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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1990-08-21 to 1990-09-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it was conducted according to OECD TG 410.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): F-133 (thermocracked kerosene), CAS No. 68333-23-3
- Substance type: Kerosine
- Physical state: Liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Sasco, Inc., Omaha, Nebraska
- Age at study initiation: Young adult
- Weight at study initiation: Males: 200 to 300 grams; Females: 125 to 200 grams
- Housing: Individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
-Acclimation period: 19 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 26
- Humidity (%): 40 to 70%
- Air changes (per hr): 10 per hour or more
- Photoperiod (hrs dark / hrs light): 12 hour dark/ 12 hour light


IN-LIFE DATES: From:1990-08-20 To: 1990-09-18

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
Route of Administration: dermal
TEST SITE
- Area of exposure: Back
- % coverage: 10%
- Type of wrap if used: Latex dental dam
- Time intervals for shavings or clippings: As needed



TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.01, 0.05, or 0.5 ml/kg/day
- Constant volume or concentration used: no



USE OF RESTRAINERS FOR PREVENTING INGESTION: no
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
6 hours a day, 5 days a week
Doses / concentrations
Remarks:
Doses / Concentrations:
0.01, 0.05, or 0.50 mL/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
Ten
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Doses were selected based on a range-finding study.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice a day
- Cage side observations checked for mortality and viability.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once a week


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Five days a week just prior to application of the test article, 24 hours after the fifth application, and just prior to necropsy


BODY WEIGHT: Yes
- Time schedule for examinations: Prior to study initiation, three days a week (Monday, Wednesday, and Friday) throughout the dosing period, and at study termination


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


WATER CONSUMPTION: No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: At study termination
- Anaesthetic used for blood collection: Yes (halothane)
- Animals fasted: Yes
- How many animals:All surviving animals
- Parameters listed in table 1 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At terminal sacrifice
- Animals fasted: Yes
- How many animals: All surviving animals
- Parameters listed in table 1 were examined.


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Organs listed in table 1 were weighed.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see table 2)
Statistics:
Clinical pathology data, terminal organ weights, and organ to body weight ratios were statistically analyzed. Bartlett's test was used to determine if the groups had equal variances. For data with equal variances a one way analysis of variance using the F distribution followed by Dunnett's test was used. For unequal data, a Kruskal-Wallis test followed by Dunn's Summed Rank test was used. A linear regression or Jonckheere's test for monotonic trend were used where appropriate to test for trends.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: There were no treatment-related effects on clinical signs (except dermal irritation) or mortality.


BODY WEIGHT AND WEIGHT GAIN: There were no treatment-related effects on body weight.


HAEMATOLOGY: There were no treatment-related effects on haematology.


CLINICAL CHEMISTRY: There were no treatment-related effects on clinical chemistry.


ORGAN WEIGHTS: There were no treatment-related effects on organ weights.


GROSS PATHOLOGY: At necropsy, the only findings occurred at the treatment site and included dry skin, oedema, and eschar.


HISTOPATHOLOGY: NON-NEOPLASTIC: In the skin there were increased incidences of acanthosis, epidermal crusting, erosion, fibrosis, chronic inflammation, and hyperkeratosis (site B).



OTHER FINDINGS: Dermal irritation occurred in treated animals. Very slight erythema, slight eschar, and slight dried skin occurred in the 0.01 mL/kg/day group. Very slight to moderate erythema, slight to moderate eschar, sporadic very slight to slight oedema, and slight to moderately dried skin occurred in the 0.05 mL/kg/day group. In the high-dose group, skin irritation was great enough that the application site changed. For the original site (site A), moderate to severe dermal irritation (erythema, eschar, oedema, dried skin, fissuring, and ulcerations) occurred with a maximum mean daily score of 8.2 in males and 8.1 in females out of a total of 17. These effects decreased after the test site was moved. Similar effects were noted at site B, but the maximum mean daily score was 5.2 in males and 5.4 in females.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 0.5 other: mL/kg bw
Sex:
male/female
Dose descriptor:
other: Skin LOAEL
Effect level:
0.01 other: mL/kg bw
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

No animals died during the study and no body weight differences occurred. Very slight to severe dermal irritation occurred during the study at the test application sites. There were no effects on the haematological or clinical chemical values measured. Organ weights were unaffected (absolute and ratios to body or brain weight). At necropsy apart from skin irritation, there were no other findings. Histopathology did not reveal any changes that were due to treatment other than skin changes due to irritation.

Applicant's summary and conclusion

Conclusions:
Thermocracked kerosine was irritating to the skin at a dose of 0.5 mL/kg/day, but did not cause any systemic toxicity at this dose.
Executive summary:

In a 28-day dermal toxicity study, thermocracked kerosine was applied to the shaved skin of 10 Sprague-Dawley rats/sex/dose at dose levels of 0, 0.01, 0.05, or 0.5 mL/kg bw/day, 6 hours/day for 5 days/week during a 28-day period.

 

The test compound irritated the skin in a dose-dependent manner. In the high-dose group, the irritation became severe so the application site was moved to a cephalad location at the beginning of the fourth week. There were no compound related effects in mortality, clinical signs, body weight, haematology, clinical chemistry, organ weights, or gross and histologic pathology (except the skin). The LOAEL for dermal irritation is 0.01 mL/kg/day, based on slight to severe dermal irritation occurring at all doses tested. No dermal irritation NOAEL was established. There was no systemic LOAEL, based on the lack of systemic effects. The systemic NOAEL is greater than or equal to 0.5 mL/kg/day.

 

This study received a Klimisch score of 1 and is classified because it was conducted according to OECD TG 410.