Registration Dossier

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Administrative data

Description of key information

Repeat dose dermal and inhalation studies are available for samples of hydrodesulphurised kerosine. Supporting data are also available for deoderised kerosine.

Based on results from read-across studies with hydrodesulphurised kerosine, the inhalation vapour NOEC  was determined to be greater than 24 mg/m3, the highest level tested. Repeated dermal exposure to hydrodesulphurised kerosine gave a sub-chronic systemic NOEL of 495 mg/kg/day; skin irritation was the only adverse effect reported.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it is an acceptable and well-documented study report.
Justification for type of information:
Read across justification included in Section 13
Reason / purpose for cross-reference:
reference to other study
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Principles of method if other than guideline:
This was a reproductive study performed in two parts. Haematology, clinical chemistry, and histopathology in males were reported in Mattie et al. 1995 and were not repeated as part of this study design. In the first part, males were treated for 70 to 90 days with 0 (1mL of distilled water), 750, 1500, or 3000 mg/kg/day of undiluted JP-8 jet fuel, then mated to untreated females (one female at a time). In the second part of the study, female rats were administered the test compound at doses of 0 (1mL of distilled water), 375, 750, or 1500 mg/kg/day undiluted JP-8 jet fuel for 90 -day prior to mating, through mating, gestation, delivery, and lactation for a total of 21 weeks.
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Labs, Kingston, New York
- Weight at study initiation: 180 to 220 grams
- Housing: Individually, except during cohabitation (1 male with 1 female)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Not reported


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 to 25 °C
- Humidity (%): Not reported
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
Males were treated for 70 to 90 days. Females were treated for 21 weeks.
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
Males: 750, 1500, or 3000 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
Females: 325, 750, or 1500 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
A minimum of 20 male rats per dose were used to test male fertility and a minimum of 35 female rats were used to test effects on female fertility.
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Doses were based on a previous 90-day study.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Not reported
- Cage side observations examined were not reported.


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations:Daily


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: 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 AND COMPOUND INTAKE (if drinking water study): No


OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At study termination
- Anaesthetic used for blood collection: No
- Animals fasted: No data
- How many animals: A maximum of 10 females per treatment group
- Parameters checked in table 1 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At study termination
- Animals fasted: No data
- How many animals: A maximum of 10 females per treatment group
- Parameters checked in table 2 were examined.


URINALYSIS: Yes
- Time schedule for collection of urine: At weaning, 24 hours prior to sacrifice
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters checked in table 3 were examined.


NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Males: fertility and sperm analysis; Females: in the same rats used for haematology and clinical chemistry, the brain, kidneys, liver, spleen, and ovaries were weighed; reproduction indices
Sacrifice and pathology:
GROSS PATHOLOGY: No data
HISTOPATHOLOGY: Yes (see table 4)
Other examinations:
Fertility parameters were measured in both males and females.
Statistics:
General toxicity data: an ANOVA with or without multiple comparisons
Reproductive measures: a one- or two-factor ANOVA and a post-hoc comparison of dose using two-tailed t-test with pooled error was used for continuous data; a Chi-square test of proportions followed by a Fischer's Exact test was used for categorical data
Clinical signs:
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 specified
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:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY: There were no changes in clinical signs or mortality.


BODY WEIGHT AND WEIGHT GAIN: Body weights in male rats were decreased in a dose-dependent manner. Terminal body weights were approximately 545 grams, 520 grams, 475 grams, and 315 grams in the control, 750, 1500, and 3000 mg/kg/day, respectively (results were approximated from a figure). In females, body weight was only significantly reduced in the high-dose group, but the differences were not significant at terminal sacrifice. The body weight in females at 20 weeks (1 week before sacrifice) was approximately 400 grams, 385 grams, 382 grams, and 335 grams in the control, 375, 750, and 1500 mg/kg/day, respectively.


HAEMATOLOGY: Haematology was not measured in the males and no effects were noted in the females.


CLINICAL CHEMISTRY: Clinical chemistry was not measured in the males and no effects were noted in the females.


URINALYSIS: Urinalysis was not measured in the males and no effects were noted in the females.


