Extracts (petroleum), heavy paraffinic distillate solvent

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

1985-01-14 to 1985-02-15

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: This study is classified as reliable with restrictions because the test compound was applied three times a week (a total of 12 times) instead of the recommended 5 times a week.

Justification for type of information:

Concawe believes that dermal is the most relevant exposure route, and is sufficiently robust, to identify any potential hazards from repeated exposures to petroleum products to be able to adequately manage the potentially associated risks. However, the primary objective of the testing required for REACH is the identification of hazard, for which the default exposure route under the regulation is oral as this is considered to maximise systemic exposure. To address the regulatory exposure route issue, Concawe will review the current data base for evidence of systemic toxicity after dermal exposure and will also conduct a number of oral OECD 422 studies on prioritized substances in each relevant petroleum category. The document attached provides a concise overview of the information to further support the dermal route of exposure and proposed additional work, as part of a larger testing strategy (the strategy document can be found in Annex 13).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Report date:

1986

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Deviations:

yes

Remarks:

Compound was administered 3 times a week.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

64742-05-8

IUPAC Name:

64742-05-8

Constituent 2

Reference substance name:

Light paraffinic distillate solvent extract

IUPAC Name:

Light paraffinic distillate solvent extract

Test material form:

liquid: viscous

Details on test material:

- Name of test material (as cited in study report): Light paraffinic distillate solvent extract (petroleum), API 83-16
- Substance type: C15 to C30 hydrocarbon
- Physical state: Liquid, clear brownish
- Lot/batch No.:F000-6837
- Storage condition of test material: Room temperature in the original container
- Viscosity, SSU: 67.2 at 100°F
- API Gravity: 16.7
- Flash Point: (°F) 335
- Pour Point (°F): 20
- Aniline Point (°F): 95.5
- Sulfur, Wt %: 2.64

- Composition of test material ASTM D-2007, Wt. %:
Saturates: 29.2
Aromatics 68.6

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton Dutchland, Denver, Pennsylvania
- Age at study initiation: young adult
- Weight at study initiation: males: 2.6 to 3.3 kilograms; females: 2.1 to 3.4 kilograms
- Housing: individually in stainless steel cages with grid bottoms
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 17 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 26
- Humidity (%): 18% to 40%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light


IN-LIFE DATES: From: 1985-01-14 To: 1985-02-15

Administration / exposure

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on exposure:

TEST SITE
- Area of exposure: dorsal trunk
- % coverage: approximately 10%
- Type of wrap if used: sheet of polyurethane secured with Blenderm
- Time intervals for shavings or clippings: 24 hours prior to first dose, then as necessary


REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped with a dry clean gauze pad
- Time after start of exposure: 6 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0, 250, 500, or 1000 mg/kg/day
- Constant volume or concentration used: no



USE OF RESTRAINERS FOR PREVENTING INGESTION: no

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

Not applicable

Duration of treatment / exposure:

28 days

Frequency of treatment:

3 times a week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 250, 500, or 1000 mg/kg/day
Basis:
nominal per unit body weight

No. of animals per sex per dose:

Five animals per sex per dose

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: based on a 5-day pilot study
- Rationale for animal assignment (if not random): random

Positive control:

None reported

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day
- Cage side observations checked for mortality and morbidity.


DETAILED CLINICAL OBSERVATIONS: No


DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: daily


BODY WEIGHT: Yes
- Time schedule for examinations: study initiation, weekly, 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: study termination
- Anaesthetic used for blood collection: No
- Animals fasted: No data
- How many animals: all animals
- Parameters checked in table 1 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: study termination
- Animals fasted: No data
- How many animals: all animals
- Parameters checked in table 2 were examined.


URINALYSIS: No
- Time schedule for collection of urine: Urine was collected at study termination from control and high-dose animals and frozen for possible analysis.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data


NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see table 3)

Other examinations:

Organs noted in table 3 were weighed.

