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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
Not reported
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it was carried out according to OECD test guideline 411 and GLP.
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:
1988
Report Date:
1988

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: Oily liquid
Details on test material:
Test material name: Stock 461 (80" white oil)
Lot No.: CRU #85018
Manufacturer: Witco Chemical Company
Density: 0.88 g/mL
-Substance Type: Highly Refined Base Oil
- Stability under test conditions: Stable for a minimum of 2 years
- Storage condition of test material: Room temperature under ventilated hood

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
No data reported.
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Lakeview, New Jersey
- Age at study initiation: 6 to 8 weeks
- Weight at study initiation: 244 to 253 g (males), 167 to 176 g (females)
- Housing: Individual
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 3 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22°C
- Humidity (%): 40 to 60%
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light


IN-LIFE DATES: From: June 18, 1985 To: October 5, 1985

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: clipped dorsal skin
- % coverage: not reported
- Time intervals for shavings or clippings: weekly

REMOVAL OF TEST SUBSTANCE
Test substance not removed

TEST MATERIAL
- Constant volume or concentration used: yes

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data reported.
Duration of treatment / exposure:
13 weeks of exposure
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 125, 500, or 2000 mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
10 per sex per dose
Control animals:
other: yes, sham-exposed and no treatment control groups
Details on study design:
- Dose selection rationale: At 2000 mg/kg, test material was a dermal irritant and produced slight maternal toxicity during gestation; 2000 mg/kg is the maximum practical dose that can be applied dermally; the selection of the low and mid-dose levels was based on results obtained from a methods development project
Positive control:
None

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

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

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: during the week prior to scheduled termination
- Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: during the week prior to scheduled termination
- Animals fasted: No data
- Parameters checked in table 2 were examined.


URINALYSIS: Yes
- Time schedule for collection of urine: during the week prior to scheduled termination
- Metabolism cages used for collection of urine: No
- Animals fasted: No data
- Parameters checked in table 3 were examined.


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
No data reported.
Statistics:
No data reported.

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:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
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:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
Administration of the test material to the skin produced skin irritation at all dose levels, which included erythema, flaking of the skin, and scabs at the site of test material application.

Male and female rats dosed at 500 and 2000 mg/kg bw/day showed a decrease in body weight when compared to the controls, and was a statistically significant decrease for males exposed to 500 and 2000 mg/kg bw/day and females exposed to 2000 mg/kg bw/day.

Urinalysis results showed an increase in ketone levels for males in the sham control group and exposed to the test material, when compared to the untreated control group.

Male serum albumin and albumin/globulin ratio for the 2000 mg/kg bw/day group were significantly different from that of the control group.

Urinalysis and haematological effects were of doubtful toxicological significance.

There were no other compound-related effects on mortality, clinical signs, food consumption, organ weights, clinical chemistry.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
systemic effects
Effect level:
>= 2 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: no systemic effects were considered to be significant
Dose descriptor:
NOAEL
Remarks:
local effects
Effect level:
< 125 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: based on skin irritation

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEL for local effects is < 125 mg/kg based on skin irritation, while the NOAEL for systemic effects is greater than or equal to 2000 mg/kg, in the absence of significant toxicological findings of concern.
Executive summary:

In a 90-day dermal toxicity study,80SUS white mineral oil was applied to the clipped skin of 10 Sprague-Dawley rats/sex/dose at dose levels of 0, 125, 500, or 2000 mg/kg bw/day during a 90-day period.

 

Administration of the test material to the skin produced skin irritation at all dose levels, which included erythema, flaking of the skin, and scabs at the site of test material application. Male and female rats dosed at 500 and 2000 mg/kg bw/day showed a decrease in body weight when compared to the controls, and was a statistically significant decrease for males exposed to 500 and 2000 mg/kg bw/day and females exposed to 2000 mg/kg bw/day. Urinalysis and haematological effects were of doubtful toxicological significance. There were no other compound-related effects on mortality, clinical signs, food consumption, organ weights, clinical chemistry. The NOAEL for local effects is < 125 mg/kg based on skin irritation, while the NOAEL for systemic effects is greater than or equal to 2000 mg/kg, in the absence of significant toxicological findings of concern.

 

This study received a Klimisch score of 1 and is classified as reliable without restrictions because it was carried out according to OECD test guideline 411 and GLP.