ORGAN WEIGHTS: Absolute and relative liver weights were increased in mid- and high-dose females (Table 1).


HISTOPATHOLOGY: The test compound caused perianal dermatitis (high-dose only) and stomach hyperplasia (mid- and high-dose) in the female rats (Table 2).

OTHER FINDINGS: There were no treatment-related effects on reproduction or sperm parameters in males. There were no effects on reproduction, gestation, or litter size in females. There was a dose-related decrease in pup weight that was significant in the 750 mg/kg/day group on postnatal day 4 only and in the 1500 mg/kg/day group from postnatal day 4 through postnatal day 21 but had recovered by postnatal day 90.
Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: body weight
Critical effects observed:
not specified

The decreased body weight in males was probably related to nephropathy that is typically produced in male rats exposed to hydrocarbon fuels. Although there were changes in liver weight in the females, this was not accompanied by any changes in clinical chemistry or liver histopathology so is likely not of biological significance.

Table 5

Body weight and liver weights in female rats

 

Control

325 mg/kg/day

750 mg/kg/day

1500 mg/kg/day

 

n=10

n=7

n=8

n=8

Terminal Body weight

351.0 ± 12.6

354.3 ± 9.0

357.5 ± 6.5

348.8 ± 16.3

Absolute liver weight

14.8 ± 0.8

15.7 ± 0.6

17.8 ± 0.7 *

19.1 ± 0.7 **

Liver to body weight

4.2 ± 0.1

4.4 ± 0.1

5.0 ± 0.2 **

5.5 ± 0.1 **

Liver to brain weight

754.9 ±38.9

823.6 ± 39.8

903.1 ± 31.8 *

993.6 ± 46.3 **

* p<0.05

** p<0.01

Table 6

Incidence and severity significant histopathological findings in female rats

 

Control

325 mg/kg/day

750 mg/kg/day

1500 mg/kg/day

 

n=8

n=4

n=5

n=6

Perianal dermatitis

0

0

0

83% (1.2) *

Anal hyperplasia

0

0

0

50% (0.7)

Stomach gastritis

0

50% (0.5)

20% (0.2)

0

Stomach hyperplasia

0

75% (0.8)

100% (1.6) *

100% (1.7) *

* p<0.05

Conclusions:
The study LOAEL for systemic effects is 1500 mg/kg/day and the NOAEL for systemic effects is 750 mg/kg/day, based on reduced body weight in dams and in pups. The LOAEL for adult males rats exposed to JP-8 orally was 750 mg/kg/day due to changes in clinical pathology, body weight, organ weights and the same irritation seen in female rats. The reproduction NOAEL was 3000 and 1500 mg/kg/day in males and females, respectively.
Executive summary:

This was a reproductive study performed in two parts. In the first part, males were treated for 70 to 90 days with 0 (1mL of distilled water), 750, 1500, or 3000 mg/kg/day of undiluted JP-8 jet fuel, then mated to untreated females (one female at a time). Males were gavaged throughout the cohabitation period and were returned to their individual cage after successful mating. In the second part of the study, female rats were administered the test compound at doses of 0 (1mL of distilled water), 375, 750, or 1500 mg/kg/day undiluted JP-8 jet fuel for 90 -day prior to mating, through mating, gestation, delivery, and lactation for a total of 21 week. During mating, they were housed with untreated males. Litters were standardized to 4 male pups and 4 female pups on postnatal day 5. Although those pups were used for neurobehavioral tests, the data was not provided in the study report.

There were no effects on clinical signs or mortality in either sex. Haematology, clinical chemistry, and urinalysis were measured only in females without any effects noted. Body weights in male rats were decreased in a dose-dependent manner and was likely related to nephropathy that is specific in male rats treated with hydrocarbons. In females, body weight was only significantly reduced in the high-dose group. Absolute and relative liver weights were increased in mid- and high-dose females, but were not likely biologically significant due to the lack of changes in clinical chemistry or histopathology in the liver. The test compound caused perianal dermatitis (high-dose only) and stomach hyperplasia (mid- and high-dose) in the female rats (histopathology was not conducted on the males for this study because previous studies have indicated nephropathy). There were no treatment-related effects on reproduction or sperm parameters in males. There were no effects on reproduction, gestation, or litter size in females. There was a dose-related decrease in pup weight that was significant in the 750 mg/kg/day group on postnatal day 4 only and in the 1500 mg/kg/day group from postnatal day 4 through postnatal day 21 but had recovered by postnatal day 90.

