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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 from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1990-01-16 to 1990-04-20
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable with restrictions because it is an acceptable and well documented study report.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1992
Report date:
1992
Reference Type:
publication
Title:
Correlation of systemic and developmental toxicities with chemical component classes of refinery steam
Author:
Feuston, M.H., Low, L.K., Hamilton, C.E., Mackerer, C.R.
Year:
1994
Bibliographic source:
Fundamental and Applied Toxicology 22:622-630

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
yes
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
Heavy atmospheric gas oil (CAS# 68915-97-9)
IUPAC Name:
Heavy atmospheric gas oil (CAS# 68915-97-9)
Details on test material:
Read-across Justification: The substance is very similar in structure to the substance being registered.
- Name of test material (as cited in study report): Heavy atmospheric gas oil
- Substance type: Heavy atmospheric gas oil
- Physical state: Liquid
- Analytical purity: 100%
- Composition of test material, percentage of components: 44% nonaromatics, 51.5% aromatics with 1-5 rings, 0.4% unident aromatics, 4.0% sulphur polycyclic aromatic compounds, 1.79% nonbasic nitrogen polycyclic aromatic compounds, and 1.32% basic nitrogen polycyclic aromatic compounds
- Lot/batch No.:86271
- Expiration date of the lot/batch: 1991-06-01
- Storage condition of test material: Not reported

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Taconic, Germantown, New York
- Age at study initiation: Approximately 49 days old
- Weight at study initiation: Not reported
- Housing: Individually in suspended stainless steel cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 21 days

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

IN-LIFE DATES: From: 1991-01-16 To: 1991-04-20

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: Dorsal trunk
- % coverage: Not reported
- Type of wrap if used: None
- Time intervals for shavings or clippings: At least once a week or as needed

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Wiped off with gauze
- Time after start of exposure: weekly (each Saturday)

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Varied depending on body weight
- Constant volume or concentration used: No

USE OF RESTRAINERS FOR PREVENTING INGESTION: Yes
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not applicable
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 days a week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 30, 125, or 500 mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
Ten
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Not provided
- Rationale for animal assignment (if not random): Randomly based on body weight
Positive control:
Not applicable

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations included appearance, behavior, excretion, and discharges.

DETAILED CLINICAL OBSERVATIONS: No data

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

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: 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: Week 5 and 13
- Anaesthetic used for blood collection: Yes (diethyl ether)
- 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: Week 5 and 13
- Animals fasted: No data
- How many animals: All animals
- Parameters checked in table 2 were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: Week 5 and 13
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table 3 were examined.

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see table 4)
Other examinations:
The following organs were weighed: adrenals, kidneys, liver, heart, prostate, spleen, ovaries, thymus, uterus, testes, epididymides, and brain. The left epididymides and testes from control and high-dose males were used for spermatozoa and spermatid evaluations.
Statistics:
Analysis of variance and associated F-test followed by Dunnett's test or Tukey's Multiple comparison test.

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:
effects observed, treatment-related
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:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
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: Two treated males became moribund and were sacrificed (one from 500 mg/kg/day dose group, one from 30 mg/kg/day dose group; time of sacrifice not specified). Skin irritation was generally slight in all treated animals, and considered to be due to local abrasion effects from the collars rather than the test sample.

BODY WEIGHT AND WEIGHT GAIN: Body weight gain was significantly decreased (11%) in males treated with 500 mg/kg/day; however, no significant body weight differences were noted in any other dose group.

HAEMATOLOGY: Red cell counts, haemoglobin concentration and haematocrit were significantly decreased by 8-9% in mid-dose males, by 30-31% in high-dose males, and by 11-13% in high-dose females (Table 1). Platelet counts were reduced by 23-48% in high-dose animals (greater effect in males).

CLINICAL CHEMISTRY: Whereas no serum chemistry values were affected by exposure to heavy atmospheric gas oil in the 30 mg/kg/day group, a limited number of parameters were significantly altered in the 125 and 500 mg/kg body weight/day groups (Table 2). This included serum urea nitrogen (increased 27% in mid-dose females and 31-35% high-dose animals of both sexes) and sorbitol dehydrogenase (increased 68% in mid-dose females and 106-124% in high-dose animals of both sexes) and serum cholesterol (increased 39% or 117% in mid- or high-dose females only). High-dose animals also exhibited statistically significant changes in alanine aminotransferase (-23%, males), total protein (+11%, females), globulin (+27%, females) and albumin/globulin ratio (-20%, females), but were expressed in one sex only making any relationship to treatment unclear. Changes in urea nitrogen, sorbitol dehydrogenase and cholesterol appeared to be treatment-related. The significance of the other differences summarised above is not clear because effects occurred only at the highest dose level and in one sex only.

