Registration Dossier

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:
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:
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

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
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 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 / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
500 and 2000 mg/kg bw Mobilsol 40
Basis:
nominal per unit body weight
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

open allclose all
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
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).