Extracts (petroleum), heavy paraffinic distillates, solvent-deasphalted

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

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.

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:

Light paraffinic distillate solvent extract (CAS# 64742-05-8)

IUPAC Name:

Light paraffinic distillate solvent extract (CAS# 64742-05-8)

Details on test material:

Treated distillate aromatic extracts (TDAEs) are a further processing of distillate aromatic extracts (DAEs) in an attempt to reduce the amount of 3-7 ring PAC that is present. Since the treatment is mostly a selective reduction of PACs, the data from DAEs can serve as read across where treatment was insufficient and a significant amount of PACs still remain (≥ 3 wt% DMSO extractables as measured by IP-346). 

- 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
- Analytical purity: not reported
- Composition of test material, percentage of components: 29.2% saturates and 68.6% aromatics
- Lot/batch No.:F000-6837
- Expiration date of the lot/batch: not reported
- Stability under test conditions: not reported
- Storage condition of test material: room temperature in the original container
-Other: specific gravity= 0.9326 g/mL

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

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.

For purposes of classification and labelling and registration under REACH aromatic extracts are sub-divided into the categories of untreated distillate aromatic extracts (DAE), treated distillate aromatic extracts (TDAE), and residual aromatic extracts (RAE). Some of the classifications are based on 3-7 ring PAC content, which is not substantively affected by whether the aromatic extract is derived from paraffinic or naphthenic or “light” or “heavy” crude. Therefore, DAEs and TDAEs are not subclassified based on crude oil source or viscosity, i.e., for any health endpoint data from any one of the untreated DAEs can be “read-across” to the remaining DAEs and whole TDAE category.

Executive summary:

Justification for Read Across

Treated distillate aromatic extracts (TDAEs) are a further processing of distillate aromatic extracts (DAEs) in an attempt to reduce the amount of 3-7 ring PAC that is present. Since the treatment is mostly a selective reduction of PACs, the data from DAEs can serve as read across where treatment was insufficient and a significant amount of PACs still remain (≥ 3 wt% DMSO extractables as measured by IP-346). Where treatment was sufficient to reduce the 3-7 ring PACs (<3 wt% DMSO extractables as measured by IP-346), the material is most similar to a lubricating base oil and it is this data that should be used for read across. 

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.