URINALYSIS: There were no treatment-related effects.

ORGAN WEIGHTS: Absolute liver weights were statistically significantly increased by 32-50% in high-dose males and females respectively, with smaller (approx. 15%), non-significant increases in mid-dose animals. Absolute thymus weights were decreased in a dose-related manner in males (reduced by 10%, 19% or 61% for low-, mid- and high dose groups, respectively) and females (9%, 24% or 41% reduction, respectively), an effect that attained statistical significance in both sexes treated with heavy atmospheric gas oil at 500 mg/kg/day. Absolute spleen weights were consistently increased by approximately 10-18% in all treatment groups, but this was only statistically significant for high dose females (18% increase). Absolute heart weight was significantly increased (11%) in high-dose females, and absolute prostate weight significantly decreased (22%) in high-dose males; however, no dose-response relationship was apparent for either tissue. Relative liver weights were statistically significantly increased in mid- (16-21%) and high- (49-56%) dose animals of both sexes (Table 3), while relative thymus weights were decreased in low-dose males (20% reduction), mid-dose males and females (15-23% reduction) and high-dose animals of both sexes (39-56% reduction, statistically significant). Relative spleen weight was increased in a dose-related manner in males (13%, 18%, 25%, respectively) and females (11%, 17%, 22%, respectively), with the changes in the mid- and high-dose groups statistically significant for both sexes (Table 3). Increases in relative kidney weight (+11%, high-dose females) and relative adrenal (+30%, high-dose males) were inconsistently expressed among the sexes and appeared unrelated to dose.

GROSS PATHOLOGY: Macroscopic changes considered related to treatment related included increased liver size, decreased thymus size, thickening of the limiting ridge between the non-glandular and glandular sections of the stomach, and enlarged and reddened lymph nodes.

HISTOPATHOLOGY: Microscopic evaluation revealed a severe reduction in haematopoiesis in sternal bone marrow from rats treated at 500 mg/kg body weight/day; males (10/10) were more susceptible to this effect than females (2/10). The increase in absolute and relative liver weight of treated high-dose rats appeared related to liver hypertrophy (large cells towards the periphery of the lobule in 8/10 males and 10/10 females), focal necrosis (3/10 males, 2/10 females) and connective tissue formation (2/10 males and 1/10 females). Other histopathological changes found in the liver included increased areas of haematopoiesis at 125 mg/kg or greater (affecting 6-8 mid-dose animals and 8-9 high-dose animals of both sexes) and a dose-related increase in individual cell death in males (affecting 0/10, 2/9, 5/10 and 7/10 animals from the control, low-, mid- and high dose groups, respectively), but only sporadic changes in females (0/10, 2/10, 2/10, 0/10). Heavy atmospheric gas oil at a dose of 500 mg/kg/day also reduced the number of lymphocytes in the thymus (10/10 males, 8/10 females), but did not appear to affect the levels of circulating lymphocytes. Microscopic evaluation did not reveal any treatment related changes in the spleen, kidney, stomach, lymph nodes or skin.

OTHER FINDINGS: There were no treatment-realted effects on sperm evaluations.

Effect levels

Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Haematology; clinical chemistry; organ weights; histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

 

Table 1. Select Haematology Data at 13 weeks

 

Control

30 mg/kg/day

125 mg/kg/day

500 mg/kg/day

Males

Red Blood Cell Count

9.58±0.16

n=10

9.37±0.34

n=9

8.83±0.41 **

n=10

6.70±1.23 **

n=8

Haemoglobin

16.5±0.4

n=10

16.5±0.6

n=9

15.1±0.7 **

n=10

11.5±2.0 **

n=8

Haematocrit

60.1±1.4

n=10

59.5±2.0

n=9

55.4±2.0 **

n=10

42.3±7.0 **

n=8

Females

Red Blood Cell Count

9.09±0.35

n=9

8.96±0.34

n=9

8.71±0.46

n=10

8.06±0.40 **

n=10

Haemoglobin

16.4±0.5

n=9

16.2±0.3

n=9

15.8±0.6

n=10

14.3±1.1 **

n=10

Haematocrit

59.4±2.0

n=9

59.0±1.5

n=9

58.3±2.1

n=10

52.5±2.3 **

n=10

Significantly different from the control * p<0.05; ** p<0.01

 

Table 2. Select Clinical Chemistry Data at 13 weeks

 

Control

30 mg/kg/day

125 mg/kg/day

500 mg/kg/day

Males

Urea nitrogen

15.9±1.7

n=8

17.5±3.0

n=9

18.6±2.6

n=10

20.9±3.0 **

n=10

Sorbol dehydrogenase

4±3

n=8

4±1

n=8

6±2

n=9

8±4 *

n=9

Females

Urea nitrogen

18.1±1.5

n=10

21.2±3.5

n=10

23.0±2.4 **

n=10

24.4±3.8 **

n=10

Cholesterol

93.9±24.6

n=10

95.6±20.7

n=10

131.0±22.2 **

n=10

203.9±19.1 **

n=10

Sorbol dehydrogenase

7±2

n=10

10±4

n=10

12±3 *

n=10

15±5 **

n=10

Significantly different from the control * p<0.05; ** p<0.01

 

Table 3. Select Relative Organ Weights

 

Control

30 mg/kg/day

125 mg/kg/day

500 mg/kg/day

Males

Liver

3.037±0.215

n=10

3.159±0.193

n=9

3.680±0.248 **

n=10

4.532±0.291 **

n=10

Spleen

0.200±0.014

n=10

0.227±0.023

n=9

0.236±0.021 *

n=10

0.251±0.033 **

n=10

Females

Liver

2.865±0.190

n=10

3.068±0.228

n=10

3.325±0.166 **

n=10

4.469±0.355 **

n=10

Spleen

0.240±0.0355

n=10

0.267±0.026

n=10

0.280±0.016 *

n=10

0.294±0.031 **

n=10

Significantly different from the control * p<0.05; ** p<0.01

 

Applicant's summary and conclusion

Conclusions:
The LOAEL was 125 mg/kg/day, based on increased liver and spleen weights, altered bone marrow function (decreased haematopoiesis, red blood cell count, haemoglobin, and haematocrit) and liver histopathology. The NOAEL is 30 mg/kg/day. These systemic changes occurred in the absence of any appreciable skin irritation, resulting in a NOAEL for local effects of at least 500 mg/kg/day, the highest dose tested.
Executive summary:

In a repeated dose toxicity study, heavy atmospheric gas oil was evaluated in a study reported by Mobil (1992) and published by Feuston et al. (1994). Straight run gas oil data can be used as read-across data for other gas oils due to similar physical/chemical properties and composition. 

The treatment protocol used in the investigation involved application of the sample at doses of 0, 30, 125, or 500 mg/kg body weight/day to clipped dorsal skin (area not specified) of Sprague-Dawley rats (10 per sex per treatment) 5 days a week for 13 weeks. All animals were fitted with 'Elizabethan' collars for the five treatment days each week to prevent ingestion of test material. Residual test sample was wiped from the skin at the end of this period, and the animals remained untreated over the weekend. Body weights were recorded before application of the first dose of test material and weekly thereafter. Daily observations were made for clinical signs of toxicity, and irritation of the treatment site was assessed once each week. Blood (orbital sinus bleed under diethyl ether anaesthesia) was collected from all animals on weeks 5 and 13, and serum analysed for an extensive range of clinical chemical and haematology parameters. Freshly voided urine was collected within one week of blood collection. The animals were killed and subject to gross necropsy at the end of the 13 week treatment period. All organs were examined for gross abnormalities and select organs were weighed. About 60 tissues from each rat were sampled and preserved in neutral buffered formalin, and around 23 of these (including any gross lesions) from all control and high-dose animals, together with liver, thymus and sternum from the low- and mid-dose groups, were processed and stained (haematoxylin and eosin) for microscopic examination. In addition tissue samples from the right kidney and median lobe of the liver were preserved in formaldehyde-gluteraldehyde. Residual reproductive tissue (not processed for histological evaluation) from control and high-dose males was prepared for spermatid- and spermatozoa counts and morphology.

