Registration Dossier
Registration Dossier
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EC number: 919-446-0 | CAS number: -
Carcinogenicity
Administrative data
Description of key information
The available read across data and weight of evidence demonstrate that Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) is highly unlikely to be carcinogenic and is not classifiable as a carcinogen.
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity, other
- Remarks:
- Oral, inhalation, and dermal
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Basic data given:comparable to guidelines/standards.
- 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: supporting information
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
- Principles of method if other than guideline:
- Test type: subchronic
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- - Concentration in vehicle: constant volume dosage of 5 ml/kg bw
- Duration of treatment / exposure:
- 30 days
- Frequency of treatment:
- daily
- Remarks:
- Doses / Concentrations:
0.14 ml/kg/day (~116 mg/kg bw)
Basis:
other: nominal - Remarks:
- Doses / Concentrations:
0.42 ml/kg/day (~347 mg/kg bw)
Basis:
other: nominal - Remarks:
- Doses / Concentrations:
1.28 ml/kg/day (~1056 mg/kg bw)
Basis:
other: nominal - No. of animals per sex per dose:
- 5 female/5 male
- Control animals:
- yes, concurrent vehicle
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, organs examined include kidneys and livers.
HISTOPATHOLOGY: Yes, organs examined include kidneys. - Other examinations:
- Clinical chemistry- including plasma glucose
hematology - including lymphocyte and platelet counts, cell volume, hemoglobin concentration, and erythrocyte counts;
Urinanalysis - including protein concentrations - Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- effects observed, treatment-related
- 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
The majority of animals in the 0.42 and 1.48 ml/kg/day groups showed salivation and/or brown facial staining from day 4 onwards, as did three animals in the 0.14 ml/kg/day group. Salivation was normally for a short period, and the staining resolved within 24 hrs.
HAEMATOLOGY
Males rats in the 1.28 ml/kg/day group showed higher lymphocyte and platelet numbers, and slightly lower packed cell volume, hemoglobin concentration and erythrocyte counts.
CLINICAL CHEMISTRY
Plasma glucose levels of rats in the 1.28 ml/kg/day group were lower than controls.
URINALYSIS
Urinary protein concentrations were higher in all male rats in the two higher dose groups, and in 2 males in the lowest dose group.
ORGAN WEIGHTS
Male rats showed a dosage related increase in liver and kidney weights. Female rats only showed higher liver weight at the highest dose level.
GROSS PATHOLOGY
One male rat in the 1.28 ml/kg/day dose group had occasional cystic spaces in the parenchyma of the left kidney.
HISTOPATHOLOGY: NON-NEOPLASTIC
The changes in the kidneys were a slight degeneration of the cells lining the proximal tubules in all treatment groups. There was tubular cell degeneration, tubular dilation with intratubular protein and regeneration. These changes were only found in three males in the low dose groups, and four males each in the medium and high dose groups.
- Dose descriptor:
- LOAEL
- Effect level:
- 0.14 other: ml/kg/day
- Sex:
- male
- Basis for effect level:
- other: This type of renal pathology is specific to male rats due to an alpha2u-globulin-mediated process that is not relevant to humans.
- Dose descriptor:
- NOAEL
- Effect level:
- 0.42 other: ml/kg/day
- Sex:
- female
- Basis for effect level:
- other: 1056 mg/kg bw
- Conclusions:
- The LOAEL for male rats was 0.14 ml/kg/day based on renal damage. This type of renal damage is specific to male rats, and is not relevant to humans. The NOAEL for female rats was 1.28 ml/kg/day.
- Executive summary:
The LOAEL for male rats was 0.14 ml/kg/day based on renal damage. This type of renal damage is specific to male rats, and is not relevant to humans. The NOAEL for female rats was 1.28 ml/kg/day.
This study examined the oral 30 -day subchronic toxicity of BP 8313 to rats. Groups of 5 rats of each sex were given doses of 0.14 (116 mg/kg), 0.42 (347 mg/kg), or 1.28 (1056 mg/kg) mL/kg of test substance in corn oil for 30 days. Animals were examined for clinical signs, mortality, body weight, food consumption, water consumption, and food conversion. After sacrifice clinical chemistry, hematology, clinical chemistry, urinalysis, organ weights, histopathology, and gross pathology were examined. There was no mortality during the experiment. Renal damage was observed in male rats at all dose levels. This type of renal pathology is specific to male rats due to a alpha2u-globulin-mediated process that is not relevant to humans. Female rats exhibited adaptive liver changes at the highest dosage. The LOAEL for male rats was 0.14 ml/kg/day based on renal damage. The female NOAEL was 1.28 (1056 mg/kg) mL/kg.