The study LOAEL for systemic effects is 1500 mg/kg/day and the NOAEL for systemic effects is 750 mg/kg/day, based on reduced body weight in dams and in pups. The LOAEL for adult males rats exposed to JP-8 orally was 750 mg/kg/day due to changes in clinical pathology, body weight, organ weights and the same irritation seen in female rats.Changes in male rats may be complicated by the male rat-specific nephropathy produced after exposure to hydrocarbon fuels such as JP-4 and JP-8. The reproduction NOAEL was 3000 and 1500 mg/kg/day in males and females, respectively.

This study received a Klimisch score of 1 and is classified as reliable without restrictions because it is an acceptable and well-documented study report.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1985-01-24 to 1985-02-22
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it was carried out in a method similar/equivalent to OECD TG 412.
Justification for type of information:
Read across justification included in Section 13
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
Only one dose tested
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan
- Age at study initiation: Approximately 6 weeks old
- Weight at study initiation: Males: 126 to 191 grams; Females: 111 to 161 grams
- Fasting period before study: No
- Housing: Each group was maintained in a 1 m3 exposure chamber made of glass and stainless steel. Ten rats were held per cage batteries which were arranged in two tiers of two batteries within each exposure chamber.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 to 26
- Humidity (%): 20 to 60%

IN-LIFE DATES: From: 1985-01-24 To: 1985-02-22
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Exposure chamber
- Method of holding animals in test chamber: In cages
- Source and rate of air: HVAC system separate from the general laboratory system
- System of generating particulates/aerosols: Spraying Systems atomizer (No. 64 SS air nozzle, No. 1650 SS liquid nozzle, 1/4 J SS body)
- Air flow rate: 200-240 L/min


TEST ATMOSPHERE
- Brief description of analytical method used: Exposure concentration was determined with a Scott Model 216 Total Hydrocarbon Analyzer (THA).
- Samples taken from breathing zone: no


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Nominal and actual exposure concentrations were determined. Nominal concentrations were calculated from the test material use rates. Actual concentrations were determined using a Total Hydrocarbon Analyzer for 15 minutes of every hour.
Duration of treatment / exposure:
Four weeks
Frequency of treatment:
6 hours/day, 5 days/week for four consecutive weeks
Remarks:
Doses / Concentrations:
24 mg/m³
Basis:
other: analytical conc. (vapour)
No. of animals per sex per dose:
Twenty
Control animals:
yes
Details on study design:
- Dose selection rationale: Based on survival in a range-finding study
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations included mortality and overt signs of toxicity.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Prior to exposure and weekly during exposure

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: Study termination
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Study termination
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in table 2 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see table 3)
Other examinations:
The heart, lung and trachea, liver, kidneys, brain, spleen, adrenals, thyroid/parathyroid, pituitary, testes and ovaries were weighed.
Statistics:
All continuous data was analyzed using an analysis of variance and Bartlett's test with group comparisons made using an appropriate t-test. Unequal data and data with heterogeneous variances were compared using nonparametric methods using rank transformed data as described by Conover andIman.
Clinical signs:
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 examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
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:
no effects observed
Dose descriptor:
NOAEC
Effect level:
>= 24 mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
other: No treatment-related effects observed.
Critical effects observed:
not specified

There were no treatment-related effects on clinical condition, growth rate, organ or organ body weight ratios or on any of the haematological or clinical chemistry determinations.


Furthermore, there were no treatment-related microscopic changes observed in any of the organs examined.

Conclusions:
There were no treatment-related effects observed at the only concentration tested (mg/m3).
Executive summary:

In a subacute inhalation toxicity study, hydrodesulfurised kerosine (CAS number 64742-81-0) was administered to 20 Sprague-Dawley rats/sex/concentration by dynamic whole body exposure at a concentration of 24 mg/m3(0.024 mg/L) for 6 hours per day, 5 days/week for 4 weeks.

