Registration Dossier

Administrative data

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report Date:
1983

Materials and methods

GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
A sample of neutralised product from acid extraction before steam distillation (ISK8) was supplied to the laboratory in April 1982 for an assessment of its skin irritation and skin sensitising potential. This material had the following constituents 3-trifluoromethylpyridine (TF) 53.2%, 2-chloro-5-trifluoromethylpyridine (CTF) 23.2%, 2,6-Dichloro-3-trifluoromethylpyridine (DCTF) 5.9%. The remainder was water, sodium chloride, sodium fluoride and sodium hydroxide.

Test animals

Species:
rat
Strain:
other: Alderley Park (Wistar Derived)
Details on test animals and environmental conditions:
Alderley Park, specific pathogen free, albino male rats were supplied by the Animal Breeding Unit, Imperial Chemical Industries PLC, Pharmaceuticals Division, Alderley Park, Macclesfield Cheshire. At the Beginning of the experiment the rats were aged between 5 and 7 weeks and weighed 200 – 350g.

The rats were housed in suspended cages (370mm length x 320mm width x 200mm height). The floor and back of each cage were 12mm square stainless steel mesh, the sides were solid stainless steel and the front was polycarbonate (Makrolon). The animals were housed individually, two per cage. For this purpose the experimental cages were divided into two equal compartments by placing a solid metal partition within each cage and one rat was kept in each compartment.
The animals were fed ad libitum with BP Nutrition Porton Combined Diet (PCD) and allowed tap water via an automatic water system.
The room in which the rats were held was maintained at a temperature of approximately 21°C with a relative humidity of approximately 55%. Temperature and relative humidity were recorded constantly using a thermohygrograph. There were 10-20 air changes per hour and the light pattern was controlled by a time switch to give alternate periods of 12 hours light and 12 hours of darkness.

The rats were acclimatised to the laboratory for a minimum of six days prior to the experiment.

Test system

Type of coverage:
occlusive
Preparation of test site:
other: 2 groups non-abraded skin, another 2 groups abraded skin
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.1ml
Duration of treatment / exposure:
2 groups of six male rats (abraded and unabraded skin) - a single exposure
2 groups of six male rats (abraded and unabraded skin) - five exposures
Observation period:
14 days
Number of animals:
4 groups of six male rats
Details on study design:
Four groups of six male rats were used. On each rat, an area of the dorso-lumbar skin, approximately 100mm x 50mm was clipped free of hair using veterinary clippers. The animals were clipped 16-32 hours before the first application of the test substance. Only those animals in which the epidermis appeared intact and normal on gross observation immediately after clipping were used. Each rat was then selected at random and given a number, unique to this study, using an ear punch.

Immediately prior to the application of the test substance, the skin in two of the groups of rats was further prepared by making epidermal abrasions in the 5x5 lattice arrangement over a 25mm square area. The abrasions were made using the back of a scalpel blade and they were sufficiently deep to penetrate the stratum corneum but not to disturb the dermis (that is, they did not cause bleeding).

A single application of the test material was made to one group of rats with non-abraded skins and one group with abraded skins. The remaining two groups of rats (one abraded and one non-abraded) were each given a total of five applications. (The test substance was applied on days 1, 3, 5, 7 and 9, and the skins were decontaminated on days 2, 4, 6, 8 and 10.

Approximately 0.1ml of the undiluted test substance was applied to the shorn backs using a sterile disposable polypropylene plastic syringe and then treated areas were covered by occlusive dressings. Each dressing consisted of a surgical gauze patch (BPC, approximate size 20mm x 20mm; 8 ply) to cover the treated area, which was held in position by a piece of polythene sheeting (approximate size 35mm x 50mm) (Poroplast, approximate size 50mm x 250mm) was then wrapped once around the body of the animal and was secured by two pieces of PVC tape (approximate size 25mm x 200mm). After 24 hours the dressings were cut using blunt tipped scissors (Rocket 127mm), removed and discarded. The skin at the site of the application, was then cleansed free of any residual test substance by using clean swabs of cotton wool soaked in clean warm water and then dried gently with clean tissue paper. The animals were examined for any skin reaction one to two hours after decontamination and then once per day for a total of fourteen days.

At the end of the test all the animals were killed by inhalation of excessive levels of halothane BP (Fluothane, Imperial Chemical Industries PLC, Pharmaceuticals Division) and those animals in the repeated application groups were examined externally and by dissection for macroscopic abnormalities. The livers, kidneys and testes were removed, weighed and stored for examination later, if necessary.

Results and discussion

In vivo

Irritant / corrosive response data:
Practically non-irritant to intact and abraded rat skin following both single and repeated 24-hour applications.

Any other information on results incl. tables

Results

Non Abraded Skin

Single application

No signs of irritation were seen in any animal following a single 24-hour application to intact rat skin.

Repeated application (x5)

One animal only showed signs of irritation following repeated 24 hour applications to intact rat skin, these signs included erythema, desquamation and scabbing, and the animal had not recovered by the end of the study period.

In conclusion the neutralised product from acid extraction before steam distillation is no irritant to intact rat skin following a single application and is practically non-irritant to intact rat skin following repeated applications.

Abraded Skin

Single application

Immediately following a single 24-hour application to abraded rat skin, one animal showed signs of slight erythema but this did not persist. No other signs of irritation were seen in any other animal.

Repeated application (x5)

One animal appeared slightly sensitive to touch on Day 5 prior to the third application of the test substance to abraded skin. No other signs of irritation was observed in any animal during the study period.

In conclusion, the neutralised product from acid extraction before steam distillation is practically non-irritant to abraded rat skin following both single and repeated 24-hour applications.

Applicant's summary and conclusion

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: not specified
Conclusions:
A process stream containing largely trifluoromethylpyridines, including some 23.2% CTF. was shown to be practically non-irritant to intact and abraded rat skin on single and repeated dose application. This result provides supporting evidence that CTF itself is unlikely to cause skin irritation.
Executive summary:

The neutralised product from acid extraction before steam distillation is a process stream in the manufacture of 2-chloro-5-trifluoromethylpyridine (CTF). This process stream contains largely trifluoromethylpyridines, including some 23.2% CTF. In single and repeated dose tests on intact and abraded rat skin this process stream was shown to be practically non-irritant. This result provides supporting evidence that CTF itself is unlikely to cause skin irritation.