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Quality of whole database:
- Supporting read across studies available for assessment.
Carcinogenicity: via inhalation route
Link to relevant study records
- Endpoint:
- carcinogenicity, other
- Remarks:
- Oral, inhalation, and dermal
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Endpoint:
- carcinogenicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1980
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Similar or equivalent to OECD TG 413.
- 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: supporting information
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day)
- Principles of method if other than guideline:
- Subchronic
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Shell Toxicology Laboratory (Tunstall) Breeding Unit
- Age at study initiation: 10-13 weeks
- Weight at study initiation: male mean weight: 396-398, female mean weight: 244-245
- Fasting period before study: food removed during exposure
- Housing: three per sex in hanging aluminum cages with stainless steel mesh bases 14 x 10 x 7 in, with two layers of cages for a total of twelve cages per exposure chamber
- Diet (e.g. ad libitum): LAD 1, Spillers Spratts Ltd., replenished daily after exposure
- Water (e.g. ad libitum): tap water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-22
- Humidity (%): 32-61
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1 m³ aluminum exposure chamber
- Method of holding animals in test chamber: cages
- Source and rate of air: laboratory air
- Method of conditioning air: dust filters
- System of generating particulates/aerosols: Solvent was evaporated into the air stream using micrometering pumps and vaporizers. Vaporizers were quartz tubes heated to a surface temperature required for complete evaporation of the solvent.
- Temperature, humidity, pressure in air chamber: 17-22°C, 32-61%
- Air flow rate: 2.0 ± 0.03 m³/min
- Air change rate:
- Method of particle size determination:
- Treatment of exhaust air: Air was exhausted into the laboratory exhaust which exited on the roof of the laboratory.
TEST ATMOSPHERE
- Brief description of analytical method used: total hydrocarbon analyser fitted with a flame-ionization detector - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Total hydrocarbon analyser fitted with a flame-ionization detector
- Duration of treatment / exposure:
- 6 hours/day
- Frequency of treatment:
- 5 days/week for 13 weeks
- Remarks:
- Doses / Concentrations:
1293 ppm
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
690 ppm
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
345 ppm
Basis:
analytical conc. - No. of animals per sex per dose:
- 18 per sex
- Control animals:
- yes, concurrent no treatment
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: general health and behaviour
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly
WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly
HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of experiment
- How many animals: all animals
- Parameters checked: erythrocyte count, mean cell volume, hemoglobin, leucocyte count, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hematocrit, red cell fragilities, reticulocyte count, prothrombin time, kaolin-cephalin coagulation time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of experiment
- How many animals: all animals
- Parameters checked: total protein, urea nitrogen, alkaline phosphatase, aspartate amino transferase, alanine animo transferase, sodium, potassium, chloride, albumin, bilirubin
- Other: Estimations of blood glucose were made after 10 weeks of exposure using samples taken from the tail vein.
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, all animals were examined and the following organs weighed: brain, liver, heart, spleen, kidneys, and testes.
HISTOPATHOLOGY: Yes, the following tissues of the high and medium exposure animals and the control animals were examined: mammary gland, mesenteric lymph node, pancreas, stomach, intestine at 5 levels, caecum, spleen, liver, adrenals, kidneys, ovaries or testes, uterus or prostate, seminal vesicles, urinary bladder, thyroid, trachea, heart, lungs, nasal cavity, thymus, eye and lachrymal glands, salivary glands, brain, spinal cord, pituitary, tongue, sciatic nerves, muscle, knee joint and femur, and macroscopic lesions. The kidneys of low exposure males were also examined. - Statistics:
- Body and organ weights were analysed using covariance analysis, with initial body weight as the covariance. Means were adjusted if a significant covariance was found. Organs weights were also analysed using terminal body weights as the covariance. Clinical chemistry and hematological parameters were analysed using analysis of variance. Differences between treatment groups and controls were analysed using Williams t-test. Dunnett's test was used if a monotonic dose response could not be assumed.
- 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):
- no effects observed
- 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:
- not examined
- 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
There were no deaths during the experiment. High exposure animals were lethargic when examined 30 minutes after exposure. Animals were fully recovered by the next morning.
BODY WEIGHT AND WEIGHT GAIN
Males in the medium and high exposure groups had body weights significantly lower than controls. High exposure females also had body weights significantly lower than controls.
FOOD CONSUMPTION
No significant differences in food consumption were observed.
