Extracts (petroleum), residual oil solvent

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

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

Adequacy of study:

supporting study

Study period:

1987-11-17 to 1988-02-18

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study is classified as reliable without restrictions because it closely followed OECD Guideline 411 and appears to be GLP compliant

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.

This study will be replaced as Key study by the 90-day dermal study currently being proposed.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)

Deviations:

yes

Remarks:

Either one or two dose levels were used instead of the requisite three dose levels; a limit test corresponding to a dose level of at least 1000mg/kg-body weight was not conducted

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

64742-10-5

Cas Number:

64742-10-5

IUPAC Name:

64742-10-5

Constituent 2

Reference substance name:

Bright Stock Extract-BSE Australia

IUPAC Name:

Bright Stock Extract-BSE Australia

Constituent 3

Reference substance name:

BSS Furfural Extract:BSE Statjford

IUPAC Name:

BSS Furfural Extract:BSE Statjford

Constituent 4

Reference substance name:

Extrait BSS: BSE Ninian

IUPAC Name:

Extrait BSS: BSE Ninian

Details on test material:

- Name of test material (as cited in study report): Mobilsol 40, Bright Stock Extract, BSS Furfural Extract, Extrait BSS
- Substance type: Residual Aromatic Extract

Test animals

Species:

rat

Strain:

other: N(SD)fBR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms, Germantown, NY
- Age at study initiation: 50 days
- Weight at study initiation: Data not reported
- Fasting period before study: Data not reported
- Housing: Data not specified
- Diet (e.g. ad libitum): Purina Certified Lab Chow, ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22
- Humidity (%): 40 to 60
- Air changes (per hr): Data not reported
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light

Administration / exposure

Type of coverage:

open

Vehicle:

unchanged (no vehicle)

Details on exposure:

TEST SITE
- Area of exposure: Dorsal trunk
- % coverage: Data not reported
- Type of wrap if used: Test material was not covered
- Time intervals for shavings or clipplings: At least once a week

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Test materials wiped using gauze pads
- Time after start of exposure: Once per week

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Volume not specified; however volume applied was adjusted based on the most recent body weight data
- Constant volume or concentration used: No, volume was adjusted based on the most recent body weight data

USE OF RESTRAINERS FOR PREVENTING INGESTION: Yes; Cardboard Elizabethan-style collars lined with latex tubing

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

5 days/week for 13 weeks

Frequency of treatment:

Though not specified, the test materials were applied once per day

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
500 and 2000 mg/kg bw Mobilsol 40
Basis:
nominal per unit body weight

Doses / concentrations 2

Remarks:

Doses / Concentrations:
2000 mg/kg bw Bright Stock Extract, BSS Furfural Extract, Extrait BSS
Basis:
nominal per unit body weight

No. of animals per sex per dose:

10 males, 10 females

Control animals:

yes

Details on study design:

- Dose selection rationale: Data not reported
- Rationale for animal assignment (if not random): Randomly assigned using Grosse system computer program

Positive control:

No used

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once per day

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Examined once a week

BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed a week prior to study initiation, immediately following first dose and once a week following dosing until study termination

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

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 data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood samples were collected during weeks 5 and 13 from all animals within a two-day period
- Anaesthetic used for blood collection: Yes: diethyl ether
- Animals fasted: Yes
- How many animals: 5/sex
- Parameters checked in table [No.?] were examined: Fifteen haematological parameters were checked

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Week 5 and 13
- Animals fasted: No data
- How many animals: 9-10 animals in untreated control group; 2 in the 500 mg/kg-BW group; 3 in the 2000 mg/kg-BW group
- Parameters checked in table [No.?] were examined: In all 15 hematological parameters were measured

URINALYSIS: Yes
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: No data

Other examinations:

Spermatozoa and spermatid evaluations were conduced along with measurement of absolute and relative organ weights.

Statistics:

Quantitative data were analyzed by parametric methods. Analysis of variance (ANOVA) and associated F-test, followed by Dunnett’s test or Tukey’s multiple range tests were performed, provided there was statistical significance in ANOVA. Differences between control and treated animals were considered to be significant only if the p-value was less than 5%.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Dermal irritation:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY: There was no mortality as a result of exposure to the four BSEs; no adverse clinical signs were reported

BODY WEIGHT AND WEIGHT GAIN: No adverse effects on body weight gain was reported

FOOD CONSUMPTION: No data

FOOD EFFICIENCY: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Changes in hematological parameters were noted in treated females, but not males. At 13 weeks, decreases in hematological parameters were noted in RBCs and hematocrit in females treated with Mobilsol 40, RBCs, hemoglobin, and hematocrit in BSE Australia, and RBC, hemoglobin, and hematocrit in BSE Statjford (only females were exposed for this BSE). These parameters were statistically significant compared to the concurrent controls.

