ad libitum; tap water
- Acclimation period: at least 1 week
- Indication of any skin lesions: only health and symptom free animals were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 °C
- Humidity (%): ca. 50%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

Test system

Route of induction exposure:

intradermal

Route of challenge exposure:

inhalation

Vehicle:

peanut oil

Concentration:

intradermal induction: 5% test item in peanut oil

No. of animals per dose:

8

Details on study design:

RANGE FINDING TESTS:

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3 times intradermal application, 2 applications of 100 µL each
- Test groups: 2 applications of 100 µL of 5% test item in peanut oil, each
- Control group: 2 applications of 100 µL of peanut oil, each
- Site: on the flank, Day 0: cranial, Day 2: thoracal, Day 4: caudal
- Frequency of applications: every second days
- Duration: 4 days
- Concentrations: solution of the test item in peanut oil

B. CHALLENGE EXPOSURE
- No. of exposures: 2 à 30 min
- Day(s) of challenge: 2
- Exposure period: day 21 to 24
- Test groups: days 22 and 24 to 66 and 63 mg/m3
- Control group: days 21 and 23 to 68 and 62 mg/m3yes
- Site: head-nose exposition
- Concentrations: 65 mg/m3 air
- Evaluation (hr after challenge): respiratory rate, respiratory volume, respiratory minute volume, inspiration and expiration time was evaluated during and 20 h after challenge exposure; animals were killed 1 day after the last challenge exposure

Challenge controls:

no (induction controls: vehicle control)

Positive control substance(s):

none

Negative control substance(s):

none

Results and discussion

Results:

Induction:
No test item-related effects; but local skin reactions at the injection site (encrusted, slightly hardened and partly also soaking skin)

Challenge:
In one test item-exposed animal a difficult breathing was observed. All other animals did not show any symptoms.

Lung function tests:
In 4 of 8 exposed animals effects of pulmonary hypersensitivity were observed. There were no delayed pulmonary reactions. See also table 2 in "Any other information on results incl. tables".

Body weight:
There were no changes in body weights observed.

Gross pathology:
In one exposed animal effects in lung (lung edema, hydrothorax, hepatisation) were found.

Lung weights:
No changes in lung weights were observed in any animals.

Positive control results:

NA

Negative control results:

No effects were observed in vehicle control animals.

Any other information on results incl. tables

Table 2 Number of Animals with positive Reaction during Challenge Phase

Induction	Anaphylaxie	Immediate	Delayed
Vehicle	0/8	0/8	0/8
Test item	0/8	4/8	1/8

Applicant's summary and conclusion

Interpretation of results:

Category 1 (respiratory sensitising) based on GHS criteria

Conclusions:

In this study, the test item showed a sensitising potential in lungs of guinea pigs.

Executive summary:

In a respiratory sensitization study with the test item, young adult Pirbright-White-Dunkin-Hartley guinea pigs (8 females/group) were tested for respiratory sensitisation. The test was carried out according to published methods of KAROL et al. 1985 and 1978; DeCEAURRIZ et al. 1987; BARROW et al, 1977, BOTHAM et al., 1988 and BOTHAM et al., 1989.

No effects in body and lung weights were observed compared to the vehicle control. Gross pathological findings in the lung of one animal were seen as Typ-1 reaction-related effects.

During and after the challenge phase, 50% of the animals showed allergic reactions of the immediate-type.

 

According to this study, the test item is a sensitiser and needs to be classified as Cat. 1 (respiratory sensitising) based on GHS criteria.