WATER CONSUMPTION
Exposed animals showed significant increase in water consumption, particularly animals in the high exposure group.
HAEMATOLOGY
Male PCV, erythrocyte count, mean cell volume, and mean corpuscular hemoglobin were significantly different from controls at all exposure levels. In females, the number of white cells, and mean cell volume were increased in the high exposure group.
CLINICAL CHEMISTRY
Alkaline phosphatase in both sexes, male aspartate amino transferase, and female albumin levels were significantly higher in the high exposure group. Female total protein was also significantly increased in the medium and high exposure groups.
ORGAN WEIGHTS
Male kidney weights at all exposure levels, and spleen weights in the medium and high exposure levels were significantly increased. Female kidney weights at the medium and high exposure levels, and liver weights at all exposure levels were also increased. However, there were no lesions in these organs found during the histopathology examination. These changes in femals were likely hyperfunctional adaptations of the organs rather than a toxic effect.
GROSS PATHOLOGY
Males in the medium and high exposure groups showed a low incidence of splenic enlargement, renal pallor, and hepatic darkening.
HISTOPATHOLOGY: NON-NEOPLASTIC
Kidneys - Male rats in all exposure group showed multiple, hyaline intracytoplasmic, inclusion droplets in the epithelium of the proximal convoluted tubules of their kidneys. This change did not seem to be dose related. These males also showed increase in the number and size of lysosomes in the cytoplasm of the proximal convoluted tubules. Exposure males also had more frequent focal tubular basophilia. Three males in the high exposure group also showed focal tubular dilatation and inspissated debris in the tubular laminae.
Spleen - Males in the medium and high exposure groups showed accelerated erythropoietic activity and increased hemosiderin deposition. Females in the high exposure group showed increased hemosiderin deposition, and mild extramedullary hematopoiesis.
Lungs - No treatment related effects were noted.
- Dose descriptor:
- LOAEC
- Effect level:
- 345 ppm
- Sex:
- male
- Basis for effect level:
- other: increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans
- Dose descriptor:
- NOEC
- Effect level:
- 1 293 ppm
- Sex:
- female
- Basis for effect level:
- other: reduced body weight; no other effects noted
- Dose descriptor:
- NOAEC
- Effect level:
- 690 ppm
- Sex:
- female
- Conclusions:
- The 90-day LOAEC for male rats was 345 ppm (inhalation). This value is based on increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans. The no-observed-effect-concentration (NOEC) was established at 1293 ppm due to a significant body weight reduction. No other effects were noted. The NOAEC for female rats was 690 ppm.
- Executive summary:
This study evaluated the subchronic toxicity of low aromatic white spirits to rats when exposed via inhalation. Groups of 18 rats per sex were exposed to 345, 690, or 1293 ppm of test substance for 6 hrs/day, 5 days/week, for 13 weeks. The highest concentration, 1293 ppm, was near the saturation point for test substance vapor. Rats were observed for clinical signs, mortality, food consumption, water consumption, and body weight. At the end of the exposure period, the animals were sacrificed, and clinical chemistry, hematology, gross pathology, and histopathology parameters were examined. Male rats at all exposure levels had degenerative effects of the as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans. The no-observed-effect-concentration (NOEC) was established at 1293 ppm due to a significant body weight reduction. No other effects were noted. The NOAEC for female rats was 690 ppm.
- Endpoint:
- carcinogenicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1980
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Similar or equivalent to OECD TG 413.
- 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: supporting information
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day)
- Principles of method if other than guideline:
- Subchronic
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Shell Toxicology Laboratory (Tunstall) Breeding Unit
- Age at study initiation: 10-13 weeks
- Weight at study initiation: male mean weight: 396-398, female mean weight: 244-245
- Fasting period before study: food removed during exposure
- Housing: three per sex in hanging aluminum cages with stainless steel mesh bases 14 x 10 x 7 in, with two layers of cages for a total of twelve cages per exposure chamber
- Diet (e.g. ad libitum): LAD 1, Spillers Spratts Ltd., replenished daily after exposure
- Water (e.g. ad libitum): tap water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-22
- Humidity (%): 32-61
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1 m³ aluminum exposure chamber
- Method of holding animals in test chamber: cages
- Source and rate of air: laboratory air
- Method of conditioning air: dust filters
- System of generating particulates/aerosols: Solvent was evaporated into the air stream using micrometering pumps and vaporizers. Vaporizers were quartz tubes heated to a surface temperature required for complete evaporation of the solvent.