 

There were no compound related effects in mortality, clinical signs, body weight, haematology, clinical chemistry, organ weights, or gross and histologic pathology. Therefore, the NOAEC is greater than or equal to 24 mg/m3. This was the highest dose tested. The test material is not classified according to EU criteria based on no upper limit for the NOAEC.

 

This study received a Klimisch score of 1 and is rated as reliable without restriction because it was carried out in a method similar/equivalent to OECD TG 412.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
24 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1985-01-24 to 1985-02-22
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it was carried out in a method similar/equivalent to OECD TG 412.
Justification for type of information:
Read across justification included in Section 13
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
Only one dose tested
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan
- Age at study initiation: Approximately 6 weeks old
- Weight at study initiation: Males: 126 to 191 grams; Females: 111 to 161 grams
- Fasting period before study: No
- Housing: Each group was maintained in a 1 m3 exposure chamber made of glass and stainless steel. Ten rats were held per cage batteries which were arranged in two tiers of two batteries within each exposure chamber.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 to 26
- Humidity (%): 20 to 60%

IN-LIFE DATES: From: 1985-01-24 To: 1985-02-22
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Exposure chamber
- Method of holding animals in test chamber: In cages
- Source and rate of air: HVAC system separate from the general laboratory system
- System of generating particulates/aerosols: Spraying Systems atomizer (No. 64 SS air nozzle, No. 1650 SS liquid nozzle, 1/4 J SS body)
- Air flow rate: 200-240 L/min


TEST ATMOSPHERE
- Brief description of analytical method used: Exposure concentration was determined with a Scott Model 216 Total Hydrocarbon Analyzer (THA).
- Samples taken from breathing zone: no


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Nominal and actual exposure concentrations were determined. Nominal concentrations were calculated from the test material use rates. Actual concentrations were determined using a Total Hydrocarbon Analyzer for 15 minutes of every hour.
Duration of treatment / exposure:
Four weeks
Frequency of treatment:
6 hours/day, 5 days/week for four consecutive weeks
Remarks:
Doses / Concentrations:
24 mg/m³
Basis:
other: analytical conc. (vapour)
No. of animals per sex per dose:
Twenty
Control animals:
yes
Details on study design:
- Dose selection rationale: Based on survival in a range-finding study
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations included mortality and overt signs of toxicity.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Prior to exposure and weekly during exposure

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: Study termination
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Study termination
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in table 2 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see table 3)
Other examinations:
The heart, lung and trachea, liver, kidneys, brain, spleen, adrenals, thyroid/parathyroid, pituitary, testes and ovaries were weighed.
Statistics:
All continuous data was analyzed using an analysis of variance and Bartlett's test with group comparisons made using an appropriate t-test. Unequal data and data with heterogeneous variances were compared using nonparametric methods using rank transformed data as described by Conover andIman.
Clinical signs:
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 examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
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:
no effects observed
Dose descriptor:
NOAEC
Effect level:
>= 24 mg/m³ air (analytical)
Sex:
male/female
Basis for effect level:
other: No treatment-related effects observed.
Critical effects observed:
not specified

There were no treatment-related effects on clinical condition, growth rate, organ or organ body weight ratios or on any of the haematological or clinical chemistry determinations.


Furthermore, there were no treatment-related microscopic changes observed in any of the organs examined.

Conclusions:
There were no treatment-related effects observed at the only concentration tested (mg/m3).
Executive summary:

In a subacute inhalation toxicity study, hydrodesulfurised kerosine (CAS number 64742-81-0) was administered to 20 Sprague-Dawley rats/sex/concentration by dynamic whole body exposure at a concentration of 24 mg/m3(0.024 mg/L) for 6 hours per day, 5 days/week for 4 weeks.

 

There were no compound related effects in mortality, clinical signs, body weight, haematology, clinical chemistry, organ weights, or gross and histologic pathology. Therefore, the NOAEC is greater than or equal to 24 mg/m3. This was the highest dose tested. The test material is not classified according to EU criteria based on no upper limit for the NOAEC.

