Registration Dossier

Diss Factsheets

Toxicological information

Repeated dose toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
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 restriction because it was conducted according to OECD guideline 413 and was GLP compliant.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Cross-reference
Reason / purpose for cross-reference:
read-across: supporting information
Reference
Endpoint:
sub-chronic toxicity: inhalation
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 restriction because it was conducted according to OECD guideline 413 and was GLP compliant.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across source
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):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: No treatment-related effects were observed.

BODY WEIGHT AND WEIGHT GAIN: No treatment-related effects were observed.

FOOD CONSUMPTION: No treatment-related effects were observed.

OPHTHALMOSCOPIC EXAMINATION: No treatment-related effects were observed.

HAEMATOLOGY: Statistically significant decreases in haemoglobin, hematocrit, and erythrocytes in blood of high-dose males when compared to controls were not found to be toxicologically relevant, as the values were within the historical range for control animals.

CLINICAL CHEMISTRY: Statistically significant decreases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in blood of high-dose females when compared to controls were not found to be toxicologically relevant, as several control female rats had elevated AST and ALT as well.

NEUROBEHAVIOUR -Motor Activity: There were statistically significant differences in the number and relative pattern of motor activity among the dose groups over the treatment testing periods, but overall, these differences did not occur in a dose-related pattern. The magnitudes of the differences were not large, and none of the treatment-group differences were larger than differences seen during the predose period.
-Functional Operational Battery: No treatment-related effects were observed.

ORGAN WEIGHTS: At terminal sacrifice, there were statistically significant dose-related increases in absolute and relative kidney weights in males of all three treatment groups. High-dose male kidney weights remained elevated after the recovery period. This correlated with microscopic observations indicating light hydrocarbon nephropathy. At terminal sacrifice, there were also statistically significant increases in absolute and relative liver weights in high-dose male and female rats. Liver weights did not remain elevated after the recovery period. There was no microscopic correlation for this condition, so this was considered a functional adaptation to treatment. There were no differences in lung and brain weights when compared to controls.

GROSS PATHOLOGY: No treatment-related effects were observed.

HISTOPATHOLOGY: NON-NEOPLASTIC: Microscopic observations included hyaline droplet formation in the proximal convoluted tubules, considered to contain an alpha2-microglobulin-hydrocarbon complex, and increase in incidence and severity of nephropathy and dilated tubules at the cortico-medullary junction.
Key result
Dose descriptor:
NOEC
Remarks:
subchronic toxicity
Effect level:
> 2 220 ppm
Sex:
male/female
Basis for effect level:
other: organ weights
Key result
Dose descriptor:
NOEC
Remarks:
neurotoxicity
Effect level:
>= 6 646 ppm
Sex:
male/female
Basis for effect level:
other: overall effects
Critical effects observed:
not specified
Conclusions:
The NOEC of the test substance was found to be > 2220 ppm for subchronic toxicity, and >= 6646 ppm for neurotoxicity. The test substance did not cause neurobehavioral or neuropathologic effects in rats after 13 weeks of inhalation exposure at a maximum concentration of 6646 ppm (24.3 mg/m^3). The test substance did induce "light hydrocarbon nephropathy", characterized by increased organ weight and microscopic effects of the kidney (increased incidence of hyaline droplets) in male rats, but since this syndrome is species and sex specific, it is not considered relevant to humans for risk assessment purposes.
Executive summary:

This data is being read across from the source study that tested light alkylate naphtha distillate based on analogue read across.

In a 90-day inhalation toxicity study, light alkylate naphtha distillate-2 was administered to 12 Sprague-Dawley rats/sex/concentration by dynamic whole body exposure at concentrations of 0, 668, 2220, or 6646 ppm (0, 2.4, 8.1, and 24.3 mg/m^3) for 6 hours per day, 5 days/week for a total of 13 weeks.