- Temperature, humidity, pressure in air chamber: 17-22°C, 32-61%
- Air flow rate: 2.0 ± 0.03 m³/min
- Air change rate:
- Method of particle size determination:
- Treatment of exhaust air: Air was exhausted into the laboratory exhaust which exited on the roof of the laboratory.
TEST ATMOSPHERE
- Brief description of analytical method used: total hydrocarbon analyser fitted with a flame-ionization detector - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Total hydrocarbon analyser fitted with a flame-ionization detector
- Duration of treatment / exposure:
- 6 hours/day
- Frequency of treatment:
- 5 days/week for 13 weeks
- Remarks:
- Doses / Concentrations:
1293 ppm
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
690 ppm
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
345 ppm
Basis:
analytical conc. - No. of animals per sex per dose:
- 18 per sex
- Control animals:
- yes, concurrent no treatment
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: general health and behaviour
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly
WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly
HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of experiment
- How many animals: all animals
- Parameters checked: erythrocyte count, mean cell volume, hemoglobin, leucocyte count, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hematocrit, red cell fragilities, reticulocyte count, prothrombin time, kaolin-cephalin coagulation time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of experiment
- How many animals: all animals
- Parameters checked: total protein, urea nitrogen, alkaline phosphatase, aspartate amino transferase, alanine animo transferase, sodium, potassium, chloride, albumin, bilirubin
- Other: Estimations of blood glucose were made after 10 weeks of exposure using samples taken from the tail vein.
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, all animals were examined and the following organs weighed: brain, liver, heart, spleen, kidneys, and testes.
HISTOPATHOLOGY: Yes, the following tissues of the high and medium exposure animals and the control animals were examined: mammary gland, mesenteric lymph node, pancreas, stomach, intestine at 5 levels, caecum, spleen, liver, adrenals, kidneys, ovaries or testes, uterus or prostate, seminal vesicles, urinary bladder, thyroid, trachea, heart, lungs, nasal cavity, thymus, eye and lachrymal glands, salivary glands, brain, spinal cord, pituitary, tongue, sciatic nerves, muscle, knee joint and femur, and macroscopic lesions. The kidneys of low exposure males were also examined. - Statistics:
- Body and organ weights were analysed using covariance analysis, with initial body weight as the covariance. Means were adjusted if a significant covariance was found. Organs weights were also analysed using terminal body weights as the covariance. Clinical chemistry and hematological parameters were analysed using analysis of variance. Differences between treatment groups and controls were analysed using Williams t-test. Dunnett's test was used if a monotonic dose response could not be assumed.
- 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):
- no effects observed
- 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:
- not examined
- 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
There were no deaths during the experiment. High exposure animals were lethargic when examined 30 minutes after exposure. Animals were fully recovered by the next morning.
BODY WEIGHT AND WEIGHT GAIN
Males in the medium and high exposure groups had body weights significantly lower than controls. High exposure females also had body weights significantly lower than controls.
FOOD CONSUMPTION
No significant differences in food consumption were observed.
WATER CONSUMPTION
Exposed animals showed significant increase in water consumption, particularly animals in the high exposure group.
HAEMATOLOGY
Male PCV, erythrocyte count, mean cell volume, and mean corpuscular hemoglobin were significantly different from controls at all exposure levels. In females, the number of white cells, and mean cell volume were increased in the high exposure group.
CLINICAL CHEMISTRY
Alkaline phosphatase in both sexes, male aspartate amino transferase, and female albumin levels were significantly higher in the high exposure group. Female total protein was also significantly increased in the medium and high exposure groups.
ORGAN WEIGHTS
Male kidney weights at all exposure levels, and spleen weights in the medium and high exposure levels were significantly increased. Female kidney weights at the medium and high exposure levels, and liver weights at all exposure levels were also increased. However, there were no lesions in these organs found during the histopathology examination. These changes in femals were likely hyperfunctional adaptations of the organs rather than a toxic effect.
GROSS PATHOLOGY
Males in the medium and high exposure groups showed a low incidence of splenic enlargement, renal pallor, and hepatic darkening.
HISTOPATHOLOGY: NON-NEOPLASTIC
Kidneys - Male rats in all exposure group showed multiple, hyaline intracytoplasmic, inclusion droplets in the epithelium of the proximal convoluted tubules of their kidneys. This change did not seem to be dose related. These males also showed increase in the number and size of lysosomes in the cytoplasm of the proximal convoluted tubules. Exposure males also had more frequent focal tubular basophilia. Three males in the high exposure group also showed focal tubular dilatation and inspissated debris in the tubular laminae.
Spleen - Males in the medium and high exposure groups showed accelerated erythropoietic activity and increased hemosiderin deposition. Females in the high exposure group showed increased hemosiderin deposition, and mild extramedullary hematopoiesis.
Lungs - No treatment related effects were noted.
- Dose descriptor:
- LOAEC
- Effect level:
- 345 ppm
- Sex:
- male
- Basis for effect level:
- other: increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans
- Dose descriptor:
- NOEC
- Effect level:
- 1 293 ppm
- Sex:
- female
- Basis for effect level:
- other: reduced body weight; no other effects noted
- Dose descriptor:
- NOAEC
- Effect level:
- 690 ppm
- Sex:
- female
- Conclusions:
- The 90-day LOAEC for male rats was 345 ppm (inhalation). This value is based on increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans. The no-observed-effect-concentration (NOEC) was established at 1293 ppm due to a significant body weight reduction. No other effects were noted. The NOAEC for female rats was 690 ppm.
- Executive summary:
This study evaluated the subchronic toxicity of low aromatic white spirits to rats when exposed via inhalation. Groups of 18 rats per sex were exposed to 345, 690, or 1293 ppm of test substance for 6 hrs/day, 5 days/week, for 13 weeks. The highest concentration, 1293 ppm, was near the saturation point for test substance vapor. Rats were observed for clinical signs, mortality, food consumption, water consumption, and body weight. At the end of the exposure period, the animals were sacrificed, and clinical chemistry, hematology, gross pathology, and histopathology parameters were examined. Male rats at all exposure levels had degenerative effects of the as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans. The no-observed-effect-concentration (NOEC) was established at 1293 ppm due to a significant body weight reduction. No other effects were noted. The NOAEC for female rats was 690 ppm.
- Endpoint:
- carcinogenicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1980
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Similar or equivalent to OECD TG 413.
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day)
- Principles of method if other than guideline:
- Subchronic
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Shell Toxicology Laboratory (Tunstall) Breeding Unit
- Age at study initiation: 10-13 weeks
- Weight at study initiation: male mean weight: 396-398, female mean weight: 244-245
- Fasting period before study: food removed during exposure
- Housing: three per sex in hanging aluminum cages with stainless steel mesh bases 14 x 10 x 7 in, with two layers of cages for a total of twelve cages per exposure chamber
- Diet (e.g. ad libitum): LAD 1, Spillers Spratts Ltd., replenished daily after exposure
- Water (e.g. ad libitum): tap water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-22
- Humidity (%): 32-61
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1 m³ aluminum exposure chamber
- Method of holding animals in test chamber: cages
- Source and rate of air: laboratory air
- Method of conditioning air: dust filters
- System of generating particulates/aerosols: Solvent was evaporated into the air stream using micrometering pumps and vaporizers. Vaporizers were quartz tubes heated to a surface temperature required for complete evaporation of the solvent.
- Temperature, humidity, pressure in air chamber: 17-22°C, 32-61%
- Air flow rate: 2.0 ± 0.03 m³/min
- Air change rate:
- Method of particle size determination:
- Treatment of exhaust air: Air was exhausted into the laboratory exhaust which exited on the roof of the laboratory.
TEST ATMOSPHERE
- Brief description of analytical method used: total hydrocarbon analyser fitted with a flame-ionization detector - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Total hydrocarbon analyser fitted with a flame-ionization detector
- Duration of treatment / exposure:
- 6 hours/day
- Frequency of treatment:
- 5 days/week for 13 weeks
- Remarks:
- Doses / Concentrations:
1293 ppm
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
690 ppm
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
345 ppm
Basis:
analytical conc. - No. of animals per sex per dose:
- 18 per sex
- Control animals:
- yes, concurrent no treatment
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: general health and behaviour
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly
WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly
HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of experiment
- How many animals: all animals
- Parameters checked: erythrocyte count, mean cell volume, hemoglobin, leucocyte count, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hematocrit, red cell fragilities, reticulocyte count, prothrombin time, kaolin-cephalin coagulation time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of experiment
- How many animals: all animals
- Parameters checked: total protein, urea nitrogen, alkaline phosphatase, aspartate amino transferase, alanine animo transferase, sodium, potassium, chloride, albumin, bilirubin
- Other: Estimations of blood glucose were made after 10 weeks of exposure using samples taken from the tail vein.
