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Diss Factsheets

Administrative data

Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented and reported study fully adequate for assessment. The study was conducted according to internationally accepted technical guidelines and in compliance with GLP in a recognized contract research organization.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report date:
2011

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Version / remarks:
of 2010
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)
Version / remarks:
of 2008
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of study:
mouse local lymph node assay (LLNA)

Test material

Constituent 1
Chemical structure
Reference substance name:
4'-[(diphenoxyphosphoryl)oxy]-[1,1'-biphenyl]-4-yl diphenyl phosphate
EC Number:
700-627-6
Cas Number:
17270-01-8
Molecular formula:
C36H28O8P2
IUPAC Name:
4'-[(diphenoxyphosphoryl)oxy]-[1,1'-biphenyl]-4-yl diphenyl phosphate
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

In vivo test system

Test animals

Species:
mouse
Strain:
CBA
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Mouse (healthy females only), strain: CBA/Ca with appropriate range of bodyweight at study start.
- Source: Charles River UK.
- Age at treatment start (1st induction): Eight to twelve weeks.
- Weight at treatment start (1st induction): Minimum 15.4 g, maximum 19.9 g.
- Housing: Individual housing in polycarbonate cages inside a barriered rodent facility.
- Bedding material: Woodflake bedding.
- Cage enrichment: Nestlets and plastic shelter
- Diet (ad libitum): Standard rodent diet (Rat and Mouse No. 1 Maintenance Diet) containing no added antibiotic,
chemotherapeutic or prophylactic agent.
- Water (ad libitum): Potable water from public supply.
- Acclimation period: At least 6 days before treatment start under laboratory conditions.

Analysis of the batch of diet used and water did not provide evidence of contamination that might have prejudiced the study.

ENVIRONMENTAL CONDITIONS

Air conditioned room kept at positve pressure without re-circulation of the filtered fresh air supplied to the room.
Controlled environment, environmental conditions were set at:
- Air changes per hour in the animal room: ca. 15
- Temperature (°C): 21 ± 2°C
- Relative Humidity (%): 40 to 70%
- Photoperiod (artificial lighting): 12 hrs day / 12 hrs night
There was no mentioning of any deviations from these ranges, which compromised the integrity or validity of the study.



Study design: in vivo (LLNA)

Vehicle:
acetone/olive oil (4:1 v/v)
Concentration:
Induction on Days 1, 2 and 3 at the following concentrations of ADK STAB FP-800 in vehicle (w/v):
- Pre-screen Test: 50% (2 females).
- Main Study: 0% (vehicle control, 4 females), 10% (4 females), 25% (4 females), 50% (4 females).
No. of animals per dose:
Pre-screen Test: 2 female animals
Main Study: 4 female animals per dose
Positive Control: 4 female animals (1 dose group)
Details on study design:
TEST SUBSTANCE SOLUBILITY:

A vehicle trial has demonstrated that the maximum practical concentration of ADK STAB FP-800 suitable for use in the LLNA is a 50 % (w/v) suspension in the vehicle, acetone:olive oil (4:1 v/v). At this concentration an off white suspension was formed.

TREATMENT PREPARATION AND ADMINISTRATION:

- Pre-screen Test
Administration of ADK STAB FP-800 at 50% w/v to two animals on three consecutive days did not produce death, signs of ill health, toxicity or local irritation over the treated area. Ear thickness was also unaffected by the treatment. A minor loss in bodyweight was recorded. Greasy fur on the head was noted post dose having resolved by Day 4. Based on this information 50% w/v was selected as high dose level for the main study.

- Main Study
On three consecutive days, groups of 4 female mice were treated by topical application to the entire dorsal surface of both ears with 25 μL/ear/day at the following concentrations (w/v) of test substance in the vehicle:

Group 1 (Vehicle Control): 0%,
Group 2 (Low Dose): 10%,
Group 3 (Mid Dose): 25%,
Group 4 (High Dose): 50%

Concomitant with the Main Study a positive control group of 4 female mice received hexylcinnamic aldehyde at the following concentration in the vehicle, acetone:olive oil v/v 4:1:
Group 5 (Positive Control): 25%

The test substance preparations were prepared on each day of administration and dosed within 4 hours of preparation.

OBSERVATIONS, MEASUREMENTS AND ENDPOINTS (POOLED TREATMENT GROUP APPROACH) DURING THE MAIN STUDY:

All animals were checked daily for signs of ill health or toxicity. The ears were also examined daily for signs of irritation. In addition, bodyweights were recorded on Days 1 (prior to treatment) and 6 (three days after the third induction administration). On Day 6, all animals were injected into the tail vein 3H-methyl thymidine diluted in phosphate buffered saline at a nominal dose of 20 µCi per mouse, in order to measure lymphocyte proliferation by radioactive labelling. Five hours afterwards the draining (auricular) lymph nodes were excised and pooled for each experimental group. After precipitating the DNA of the lymph node cells, radioactivity measurements were performed on Day 7. Radioactivity was expressed as the number of radioactive disintegrations per minute (dpm). The ratio of the proliferation (reflected by the magnitude of measured dpm/node) in treated groups to that in the vehicle control group, termed the stimulation index (SI) or test/control ratio, was subsequently calculated for each group.

Criteria Used to Consider a Positive Response:

The test substance is regarded as a sensitizer if at least one concentration of the test substance produces a stimulation index (SI) ≥ 3.


Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Statistics:
Data were not statistically analysed.

Results and discussion

Positive control results:
A stimulation index (SI) of 6.7 was attained in a concomittant positive control assay with the same strain of mice (CBA/Ca) in response to 25% v/v hexyl cinnamic aldehyde in acetone:olive oil (4:1 v/v), thus demonstrating the reliability and sensitivity of this test system and assay to detect skin sensitization potential in this laboratory.

In vivo (LLNA)

Resultsopen allclose all
Parameter:
SI
Remarks on result:
other: Stimulation Index (SI) values for the experimental groups treated with 10, 25 and 50% w/v test substance suspensions were 0.5, 0.7 and 0.7, respectively.
Parameter:
other: disintegrations per minute (DPM)
Remarks on result:
other: Overall DPM/lymph node values for the experimental groups treated with 10, 25 and 50% w/v test substance suspensions were 273.44, 387.46 and 397.87 DPM/node, respectively. For the vehicle control group, 563.26 DPM/node were recorded.

Any other information on results incl. tables

Mortality / clinical signs:

There were no deaths, no signs of ill health or toxicity and no signs of dermal irritation over the treated area.

Greasy fur on the head was noted for all animals from the vehicle control, test and positive control groups following each dosing occasion and had resolved by Day 4 in the vehicle control and test groups and by Day 6 in the positive control group. Ear thickness measured only during the pre-screen test was also unaffected.

Body weight:

There was no indication of adverse effects of the test substance on bodyweight in main study animals. Marginal to slight bodyweight loss in the pre-screen test was not considered to be toxicologically relevant.

Applicant's summary and conclusion

Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU