Distillates (petroleum), solvent-dewaxed light paraffinic

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Study period:

1986-12-02 to 1987-03-06

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study is classified as reliable without because it was a well conducted study.

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 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

64742-04-7

Cas Number:

64742-04-7

IUPAC Name:

64742-04-7

Constituent 2

Reference substance name:

Heavy paraffinic distillate aromatic extract

IUPAC Name:

Heavy paraffinic distillate aromatic extract

Test material form:

other: Oily liquid

Details on test material:

Read across from untreated distillate aromatic extracts

- Name of test material (as cited in study report): 318 Isthmus Furfural Extract
- Substance type:heavy paraffinic distillate solvent extract (petroleum)
- Physical state: liquid
- Analytical purity: not provided
- Impurities (identity and concentrations): not provided
- Composition of test material, percentage of components (wt. %): total non-aromatics- 22.3, total aromatics- 77.7%, less than 3 ring polynuclear aromatic hydrocarbons- 37.2%, 3 to 5 ring polynuclear aromatic hydrocarbons- 23.0%, N-polynuclear aromatic hydrocarbons- 2.3% (non-basic = 1.6; basic 0.7), S-polynuclear aromatic hydrocarbons- 12.8%
- Isomers composition: not provided
- Purity test date: not provided
- Lot/batch No.: CRU no. 86187
- Expiration date of the lot/batch: April 30, 1991
- Stability under test conditions: 5 years
- Storage condition of test material: not provided

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic, Germantown, NY
- Age at study initiation: 49 days
- Weight at study initiation: not reported
- Fasting period before study: not reported
- Housing: individual housing in hanging stainless steel cages with wire bottoms and fronts
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 13 days in a quarantine room


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 21°C
- Humidity (%): 40 to 60%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

IN-LIFE DATES:
From 1986-12-02 to 1987-03-06

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

No data provided.

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

Frequency of treatment:

Five days per week

Doses / concentrations

Remarks:

Doses / Concentrations:
125 or 500 mg/kg/day via oral gavage
Basis:
no data

No. of animals per sex per dose:

10 male rats per dose

Control animals:

yes, concurrent no treatment

Details on study design:

No data reported.

Positive control:

No data reported.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day
- Cage side observations included morbidity and mortality.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


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


BODY WEIGHT: Yes
- Time schedule for examinations: study initiation and 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: weeks 5 and 13
- Anaesthetic used for blood collection: Yes (diethyl ether)
- Animals fasted: Yes
- How many animals: all animals
- Parameters in table 1 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: weeks 5 and 13
- Animals fasted: Yes
- How many animals: all animals
- Parameters in table 2 were examined.


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


NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, but details were not provided.
HISTOPATHOLOGY: Yes (see table 4)

Other examinations:

Organ weights double XX in table 4 were weighed. Sperm morphology was examined in the 500 mg/kg/day group.

Statistics:

An analysis of variance with associated F-test followed by Student-Newman-Keuls test were used when appropriate.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

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:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY: Four of ten mice in the 500 mg/kg/day group were sacrificed prior to scheduled termination. All animals in the 125 mg/kg/day survived to date of sacrifice. No details on clinical signs were provided.


BODY WEIGHT AND WEIGHT GAIN: Body weight was significantly reduced in the 500-mg/kg/day group (Table 1)



HAEMATOLOGY:A significant decrease (p<0.05) in red blood cell (RBC) parameters (including RBC count, haemoglobin, and haematocrit) and platelet in males dosed orally at 500 mg/kg/day(Table 2). Males orally dosed at 125 mg/kg/day showed a significant decrease in RBC parameters; platelet counts were slightly decreased in these rats but did not achieve statistical significance. There were no significant differences in the RBC morphology or WBC differential data.


CLINICAL CHEMISTRY: The only statistically significant difference between the serum data from control and orally dosed rats was observed for SDH (0 mg/kg/day = 5±2 IU/l, 150 mg/kg/day = 8±2 IU/l, 500 mg/kg/day = 9±7 IU/l).


URINALYSIS: There were no treatment-related effects on urinalysis.


ORGAN WEIGHTS:Significantly different absolute and/or relative weights in liver, heart, brain, thymus, prostate, seminal vesicles and adrenal glands compared to control were observed. Some of the effects are secondary to reduced body weight. Those that are considered related to treatment are presented in Table 3.

GROSS PATHOLOGY: Focal areas of red discoloration and or generalized reddening were also observed in the brain, spinal cord, stomach and testes of many of the rats dosed orally at 500 mg/kg/day.


HISTOPATHOLOGY: Treatment-related histopathology was generally dose-dependent and occurred in the following tissues: adrenals, bone marrow, liver, stomach and thymus (Table 9). Atrophy occurred in the male sex organs (testes, seminal vesicle, and prostate).


OTHER FINDINGS: Sperm evaluations showed a significant increase in the frequency of sperm with abnormal heads in the rats dosed orally at 500 mg/kg/day (1.9% in controls and 3.2% in treated rats).

Effect levels

1

Dose descriptor:

NOAEL

Sex:

male

Basis for effect level:

other: adverse effects observed at 125 mg/kg/day dosed orally

Remarks on result:

not determinable

Remarks:

no NOAEL identified

2

Dose descriptor:

LOAEL

Effect level:

125 mg/kg bw/day (nominal)

Sex:

male

Basis for effect level:

other: overall effects

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1. Mean group body weights on week of study.