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, all animals were examined and the following organs weighed: brain, liver, heart, spleen, kidneys, and testes.
HISTOPATHOLOGY: Yes, the following tissues of the high and medium exposure animals and the control animals were examined: mammary gland, mesenteric lymph node, pancreas, stomach, intestine at 5 levels, caecum, spleen, liver, adrenals, kidneys, ovaries or testes, uterus or prostate, seminal vesicles, urinary bladder, thyroid, trachea, heart, lungs, nasal cavity, thymus, eye and lachrymal glands, salivary glands, brain, spinal cord, pituitary, tongue, sciatic nerves, muscle, knee joint and femur, and macroscopic lesions. The kidneys of low exposure males were also examined. - Statistics:
- Body and organ weights were analysed using covariance analysis, with initial body weight as the covariance. Means were adjusted if a significant covariance was found. Organs weights were also analysed using terminal body weights as the covariance. Clinical chemistry and hematological parameters were analysed using analysis of variance. Differences between treatment groups and controls were analysed using Williams t-test. Dunnett's test was used if a monotonic dose response could not be assumed.
- 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):
- no effects observed
- 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:
- not examined
- 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
There were no deaths during the experiment. High exposure animals were lethargic when examined 30 minutes after exposure. Animals were fully recovered by the next morning.
BODY WEIGHT AND WEIGHT GAIN
Males in the medium and high exposure groups had body weights significantly lower than controls. High exposure females also had body weights significantly lower than controls.
FOOD CONSUMPTION
No significant differences in food consumption were observed.
WATER CONSUMPTION
Exposed animals showed significant increase in water consumption, particularly animals in the high exposure group.
HAEMATOLOGY
Male PCV, erythrocyte count, mean cell volume, and mean corpuscular hemoglobin were significantly different from controls at all exposure levels. In females, the number of white cells, and mean cell volume were increased in the high exposure group.
CLINICAL CHEMISTRY
Alkaline phosphatase in both sexes, male aspartate amino transferase, and female albumin levels were significantly higher in the high exposure group. Female total protein was also significantly increased in the medium and high exposure groups.
ORGAN WEIGHTS
Male kidney weights at all exposure levels, and spleen weights in the medium and high exposure levels were significantly increased. Female kidney weights at the medium and high exposure levels, and liver weights at all exposure levels were also increased. However, there were no lesions in these organs found during the histopathology examination. These changes in femals were likely hyperfunctional adaptations of the organs rather than a toxic effect.
GROSS PATHOLOGY
Males in the medium and high exposure groups showed a low incidence of splenic enlargement, renal pallor, and hepatic darkening.
HISTOPATHOLOGY: NON-NEOPLASTIC
Kidneys - Male rats in all exposure group showed multiple, hyaline intracytoplasmic, inclusion droplets in the epithelium of the proximal convoluted tubules of their kidneys. This change did not seem to be dose related. These males also showed increase in the number and size of lysosomes in the cytoplasm of the proximal convoluted tubules. Exposure males also had more frequent focal tubular basophilia. Three males in the high exposure group also showed focal tubular dilatation and inspissated debris in the tubular laminae.
Spleen - Males in the medium and high exposure groups showed accelerated erythropoietic activity and increased hemosiderin deposition. Females in the high exposure group showed increased hemosiderin deposition, and mild extramedullary hematopoiesis.
Lungs - No treatment related effects were noted.
- Dose descriptor:
- LOAEC
- Effect level:
- 345 ppm
- Sex:
- male
- Basis for effect level:
- other: increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans
- Dose descriptor:
- NOEC
- Effect level:
- 1 293 ppm
- Sex:
- female
- Basis for effect level:
- other: reduced body weight; no other effects noted
- Dose descriptor:
- NOAEC
- Effect level:
- 690 ppm
- Sex:
- female
- Conclusions:
- The 90-day LOAEC for male rats was 345 ppm (inhalation). This value is based on increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans. The no-observed-effect-concentration (NOEC) was established at 1293 ppm due to a significant body weight reduction. No other effects were noted. The NOAEC for female rats was 690 ppm.
- Executive summary:
This study evaluated the subchronic toxicity of low aromatic white spirits to rats when exposed via inhalation. Groups of 18 rats per sex were exposed to 345, 690, or 1293 ppm of test substance for 6 hrs/day, 5 days/week, for 13 weeks. The highest concentration, 1293 ppm, was near the saturation point for test substance vapor. Rats were observed for clinical signs, mortality, food consumption, water consumption, and body weight. At the end of the exposure period, the animals were sacrificed, and clinical chemistry, hematology, gross pathology, and histopathology parameters were examined. Male rats at all exposure levels had degenerative effects of the as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans. The no-observed-effect-concentration (NOEC) was established at 1293 ppm due to a significant body weight reduction. No other effects were noted. The NOAEC for female rats was 690 ppm.