 

There were no treatment-related effects in mortality, clinical signs, neurotoxicity, body weight, or food consumption. Significant effects noted in haematology and clinical chemistry were not determined to be toxicologically relevant, and kidney weight increases found in high-dose males were not determined to be relevant to human toxicity risk assessments.  The LOEC for subchronic toxicity is >= 6646 ppm, based on haematology, clinical chemistry and organ weights. The NOEC is > 2220 ppm for subchronic toxicity and >= 6646 ppm for neurotoxicity.

 

This study received a Klimisch score of 1 and is classified as reliable without restriction because it was conducted according to OECD guideline 413 and was GLP compliant.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1998
Report date:
1998

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
64741-66-8
Cas Number:
64741-66-8
IUPAC Name:
64741-66-8
Details on test material:
- Name of test material (as cited in study report): Light alkylate naphtha distillate-2
- Molecular weight (if other than submission substance): 89.2
- Substance type: C5 aliphatic
- Physical state: Vapour
- Composition of test material, percentage of components: C4-3.25%; C5-33.30%; C6-18.91%; C7-9.81%; C8-31.14%; C9-3.21%; C10-0.39%
n-Paraffins-3.47%; Total paraffins-99.97%; Total olefins-0.03%
iso-Pentane-33.517%
- Stability under test conditions: Stable
- Storage condition of test material: Ambient temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Kingston, NY
- Age at study initiation: 7 weeks
- Weight at study initiation: Not reported
- Housing: Individual
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 26 °C
- Humidity (%): 40 to 70%
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: nitrogen
Remarks on MMAD:
MMAD / GSD: Measured, but not reported
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1000 litre exposure chamber
- Method of holding animals in test chamber: Cages
- Source and rate of air: 5-gallon container, flushed with nitrogen using laboratory pump
- Method of conditioning air: System of coarse filter, HEPA filter, charcoal filter
- System of generating particulates/aerosols: Volatilization chamber
- Temperature, humidity, pressure in air chamber: Monitored every half hour during exposure; 20 to 24 degrees C, 40 to 60% relative humidity
- Air flow rate: 200 litres per minute
- Method of particle size determination: TSI Aerodynamic Particle Sizer, once each exposure

TEST ATMOSPHERE
- Brief description of analytical method used: Gas chromatography
- Samples taken from breathing zone: yes

VEHICLE (if applicable)
- Composition of vehicle: Nitrogen
- Purity of vehicle: 99.98%
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples for determination of analytical exposure levels were withdrawn by vacuum pump from the breathing zone in the exposure chambers three times per exposure for treated groups, and once per exposure for controls. Samples were analyzed using gas chromatography using a flame ionization detector.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours per day, 5 days per week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
668 ppm (2.4 mg/m^3)
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
2220 ppm (8.1 mg/m^3)
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
6646 ppm (24.3 mg/m^3)
Basis:
analytical conc.
No. of animals per sex per dose:
12
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Highest concentration approximately 75% of the lower explosive limit
- Post-exposure recovery period in satellite groups: 28 days

An extra 12 rats per sex for the high dose and control recovery groups were maintained untreated for 28 days after termination of exposure, to assess reversibility of effects.
Positive control:
None

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice pretest, weekly during the study period

BODY WEIGHT: Yes
- Time schedule for examinations: Twice pretest, weekly during the study period, prior to sacrifice

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

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Pretest and prior to sacrifice
- Dose groups that were examined: All

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to sacrifice
- Anaesthetic used for blood collection: Yes (carbon dioxide/oxygen)
- Animals fasted: Yes
- How many animals: 12 per sex per group
- Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to sacrifice
- Animals fasted: Yes
- How many animals: 12 per sex per group
- Parameters checked in table 2 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Pretest, weeks 5, 9, 14, and 18 (recovery groups)
- Dose groups that were examined: All
- Battery of functions tested: sensory activity / grip strength / motor activity / handling / open-field behaviour / reflexes
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Organs weighed: adrenals, brain, heart, kidneys, liver, lung, ovaries, prostate, spleen, testes (with epididymides), thymus, and uterus
Tissues histopathologically examined: 39, preserved, not reported
Statistics:
Statistical evaluations to determine variance and significance were performed on the following parameters: body weights, body weight change from week 0, food consumption, haematology, clinical chemistry, organ weights, organ/terminal body weight ratio, and organ/brain weight ratio.