 

This study received a Klimisch score of 1 and is rated as reliable without restriction because it was carried out in a method similar/equivalent to OECD TG 412.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Justification for type of information:
Read across justification included in Section 13
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Type of coverage:
other: open with elizabethan collars
Vehicle:
other: mineral oil
Details on exposure:
Route of Administration: dermal
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Six hours each day
Frequency of treatment:
Daily, five days per week for 13 weeks
Remarks:
Doses / Concentrations:
165, 330 & 495 mg/kg/day
Basis:

No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
Test material was applied at concentrations of 20, 40 or 60% (v/v) at a rate of 1 ml/kg/day to the shorn intrascapular region of the rats. This was equivalent to doses of test material of 165, 330 or 495 mg/kg/day. Dosing was continued daily for five consecutive days each week, five days a week for 13 weeks. In addition a group of 12 male and 12 female rats of similar age were administered mineral oil at a dose rate of 1 ml/kg/day; these animals served as vehicle controls. An additional 12 rats/sex/group in the vehicle controls and high dose group were maintained for a 4-week recovery period following dosing for 13 weeks. All animals were fitted with collars to prevent ingestion and these were removed six hours after dosing and any residual test or control material was wiped from the skin. Animals were observed for clinical signs prior to dosing and 1, 6 and 24 hours after the first dose. Subsequently, observations were made prior to each dose being applied.
Sacrifice and pathology:
A complete necropsy was performed on six rats/sex/group following 13 weeks dosing, and on 6 rats/sex/group of the recovery animals (high dose and controls) at week 18. A limited necropsy was performed on the remaining six animals and their organs were not weighed (see below). Each full necropsy included an examination of the external surface of the body, all orifices, cranial, thoracic, abdominal and pelvic cavities and their contents. Gross observations were recorded and the following organs were weighed: Adrenal glands, brain, epididymides, heart, kidneys, liver, ovaries, prostate, spleen, testes, thymus and uterus.
The following tissues were collected, processed and then examined microscopically. Adrenal glands                   Nose (nasal cavity & turbinates) Animal identification               Ovaries Bone marrow (from sternum)        Oviducts Brain                               Pancreas Epididymides                       Parathyroid glands Oesophagus                       Pituitary gland Exorbital lacrimal glands       Prostate Eyes with optic nerve               Salivary glands Femur (incl. articular surface)       Seminal vesicles Gross lesions                       Skin (application site) Harderian gland                       Skin (inguinal) Heart and aorta                       Spinal cord (3 levels) Intestine (3 levels)               Spleen Kidneys                               Stomach Larynx and pharynx               Testes Liver                               Thymus Lungs with mainstream bronchi       Thyroid gland Lymph nodes (mandibular/mesenteric) Urinary bladder Mammary glands with adjacent skin  Uterus Muscle (thigh)                       Vagina Nerve (sciatic) The remaining six rats of each group were anesthetized with an intraperitoneal injection of Pentothal ® and transcardially perfused in-situ using 10% neutral-buffered formalin and given a limited necropsy. For these rats, no organs were weighed and the following tissues were collected: Head/skull       Sural nerve Brain               Tibial nerve Spinal cord       Gross lesions Sciatic nerve The following tissues were examined microscopically in these animals: Brain (forebrain, cerebrum, midbrain, cerebellum, pons and medulla obligata) Gasserian ganglia Dorsal root ganglia Dorsal and ventral root fibers Sural nerve Tibial nerve Spinal cord (cervical and lumbar areas) Sciatic nerve.
Other examinations:
At the 14 week necropsy, blood samples were collected from 12 animals/sex/group and at the week 18 necropsy from the recovery rats (vehicle and high dose groups). The following haematological and clinical chemical parameters were measured. Haematology Erythrocyte count Haemoglobin Haematocrit Mean corpuscular volume Mean corpuscular haemoglobin Mean corpuscular hemoglobin concentration Platelet count Reticulocyte count Total leukocyte count Differential leukocyte count Morphological examination of erythrocytes and platelets Coagulation determinations (prothrombin time & activated partial thromboplastin time) were also carried out on six animals from each group at week 14 and from the recovery groups at the week 18 necropsy.
Key result
Dose descriptor:
NOEL
Effect level:
>= 495 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: test material
Critical effects observed:
not specified

All animals survived until scheduled termination. There were no test substance-related effects on survival, clinical observations (apart from skin irritation), neurobehavioral signs or ophthalmological findings. The only clinical observations during the study were related to skin irritation at the application site. There was a generally dose-related increase in the incidence and severity of erythema, oedema, epidermal scaling, scab formation, thickening of the skin and ulceration at the treated site. Males seemed to be more sensitive than females.