Dose	Week 1	Week 2	Week 3	Week 4	Week 5	Week 6	Week 7	Week 8	Week 9	Week 10	Week 11	Week 12	Week 13	Week 14
0 mg/kg/day	227.2	273.9	318.6	348.5	-	380	405.4	419.1	433.2	440.4	462.4	460.8	468.9	461.5
125 mg/kg/day	224.4	270.9	314.5	347.7	-	375.4	395	403.9	416	422.7	431.6	439	451.8	445.5
500 mg/kg/day	224.1	285.3	308.9	335.3	-	348.8*	354.3*	352.2*	359.9*	359.1*	373.2*	374.6*	380.1*	386.5*

*indicates significantly different from control (p<0.05)

Body weights were inadvertently not measured on week 5.

Table 2. Haematological parameters at the end of the study period.

Haematological Parameter	0 mg/kg/day	125 mg/kg/day	500 mg/kg/day
RBC(10^6/mm^3)	9.17	8.72	8.51*
WBC (10^3/mm^3)	14.4	13.3	12.7
Platelets (10^^3/mm3)	1152	1055	930
Hgb (g/dl)	17.1	16.0*	15.2*
Hct (%)	53.7	50.7*	47.7*
MCV (cubic microns)	59	58	56*
MCH (pcg)	18.7	18.4	17.8*
MCH Conc. (%)	31.9	31.6	31.8

*indicates significantly different from control (p<0.05)

Abbreviations: RBC=red blood cells, WBC=white blood cells, Hgb=haemoglobin, Hct=haematocrit,

MCV=mean corpuscular volume, MCH=mean corpuscular haemoglobin

 

Table 3. Mean final fasted body weight and relative organ weights in grams.

Body/Organ Weight	0 mg/kg/day	125 mg/kg/day	500 mg/kg/day
Final Body Weights	435.1±36.7	407.1±32.6	350.3±29.4*
Liver	3.03±0.24	4.17±0.40*	5.29±0.46*
Prostate	0.26±0.03	0.20±0.05*	0.11±0.07*
Seminal Vesicles	0.20±0.04	0.18±0.05	0.12±0.04*
Thymus	0.093±0.029	0.054±0.015*	0.018±0.007*

 

Table 4

Incidences of treatment-related histopathology after dermal exposure to 318 Isthmus Furfural Extract for 13 weeks
	Control	125 mg/kg/day	500 mg/kg/day
Males	n=10	n=10	n=10
vacuolation, cortical	0	Not examined	3
hyperplasia, zona glomerulosa	0	Not examined	2
decreased cellularity in femur	0	4	8
Fibrosis in femur	0	1	5
decreased cellularity in sternum	0	2	7
Fibrosis in sternum	0	0	4
haemorrhage, multifocal (brain)	0	Not examined	5
Dialation, sinusoidal, centrilobular	0	0	3
Hypertrophy, hepatocytes	0	0	9
Necrosis, centrilobular	0	0	4
Vacuolation, hepatocellular, periportal	0	2	5
Atrophy (prostate)	0	Not examined	9
Atrophy (seminal vesicle)	0	Not examined	5
Congestion/haemorrhage, glandular mucosa	0	Not examined	4
Hyperplasia/hyperkeratosis, limiting ridge	0	Not examined	8
Atrophy (thymus)	0	9	10

 

Applicant's summary and conclusion

Conclusions:

NOAEL for heavy paraffinic distillate aromatic extract could not be identified and is less than 125 mg/kg/day when administered orally.

Executive summary:

Read across justification

This compound is an untreated distillate aromatic extract and provides a worst case scenario for insufficiently refined other lubricant base oils due to the concentration effect of the solvent extraction process.

In a subchronic oral toxicity study, heavy paraffinic distillate aromatic extract was administered to 10 male Sprague-Dawley rats/dose at dose levels 0, 125, or 500 mg/kg bw/day 5 days a week for 13 weeks. Four of ten mice in the 500 mg/kg/day group were sacrificed prior to scheduled termination. All animals in the 125 mg/kg/day survived to date of sacrifice. No details on clinical signs were provided. Body weight was significantly reduced in the 500-mg/kg/day group. A significant decrease (p<0.05) in red blood cell (RBC) parameters (including RBC count, haemoglobin, and haematocrit) and platelet in males dosed orally at 500 mg/kg/day. Males orally dosed at 125 mg/kg/day showed a significant decrease in RBC parameters; platelet counts were slightly decreased in these rats but did not achieve statistical significance. There were no significant differences in the RBC morphology or WBC differential data. The only statistically significant difference between the serum data from control and orally dosed rats was observed for SDH (0 mg/kg/day = 5±2 IU/l, 150 mg/kg/day = 8±2 IU/l, 500 mg/kg/day = 9±7 IU/l). Treatment-related dose-dependent changes in relative organ weights included increased liver weight in both groups, decreased prostate weight in both groups, decreased seminal vesicle weight in the high-dose group, and decreased thymus weight in both groups. Focal areas of red discoloration and or generalized reddening were also observed in the brain, spinal cord, stomach and testes of many of the rats dosed orally at 500 mg/kg/day. Treatment-related histopathology was generally dose-dependent and occurred in the following tissues: adrenals, bone marrow, liver, stomach and thymus. Atrophy occurred in the male sex organs (testes, seminal vesicle, and prostate). Sperm evaluations showed a significant increase in the frequency of sperm with abnormal heads in the rats dosed orally at 500 mg/kg/day (1.9% in controls and 3.2% in treated rats). 

NOAEL for heavy paraffinic distillate aromatic extract could not be identified and is less than 125 mg/kg/day when administered orally.

This study received a Klimisch score of 1 and is classified as reliable without restriction because it is a well conducted study.