- Endpoint:
- carcinogenicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1979
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Comparable to guideline study.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day)
- Principles of method if other than guideline:
- subchronic
- GLP compliance:
- 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
- Age at study initiation: 4 weeks males, 5 weeks females
- Weight at study initiation: males 142-214 g, females 140-189 g
- Housing: elevated stainless steel wire mesh cages, individually outside of chamber, pairs within exposure chamber
- Diet (e.g. ad libitum): Purina Laboratory Chow, ad libitum except during exposure
- Water (e.g. ad libitum): ad libitum except during exposure
- Acclimation period:
IN-LIFE DATES: From: April 17, 1978 To: July 12, 1978 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel and glass chamber, 760 l
- Method of conditioning air: Test substance was metered using a syringe pump driven 50 cc Tomac glass syringe from a 500 ml Erlenmeyer flask into a heated flask and flash evaporated. Clean air was passed through this flask to pick up vapor. The test atmosphere was then fed into the chamber air inlet line where it was diluted to the desired concentration.
- Temperature, humidity, pressure in air chamber:
- Air flow rate: 134 lpm
- Air change rate: 7.46 min, with a 99% equilibration time of 34.3 min.
TEST ATMOSPHERE
- Brief description of analytical method used: Miran IA Ambient Air Analyser IR analyzed at 3.4 microns. Samples were drawn at 1, 3, and 5 hrs of exposure. Charcoal trapped vapor samples were also analyzed using GC.
- Samples taken from breathing zone: yes
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Miran IA Ambient Air Analyser IR analyzed at 3.4 microns. Samples were drawn at 1, 3, and 5 hrs of exposure. Charcoal trapped vapor samples were also analyzed using GC.
- Duration of treatment / exposure:
- 6 hrs/day
- Frequency of treatment:
- 5 days/week for 12 weeks
- Remarks:
- Doses / Concentrations:
100 ppm
Basis:
nominal conc. - Remarks:
- Doses / Concentrations:
300 ppm
Basis:
nominal conc. - Remarks:
- Doses / Concentrations:
103 ppm
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
294 ppm
Basis:
analytical conc. - No. of animals per sex per dose:
- 35 per sex/per dose
- Control animals:
- yes, concurrent no treatment
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly starting five days prior to exposure
HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 0, 4 weeks, 8 weeks, and 12 weeks
- How many animals: 10 animals per sex
- Parameters examined: hemoglobin, hematocrit, erythrocyte count, clotting time, total and differential leucocytes
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 0, 4 weeks, 8 weeks, and 12 weeks
- How many animals: 10 animals per sex
- Parameters examined: blood urea nitrogen, serum glutamic pyruvic transaminase, alkaline phosphatase
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
10 animals per sex per group were sacrificed at 4, 8, and 12 weeks (all survivors) by exsanguination with anesthesia. The adrenals, brain, gonads, kidneys, liver, and lungs were weighed.
HISTOPATHOLOGY: Yes
The organs of the sacrificed animals from groups I and III were examined histopathologically. The following organs were examined: adrenals, bone marrow, brain, eye, gonad, heart, colon, duodenum, ileum, kidneys, liver, lung, lymph node, mammary gland, pancreas, pituitary, salivary gland, skeletal muscle, skin, spinal cord, spleen, stomach, thyroid, trachea, urinary bladder, uterus or prostate, gross lesions, tissue masses.
- Statistics:
- hematology, and clinical chemistry: Snedecor, GS, and Cochran, WG, Statistical Methods. 6th ed., Iowa State University Press, Ames, 1967, 104-106, 114-119.
body weight, organ weight, and organ/body weight ratios: Dunnett, CW, J. Am. Stat. Assn. 50: 1096-1121, 1955, and Biometrics 20: 482, September, 1964. - Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- no effects observed
- 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:
- 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:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
There was no mortality during the study. Females in both exposure groups had yellow staining of the ano-genital fur, which was possibly treatment related. Several animals in all groups exhibited dry rales, mucoid nasal discharge, and red nasal discharge. There was not a clear treatment related pattern. A few animals in all groups exhibited moist rales, chromodacryorrhea, excessive lacrimation, excessive salivation, alopecia, and brown staining of the ano-genital area. There was singular observations of a film covered eye and labored breathing in the high exposure group, and also one observation of loose stool in this group.