The FOB screen did not demonstrate any substance-related effects. The areas monitored were: behavioural parameters, including autonomic, muscle tone and equilibrium, sensorimotor responses, central nervous system.
 In addition the test substance had little effect on motor activity or startle response.

Growth rates were unaffected by treatment.

At necropsy no substance-related observations were made for males in any group.
 In the females there was a suggestion of a possible treatment-related effect which occurred in 7 rats across all groups and consisted of skin crusts or ulceration at the site of application of test material.

Haematological and serum clinical parameters were unaffected by treatment.

The only organ weight effects noted were an increase in spleen/body weight and spleen/brain weight ratios in the high dose group females at the 13 week necropsy and an increase in absolute spleen weight in the same dose group females after the 4 weeks recovery period.
 Since there were no associated microscopic or clinical chemical findings, these differences were not considered to be of biological relevance.

There were no treatment-related microscopic changes in the tissues examined with the exception of the findings in the skin.
 The skin observations were minimal in nature with a severity score less than 1 on a 1 [low] to 4 [severe] scale.
The findings included acanthosis, ulceration, parakeratosis, chronic active inflammation and hyperkeratosis.
 The males were affected at all doses, however, the effects indicated very little irritation. Recovery group animals revealed complete recovery in the females and minimal hyperkeratosis in the high dose group males.
No effects were found in the animals subjected to a detailed
 neuropathological examination.

Conclusions:
In a 90-day dermal toxicity study in rats the NOEL was >495 mg/kg/day
Executive summary:

In a 90-day dermal toxicity study, groups of male and female rats were exposed dermally to hydrodesulphurised kerosine diluted in mineral oil, at treatment rates of 165, 330 or 495 mg/kg/day. There were no deaths during the study and no treatment related efftcts were reported. The NOEL was determined to be >495 mg/kg/day

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
495 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Data on related substances have been used to 'read-across' and predict the hazard properties. A 'read-across' justification document can be found in section 13.

Repeated dose toxicity studies by the dermal and inhalation routes are available for the read-across substance hydrodesulphurised kerosine. No relevant repeat dose oral studies were identified.

 

Inhalation Exposure

In a key subacute inhalation toxicity study (API, 1986), hydrodesulfurised kerosine vapour was administered to 20 Sprague-Dawley rats/sex/concentration by dynamic whole body exposure at a concentration of 24 mg/m3(0.024 mg/L) for 6 hours per day, 5 days/week for 4 weeks. There were no compound related effects in mortality, clinical signs, body weight, haematology, clinical chemistry, organ weights, or gross and histologic pathology.  Therefore, the NOAEC is greater than or equal to 24 mg/m3. This was the highest dose tested in the study. These data are supported by a published study (Carpenter et al 1976) in which rats were exposed to kerosine vapour for 90 days. No effects were reported at levels up to 100 mg/m3

 

Dermal Exposure

In a 90-day dermal toxicity study, groups of male and female rates were exposed dermally to hydrodesulphurised kerosine diluted in mineral oil, at treatment rates of 165, 330 or 495 mg/kg/day. There were no deaths during the study and no treatment related effects were reported. The NOEL was determined to be >495 mg/kg/day

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

well conducted 28 day study, supported by a published study involving exposure to kerosine for 90 days

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:

well conducted 90-day study supported by a well conducted 28 day study

Repeated dose toxicity: dermal - systemic effects (target organ) other: skin

Justification for classification or non-classification

Based on the lack of adverse systemic effects even with the highest doses administered, the material is not classified under the EU CLP Regulation (EC No. 1272/2008).