Statistics:

Two-tailed Student's t-test

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:

effects observed, treatment-related

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: Dermal irritation was the only clinical sign related to treatment. Erythema and oedema were observed at the application site in all treated groups, with increasing frequency and severity as the dose level increased. Minimal skin irritation (0.9 in males and 1.0 in females) at 250 mg/kg and moderate irritation at 500 (2.3 in males and 2.2 in females) and 1000 mg/kg (2.9 in males and 3.4 in females) was noted for both males and females. Flaking and/or cracked skin areas and leathery skin texture were observed and considered to be treatment related. Dry, scaly, rough, crusted, red and/or fissured skin and thickened dermis were observed.

BODY WEIGHT AND WEIGHT GAIN: One high-dose male lost weight over the study duration, which caused a statistically significant decrease in mean body weight. However, body weight gains in the remaining high-dose males were similar to the control males. There was no treatment-related changes in body weight observed in the females.

HAEMATOLOGY: No treatment-related effects were observed.

CLINICAL CHEMISTRY: No treatment-related effects were observed.

ORGAN WEIGHTS: Changes in organ weights considered to be treatment-related included an increase in the liver weights in high-dose males. All other changes were within normal ranges or there was no dose-response relationship.

GROSS PATHOLOGY: Gross pathological findings related to treatment were only found in the skin.

HISTOPATHOLOGY: Microscopic findings of slight to moderately proliferative changes were observed in the treated skin of all of the male and female rabbits at the 1000 mg/kg dose level. The testes of one of the five males at 1000 mg/kg had bilateral diffuse tubular hypoplasia accompanied by aspermatogenesis and a hyploplasia of the accessory sex organs. These findings were not observed in other animals, and hence considered to represent immature testes and hence not treatment-related.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: lack of systemic toxicity

2

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: dermal irritation

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Based on skin irritation, a NOAEL of 500 mg/kg can be established. The NOAEL for effects on tissues other than skin would be > 1000 mg/kg, the highest dose tested.

Executive summary:

Light paraffinic distillate solvent extract (CAS# 64742 -05 -8) was tested in a subacute dermal exposure study. The undiluted test substance was applied to the shaved intact skin of 5 male and 5 female New Zealand White rabbits 3 times a week, on alternate days (occluded, 6 hours) for a total of 12 applications over a period of 28 days. Doses were 0, 250, 500, and 1000 mg/kg/application; these doses were chosen based on results from a five-day pilot study.

 

Erythema and oedema were observed at the application site in all treated groups, with increasing frequency and severity as the dose level increased. Minimal skin irritation at 250 mg/kg and moderate irritation at 500 and 1000 mg/kg was noted for both males and females. Flaking and/or cracked skin areas and leathery skin texture were observed and considered to be treatment related. Dry, scaly, rough, crusted, red and/or fissured skin and thickened dermis were observed. No statistical differences or noteworthy trends were seen in haematological and clinical chemistry.

 

Organ weight changes generally were either within the normal range or showed no dose-response relationship. However significantly elevated liver weights were observed for the high-dose males, which suggests a treatment-related finding. The authors concluded this finding not to be adverse based on histopathology analysis.

 

Microscopic findings of slight to moderately proliferative changes were observed in the treated skin of all of the male and female rabbits at the 1000 mg/kg dose level. The testes of one of the five males at 1000 mg/kg had bilateral diffuse tubular hypoplasia accompanied by aspermatogenesis and a hyploplasia of the accessory sex organs. These findings were not observed in other animals, and hence considered to represent immature testes and hence not treatment-related. No other relevant histopathological changes were observed. The authors concluded the test material had a significant effect only on dermal tissues under the conditions of this study. Based on skin irritation, a NOAEL of 500 mg/kg can be established. The NOAEL for effects on tissues other than skin would be >1000 mg/kg, the highest dose tested.

This study received a Klimisch score of 2 and is classified as reliable with restrictions because the test compound was applied three times a week (a total of 12 times) instead of the recommended 5 times a week.