BODY WEIGHT AND WEIGHT GAIN
Male body weights were significantly increased at week 2 in both exposure groups. Females in the 300 ppm exposure group had significantly decreased body weights at day 0, week 1, and week 3. These weight differences were not considered to be treatment related.
HAEMATOLOGY
A significant decrease in hematocrit levels was seen in males exposed to 300 ppm at week 8 and week 12. Females in the 100 ppm group had decreased hematocrit values at week 4, and week 8, and females in the 300 ppm group had decreased values at week 4 only. Hemoglobin values were decreased in 100 ppm and 300 ppm exposed females at week 4, and 300 ppm exposed females had significantly decreased mean red blood cell counts at week 4. None of these findings appeared to be biologically significant. Males in the 300 ppm exposure group had elevated mean total leucocyte values at week 12. This was possibly treatment related.
CLINICAL CHEMISTRY
A significant increase in blood urea was seen in both groups of exposed males, indicating a possible treatment related effect. The males in the 100 ppm group had decreased mean glucose level at week 12. Females in the 300 ppm exposure group had decreased mean serum glutamic pyruvic transaminase level in week 4. These effects did not show a treatment related pattern, or indicate an abnormal condition, so they were not considered significant.
ORGAN WEIGHTS
Male kidney weight and kidney/body weight ratios were significantly elevated in the 100 ppm group at the week 4 sacrifice. At the week 12 sacrifice, males in both exposure groups had significantly elevated kidney/body weight ratios, and males in the 300 ppm group also had significanlty elevated kidney weights. At the week 8 sacrifice, females in the 300 ppm exposure group also had elevated kidney weights, and kidney/body weight ratios. These effects did not follow a clear dose related pattern.
HISTOPATHOLOGY
No treatment related effects were observed. - Dose descriptor:
- LOAEC
- Effect level:
- 100 ppm
- Sex:
- male
- Basis for effect level:
- other: increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans
- Dose descriptor:
- NOAEL
- Effect level:
- >= 300 ppm
- Sex:
- female
- Conclusions:
- For male rats, the LOAEC was 100 ppm via inhalation. This value is based on kidney effects due to a alpha2u-globulin-mediated process that is not regarded as relevant to humans that are not relevant to humans. For female rats, the NOAEC was 300 ppm. These results do not warrant classification under either the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC or under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).
- Executive summary:
This study examined the subchronic toxicity of MRD-78-25 to rats via inhalation. Groups of 35 rats per sex were exposed to 0, 100, or 300 ppm of test substance vapors. Exposure was 6 hrs/day, 5 days/week, for 12 weeks. 10 rats/sex from each group were sacrificed at week 4 and week 8. Animals were observed for clinical signs daily, and weighed weekly. At the end of the study, all surviving animals were sacrificed. After sacrifice, hematological, clinical chemistry, and histopathological parameters were examined. There was no treatment related mortality during the study, and no treatment related body weight effects. For male rats, the LOAEC was 100 ppm via inhalation. This value is based on kidney effects due to a alpha2u-globulin-mediated process that is not regarded as relevant to humans that are not relevant to humans. For female rats, the NOAEC was 300 ppm. These results do not warrant classification under either the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC or under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).
Referenceopen allclose all
Mean Body Weights of Male Rats (g)
Mean Body Weights of Female Rats (g)
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Mean Body Weights of Male Rats (g)
Mean Body Weights of Female Rats (g)
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Mean Body Weights of Male Rats (g)
Mean Body Weights of Female Rats (g)
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Mean Body Weight of Male Rats
Mean Body Weight of Female Rats
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Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Quality of whole database:
- Supporting substance specific and read across studies available for assessment.
Carcinogenicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) does not meet the criteria for classification as a carcinogen under the Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).
Additional information
The available read across data and available weight of evidence demonstrate that Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) is highly unlikely to be carcinogenic and is not classifiable as a carcinogen. Further testing is not required under Annex XI, section 1.2.
No standard carcinogenicity studies are available for Hydrocarbons, C9-C12, n-alkanes, isoalkanes, cyclics, aromatics (2-25%). However, with regard to the molecular structure of the substance, no carcinogenic potential is expected. Moreover, in investigations on read across mutagenicity (in vitro and in vivo) as well as in substance specific and read across repeated dose toxicity studies (oral route and via inhalation), neither genotoxicity nor an indication for neoplastic lesions was observed.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