Results and discussion

Results of examinations

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):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: No treatment-related effects were observed.

BODY WEIGHT AND WEIGHT GAIN: No treatment-related effects were observed.

FOOD CONSUMPTION: No treatment-related effects were observed.

OPHTHALMOSCOPIC EXAMINATION: No treatment-related effects were observed.

HAEMATOLOGY: Statistically significant decreases in haemoglobin, hematocrit, and erythrocytes in blood of high-dose males when compared to controls were not found to be toxicologically relevant, as the values were within the historical range for control animals.

CLINICAL CHEMISTRY: Statistically significant decreases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in blood of high-dose females when compared to controls were not found to be toxicologically relevant, as several control female rats had elevated AST and ALT as well.

NEUROBEHAVIOUR -Motor Activity: There were statistically significant differences in the number and relative pattern of motor activity among the dose groups over the treatment testing periods, but overall, these differences did not occur in a dose-related pattern. The magnitudes of the differences were not large, and none of the treatment-group differences were larger than differences seen during the predose period.
-Functional Operational Battery: No treatment-related effects were observed.

ORGAN WEIGHTS: At terminal sacrifice, there were statistically significant dose-related increases in absolute and relative kidney weights in males of all three treatment groups. High-dose male kidney weights remained elevated after the recovery period. This correlated with microscopic observations indicating light hydrocarbon nephropathy. At terminal sacrifice, there were also statistically significant increases in absolute and relative liver weights in high-dose male and female rats. Liver weights did not remain elevated after the recovery period. There was no microscopic correlation for this condition, so this was considered a functional adaptation to treatment. There were no differences in lung and brain weights when compared to controls.

GROSS PATHOLOGY: No treatment-related effects were observed.

HISTOPATHOLOGY: NON-NEOPLASTIC: Microscopic observations included hyaline droplet formation in the proximal convoluted tubules, considered to contain an alpha2-microglobulin-hydrocarbon complex, and increase in incidence and severity of nephropathy and dilated tubules at the cortico-medullary junction.

Effect levels

open allclose all
Key result
Dose descriptor:
NOEC
Remarks:
subchronic toxicity
Effect level:
> 2 220 ppm
Sex:
male/female
Basis for effect level:
other: organ weights
Key result
Dose descriptor:
NOEC
Remarks:
neurotoxicity
Effect level:
>= 6 646 ppm
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOEC of the test substance was found to be > 2220 ppm for subchronic toxicity, and >= 6646 ppm for neurotoxicity. The test substance did not cause neurobehavioral or neuropathologic effects in rats after 13 weeks of inhalation exposure at a maximum concentration of 6646 ppm (24.3 mg/m^3). The test substance did induce "light hydrocarbon nephropathy", characterized by increased organ weight and microscopic effects of the kidney (increased incidence of hyaline droplets) in male rats, but since this syndrome is species and sex specific, it is not considered relevant to humans for risk assessment purposes.
Executive summary:

In a 90-day inhalation toxicity study, light alkylate naphtha distillate-2 was administered to 12 Sprague-Dawley rats/sex/concentration by dynamic whole body exposure at concentrations of 0, 668, 2220, or 6646 ppm (0, 2.4, 8.1, and 24.3 mg/m^3) for 6 hours per day, 5 days/week for a total of 13 weeks.

 

There were no treatment-related effects in mortality, clinical signs, neurotoxicity, body weight, or food consumption. Significant effects noted in haematology and clinical chemistry were not determined to be toxicologically relevant, and kidney weight increases found in high-dose males were not determined to be relevant to human toxicity risk assessments.  The LOEC for subchronic toxicity is >= 6646 ppm, based on haematology, clinical chemistry and organ weights. The NOEC is > 2220 ppm for subchronic toxicity and >= 6646 ppm for neurotoxicity.

 

This study received a Klimisch score of 1 and is classified as reliable without restriction because it was conducted according to OECD guideline 413 and was GLP compliant.