CLINICAL CHEMISTRY: Mobilsol 40, BSE Statjford, and BSE Ninian slightly affected the normal serum chemistry of treated rats. The serum chemistry of animals exposed to BSE Australia was more adverse compared to animals exposed to other BSEs.

URINALYSIS: No adverse effects

NEUROBEHAVIOUR: No data

ORGAN WEIGHTS: Liver weights of male rats treated with Mobilsol 40 were increased in the 2000 mg/kg-day group and in male and female rats treated with 2000 mg/kg-day BSE Australia. The study authors reported that the increase in liver weight was more of an adaptive response rather than an adverse effect.

GROSS PATHOLOGY: No remarkable observations were noted

HISTOPATHOLOGY: NON-NEOPLASTIC: No treatment related changes were noted.

HISTOPATHOLOGY: NEOPLASTIC (if applicable): No data


HISTORICAL CONTROL DATA (if applicable)


OTHER FINDINGS

Effect levels

1

Dose descriptor:

NOAEL

Remarks:

Mobilsol 40

Effect level:

500 mg/kg bw/day (nominal)

Sex:

female

Basis for effect level:

other: overall effects Haematology; clinical chemistry; organ weights

2

Dose descriptor:

LOEL

Remarks:

BSE Australia, BSE Ninian, BSE Statjford

Effect level:

2 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: overall effects Haematology; clinical chemistry; organ weights

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Liver weights of male rats treated with Mobilsol 40 were increased in the 2000 mg/kg-day group and in male and female rats treated with 2000 mg/kg-day BSE Australia. The study authors reported that the increase in liver weight was more of an adaptive response rather than an adverse effect.

 

No signs of skin irritation were reported as result of exposure to the four BSEs. No adverse clinical signs were attributed as a result of exposure to the test materials. Body weight gains were normal in all rats treated with the four BSEs. Urinalyses and sperm evaluations were not impacted as a result of exposure to the test materials. No histopathological changes were noted in the reproductive organs of male or female rats. Further, neither epididymal spermatozoa morphology and count nor testicular spermatid counts were affected by treatment with RAEs as shown in the table.

Table 1. Summaries of data on reproductive organs from subchronic studies with RAEs (CAS RN. 64742-10-5), derived from Mobil, 1990.
Test Material	Route, Species, Doses, Exposure Regimen	Endpoints	Results
Mobilsol 40	Dermal. Male and female rats. 0, 500, 2000 mg/kg on 5 d/wk for 13 wk.	Full necropsy. Weights of testes, prostate, epididymides, ovaries, and uterus. Histopathology of testes and ovaries. Weight of testicular parenchyma and cauda epididymis. Number of testicular sperm and number/g testis. Number and morphology of epididymal sperm, number/g cauda.	No treatment-related effect noted.
BSE - Australia	Dermal. Male and female rats. 0, 2000 mg/kg on 5 d/wk for 13 wk.	Full necropsy. Weights of testes, prostate, epididymides, ovaries, and uterus. Histopathology of testes and ovaries. Weight of testicular parenchyma and cauda epididymis. Number of testicular sperm and number/g testis. Number and morphology of epididymal sperm, number/g cauda.	No treatment-related effect noted.
BSE – Ninian	Dermal. Male rats. 2000 mg/kg on 5 d/wk for 13 wk.	Full necropsy. Weights of testes, prostate, and epididymides. Histopathology of testes.	No treatment-related effect noted.
BSE-Statfjord	Dermal. Female rats. 2000 mg/kg on 5 d/wk for 13 wk.	Full necropsy. Weights of ovaries and uterus. Histopathology of ovaries.	No treatment-related effect noted.

Changes in hematological parameters were noted in treated females, but not males. At 13 weeks, significant decreases in hematological parameters, compared to the control group, were noted in red blood cells (RBCs) and hematocrit in females treated with Mobilsol 40, RBCs, hemoglobin, and hematocrit in BSE Australia, and RBC, hemoglobin, and hematocrit in BSE Statjford (only females were exposed for this BSE).