 

Two treated males became moribund and were sacrificed (one from 500 mg/kg/day dose group, one from 30 mg/kg/day dose group; time of sacrifice not specified). Skin irritation was generally slight in all treated animals, and considered to be due to local abrasion effects from the collars rather than the test sample. Body weight gain was significantly decreased (11%) in males treated with 500 mg/kg/day; however, no significant body weight differences were noted in any other dose group. Whereas no serum chemistry values were affected by exposure to heavy atmospheric gas oil in the 30 mg/kg/day group, a limited number of parameters were significantly altered in the 125 and 500 mg/kg/day groups. The changes that were considered treatment related included serum urea nitrogen (increased 27% in mid-dose females and 31-35% high-dose animals of both sexes) and sorbitol dehydrogenase (increased 68% in mid-dose females and 106-124% in high-dose animals of both sexes) and serum cholesterol (increased 39% or 117% in mid- or high-dose females only).

 

Red cell counts, haemoglobin concentration and haematocrit were significantly decreased by 8-9% in mid-dose males, by 30-31% in high-dose males, and by 11-13% in high-dose females. Platelet counts were reduced by 23-48% in high-dose animals (greater effect in males).

 

Urinalysis and sperm evaluations showed no treatment-related effects.

 

Macroscopic changes considered related to treatment related included increased liver size, decreased thymus size, thickening of the limiting ridge between the non-glandular and glandular sections of the stomach, and enlarged and reddened lymph nodes.

 

Absolute liver weights were statistically significantly increased by 32-50% in high-dose males and females respectively, with smaller (approx. 15%), non-significant increases in mid-dose animals. Absolute thymus weights were decreased in a dose-related manner in males (reduced by 10%, 19% or 61% for low-, mid- and high dose groups, respectively) and females (9%, 24% or 41% reduction, respectively), an effect that attained statistical significance in both sexes treated with heavy atmospheric gas oil at 500 mg/kg/day. Absolute spleen weights were consistently increased by approx. 10-18% in all treatment groups, but this was only statistically significant for high dose females (18% increase). Absolute heart weight was significantly increased (11%) in high-dose females, and absolute prostate weight significantly decreased (22%) in high-dose males; however, no dose-response relationship was apparent for either tissue. Relative liver weights were statistically significantly increased in mid- (16-21%) and high- (49-56%) dose animals of both sexes, while relative thymus weights were decreased in low-dose males (20% reduction), mid-dose males and females (15-23% reduction) and high-dose animals of both sexes (39-56% reduction, statistically significant). Relative spleen increased in a dose-related manner in males (13%, 18%, 25%, respectively) and females (11%, 17%, 22%, respectively), with the changes in the mid- and high-dose groups statistically significant for both sexes. Increases in relative kidney weight (+11%, high-dose females) and relative adrenal (+30%, high-dose males) were inconsistently expressed among the sexes and appeared unrelated to dose.

 

Microscopic evaluation revealed a severe reduction in haematopoiesis in sternal bone marrow from rats treated at 500 mg/kg body weight/day; males (10/10) were more susceptible to this effect than females (2/10). The increase in absolute and relative liver weight of treated high-dose rats appeared related to liver hypertrophy (large cells towards the periphery of the lobule in 8/10 males and 10/10 females), focal necrosis (3/10 males, 2/10 females) and connective tissue formation (2/10 males and 1/10 females). Other histopathological changes found in the liver included increased areas of haematopoiesis at>125 mg/kg (affecting 6-8 mid-dose animals and 8-9 high dose animals of both sexes) and a dose-related increase in individual cell death in males (affecting 0/10, 2/9, 5/10 and 7/10 animals from the control, low-, mid- and high dose groups, respectively) but only sporadic changes in females (0/10, 2/10, 2/10, 0/10). Heavy atmospheric gas oil at a dose of 500 mg/kg body weight/day also reduced the number of lymphocytes in the thymus (10/10 males, 8/10 females), but did not appear to affect the levels of circulating lymphocytes. Microscopic evaluation did not reveal any treatment related changes in the spleen, kidney, stomach, lymph nodes or skin.

 

The LOAEL was 125 mg/kg/day, based on increased liver and spleen weights, altered bone marrow function (decreased haematopoiesis, red blood cell count, haemoglobin, and haematocrit) and liver histopathology. The NOAEL is 30 mg/kg/day. These systemic changes occurred in the absence of any appreciable skin irritation, resulting in a NOAEL for local effects of at least 500 mg/kg/day, the highest dose tested.

The study recieved a Klimisch score of 2 and is classified as reliable with restrictions because it is an acceptable and well documented study report.