Registration Dossier

Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1959
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Current research in polyphenyl compounds as atomic reactor moderator-coolants was conducted to determine whether heating and irradiation woudl increase their toxicity. Testing was performed with mixtures of different composition from the registration substance, or with individual constituents. The study is therefore not fully appropriate for safety assesment.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1959
Report date:
1959

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Intradermal injection of 0.05 mL of each compound was made three times weekly for a total of 10 injections. Two weeks after the last injection, each animal received a test in jection of 0.05 mL test material.
GLP compliance:
no
Type of study:
intracutaneous test

Test material

Constituent 1
Reference substance name:
Terphenyl mixture (OMRE)
IUPAC Name:
Terphenyl mixture (OMRE)
Constituent 2
Reference substance name:
Reactor irradiated terphenyl mixture (ROMRE)
IUPAC Name:
Reactor irradiated terphenyl mixture (ROMRE)
Details on test material:
Name of test material (as cited in study report):
OMRE (terphenyl mixture): 17.0% biphenyl, 45.3% OTP, 29.2% MTP, 5.6% PTP, 2.9% otther aromatics
ROMRE (reactor irradiated terphenyl mixture): 16.0% biphenyl, 34.8% OTP, 25.4% MTP, 5.0% PTP, 11.7% high-boiling residue operational loss
OTP (ortho-terphenyl)
MTP (meta-terphenyl)
PTP (para-terphenyl)

In vivo test system

Test animals

Species:
guinea pig

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
corn oil
Concentration / amount:
0,05mL
Challengeopen allclose all
Route:
intradermal
Vehicle:
corn oil
Concentration / amount:
0,05mL
No. of animals per dose:
3
Details on study design:
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 10
- Exposure period: 3-4 weeks
- Test groups: 3 albino guinea pigs for each concentration
- Frequency of applications: 3 times weekly

B. CHALLENGE EXPOSURE
- No. of exposures: 1 , two weeks after the last induction exposure


Results and discussion

Any other information on results incl. tables

All injections of concentrated OMRE and ROMRE gave the maximum irritation index of 8. Furthermore there was no diminution in edema, erythema, or eschar formation observed during the injection series. At autopsy all animals receiving this materials had adhesions at the injection sites and petechial hemorrhages on the underlying skin surfaces remote from the site of the test injection. ROMRE also stained the area black. With the exception of the last two or three injection sites, which were not completely healed, scars at least 10 mm in length were observed with the above compounds. Necrosis and scarring were produced by 48% OTP, 30,5% MTP, and 5,5% PTP, but these effects were not as pronounced as with the other compounds. Histological examination of the skin revealed that all the materials produced the same type of response. There was a zone of edema and coagulative dermal necrosis free of inflammation surrounded by a broad rim of polymorphonuclear cells and cellular debris which was focally rich in eosinophiles. This layer also contained a few lymphocytes and histiocytes. The inflammatory infiltration extended for a short distance into the surrounding dermis, subcutaneous fat, and skeletal muscle layer. Foreign body giant cells partly surrounded small lipid deposits. There was an extensive bleb within the overlying epidermis with some infiltration by polymorphonuclear cells and cellular necrosis. Farther from the center of the injection site, the bleb was subepidermal rather than epidermal. Such effects are primarily chemical necrosis, but the eosinophylic infiltration is indicative for an allergic response also.

Multiple injections of 10% solutions of OMRE, ROMRE and MTP produced no increase in skin irritation over that seen on the initial injection. However, there were numerous adhesions and some petechial hemorrhages underlying the older injection scars. Histopathologic examination revealed mild fibrosis, a diffuse edema in the dermis and subcutaneous tissue, and foreign body reaction indicative of chemical toxicity. There was no evidence of an allergic response.

The wheal and flare response of 1% OMRE was 22-28mm compared to the initial response of 12-16mm. This indicates the development of sensitivity to these materials. The histopathologic examination showed edema, fibrosis, foreign body giant cells, eosinophile and polymorphonuclear cell infiltration of the deep dermis and subcutaneous fat. The eosinophyle infiltration adds confirmatory evidence to the previous data on the development of sensitivity to OMRE, while the other data indicate a chemical toxicity also.The other compounds showed no evidence of an allergenic response, but this may have been due to their insolubility and poor absorption from the vehicle.

Control injection of the corn oil solvent did not increase the wheal and flare reaction, but skin sections indicated a slight allergic response which could not have contributed materially to responses obtained with the moderator dilutions.

Applicant's summary and conclusion

Interpretation of results:
sensitising
Remarks:
Migrated information
Conclusions:
OMRE and the components of OMRE were highly damaging to guinea pig skin following intracutaneous injection. All the polyphenyl compounds produced sensitization and chemical necrosis.
Executive summary:

Intradermal injection of 0.05 mL of each compound was made three times weekly for a total of 10 injections. Two weeks after the last injection, each animal received a test injection of 0.05 mL test material. All injections of concentrated OMRE and ROMRE gave the maximum irritation index of 8. Furthermore there was no diminution in edema, erythema, or eschar formation observed during the injection series. At autopsy all animals receiving this materials had adhesions at the injection sites and petechial hemorrhages on the underlying skin surfaces remote from the site of the test injection. ROMRE also stained the area black. With the exception of the last two or three injection sites, which were not completely healed, scars at least 10 mm in length were observed with the above compounds. Necrosis and scarring were produced by 48% OTP, 30,5% MTP, and 5,5% PTP, but these effects were not as pronounced as with the other compounds. Histological examination of the skin revealed that all the materials produced the same type of response. There was a zone of edema and coagulative dermal necrosis free of inflammation surrounded by a broad rim of polymorphonuclear cells and cellular debris which was focally rich in eosinophiles. This layer also contained a few lymphocytes and histiocytes. The inflammatory infiltration extended for a short distance into the surrounding dermis, subcutaneous fat, and skeletal muscle layer. Foreign body giant cells partly surrounded small lipid deposits. There was an extensive bleb within the overlying epidermis with some infiltration by polymorphonuclear cells and cellular necrosis. Farther from the center of the injection site, the bleb was subepidermal rather than epidermal. Such effects are primarily chemical necrosis, but the eosinophylic infiltration is indicative for an allergic response also.