 

Mobilsol 40, BSE Statjford, and BSE Ninian slightly affected the normal serum chemistry of treated rats. The serum chemistry of animals exposed to BSE Australia was more adverse compared to animals exposed to other BSEs. In Mobilsol 40, glucose, albumin, calcium (in males), glucose, and sorbitol dehydrogenase (SDH) (females) were significantly different from the control group. Animals treated with BSE Australia showed significant differences in urea nitrogen, creatinine, total protein, albumin, albumin/globulin ratio and SDH (males) levels compared to the concurrent controls. Alkaline phosphatase, calcium, and SDH levels were significantly different compared to the controls in animals treated with BSE Statjford (only females were treated with this BSE). Animals treated with BSE Ninian (only male rats were exposed to this BSE) exhibited significant changes in uric acid, albumin, calcium, inorganic phosphorus, chloride, and SDH compared to the concurrent controls.

 

Liver weights of male rats treated with Mobilsol 40 were increased in the 2000 mg/kg-day group and in male and female rats treated with 2000 mg/kg-day BSE Australia. The study authors reported that the increase in liver weight was more of an adaptive response rather than an adverse effect.

 

Based on these results, the study authors concluded that the No-Observed-Adverse-Level (NOAEL) for Mobilsol 40 is 500 mg/kg-day. A NOAEL of < 2000 mg/kg-day could not be clearly established for the BSE Australia, Ninian and Statjford, since only a single dose level was evaluated for these three extracts.

Applicant's summary and conclusion

Conclusions:

The study authors concluded that the No-Observed-Adverse-Level (NOAEL) for Mobilsol 40 is 500 mg/kg-day. A NOAEL of < 2000 mg/kg-day could not be clearly established for the BSE Australia, Ninian and Statjford, since only a single dose level was evaluated for these three extracts.

Executive summary:

In a repeated dose dermal study, ten male and female [N(SD)fBR] rats were dosed dermally with four Bright Stock Extracts (BSEs) comprised of Mobilsol 40, BSE Australia, BSE Ninian, and BSE Statfjord 5 days/week for 13 weeks. A group of ten male and female rats served as the control group. Prior to test material(s) application, each animal was clipped free of hair from the entire dorsal trunk area. Hair was re-clipped as required at least once per week. Mobilsol was applied at a dose of 500 and 2000 mg/kg-day, whereas, the other three BSE extracts were applied at a dose of 2000 mg/kg-day. The exposure sites were left uncovered. All treated and control rats were fitted with a cardboard Elizabethan-style collars lined with latex tubing to minimize ingestion of the test materials. Collars were fitted on the rats several days prior to dose administration and replaced as needed during the dosing period.

 

No signs of skin irritation were reported as result of exposure to the four BSEs. No adverse clinical signs were attributed as a result of exposure to the test materials. Body weight gains were normal in all rats treated with the four BSEs. Urinalyses and sperm evaluations were not impacted as a result of exposure to the test materials.

 

Changes in hematological parameters were noted in treated females, but not males. At 13 weeks, significant decreases in hematological parameters, compared to the control group, were noted in red blood cells (RBCs) and hematocrit in females treated with Mobilsol 40, RBCs, hemoglobin, and hematocrit in BSE Australia, and RBC, hemoglobin, and hematocrit in BSE Statjford (only females were exposed for this BSE).

 

Mobilsol 40, BSE Statjford, and BSE Ninian slightly affected the normal serum chemistry of treated rats. The serum chemistry of animals exposed to BSE Australia was more adverse compared to animals exposed to other BSEs. In Mobilsol 40, glucose, albumin, calcium (in males), glucose, and sorbitol dehydrogenase (SDH) (females) were significantly different from the control group. Animals treated with BSE Australia showed significant differences in urea nitrogen, creatinine, total protein, albumin, albumin/globulin ratio and SDH (males) levels compared to the concurrent controls. Alkaline phosphatase, calcium, and SDH levels were significantly different compared to the controls in animals treated with BSE Statjford (only females were treated with this BSE). Animals treated with BSE Ninian (only male rats were exposed to this BSE) exhibited significant changes in uric acid, albumin, calcium, inorganic phosphorus, chloride, and SDH compared to the concurrent controls.

 

Liver weights of male rats treated with Mobilsol 40 were increased in the 2000 mg/kg-day group and in male and female rats treated with 2000 mg/kg-day BSE Australia. The study authors reported that the increase in liver weight was more of an adaptive response rather than an adverse effect.

 

Based on these results, the study authors concluded that the No-Observed-Adverse-Level (NOAEL) for Mobilsol 40 is 500 mg/kg-day. A NOAEL of < 2000 mg/kg-day could not be clearly established for the BSE Australia, Ninian and Statjford since only a single dose level was evaluated for these three extracts.

This study received a Klimisch score of 1 and is classified as “reliable without restrictions” it closely followed OECD Guideline 411 and appears to be GLP compliant.

 

This study will influence the DNEL(s).