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Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report similar or equivalent to OECD TG 407 performed on an analogue substance.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Principles of method if other than guideline:
A series of gavage studies performed male F-344 rats using components of gasoline administered once daily, 5 days per wk for 4 wk (20 doses total).
GLP compliance:
not specified
Limit test:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
once per day for five days per week
Remarks:
Doses / Concentrations:
500 mg/kg/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
2000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
10 rats per dose
Control animals:
yes
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 specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
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:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY: There were no deaths. The dosages were well tolerated, with lethargy being the prominent clinical sign of toxicity.

BODY WEIGHT AND WEIGHT GAIN: The high dose group exhibited statistically significantly lower body weight gains than the saline control group. Decreased body weight gain is consistent with alpha 2u-globulin-mediated nephropathy, an effect considered not relevant for human risk assessment.

GROSS PATHOLOGY: The most common pathologic findings were confined to the kidneys, stomachs, and, to a lesser degree, the livers. Stomach lesions appeared related to the irritant effect of the hydrocarbons on the stomach lining. Such lesions included erythema, erosion of the gastric mucosa, rasied discolored foci on the gastric epithelial lining and ulceration. The severity and incidence of these lesions were generally dose-related.

HISTOPATHOLOGY: NON-NEOPLASTIC: Renal: The test material induced a weak-to-moderate nephrotoxic response which was characterized by (a) hyaline droplet accumulation in the cytoplasm of epithelial lining cells of the proximal convoluted tubules, (b) degeneration or regeneration of the epithelial cells in the renal cortex, and (c) the development of granular proteinaceous casts in the lumina of tubules located between the inner and outer stripe of the medulla. These effects are consistent with alpha 2u-globulin-mediated nephropathy, an effect considered not relevant for human risk assessment.
Dose descriptor:
NOEL
Effect level:
< 500 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
body weight and weight gain
clinical signs
gross pathology
histopathology: non-neoplastic
Critical effects observed:
not specified
Conclusions:
The procedure was designed to investigate hydrocarbon nephropathy. The NOEL for light catalytic cracked naphtha was determined to be less than 500 mg/kg.
Executive summary:

Four naphtha streams, among fifteen hydrocarbon compounds, were administered to two groups of male Fischer 344 rats by oral gavage at the dose levels of 500 mg/kg/day and 2000 mg/kg/day five days per week for four weeks. The procedure was designed to investigate hydrocarbon nephropathy. Animals in both groups experienced lethargy and significantly lower body weight gain was observed in the animals at the high-dose group. The only histopathological difference found was in the kidneys of all male rats. The kidney effects observed in male rats are indicative of alpha-2u-globulin nephropathy. These kidney effects are specific to male rats and are not considered to be of biological relevance to humans. Light catalytic cracked naphtha induced a weak to moderate nephrotoxic response in a dose-dependent manner. The NOEL was determined to be less than 500 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
500
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report similar or equivalent to OECD 413 TG under GLP conditions performed on an analogue substance.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes (incl. QA statement)
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Scott Model 216 THA
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours per day five days per week
Remarks:
Doses / Concentrations:
7248 mg/m3
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
12528 mg/m3
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
21792 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
20 males and 20 females per dose
Control animals:
yes, sham-exposed
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
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:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY: High-dose males and females exhibited red material around the nose. Other clinical signs seen did not show any treatment-related trends. All animals survived to termination of the study.

BODY WEIGHT AND WEIGHT GAIN: Statistically significant decreases in mean body weights were noted in study weeks 2 through 13 for high-dose males and during weeks 4 and 5 for mid-dose males, when compared with control males. Group mean body weights were similar between control and treated females.

HAEMATOLOGY: There were no differences between exposed and control animals for any of the hematologic parameters which could be ascribed to the test material exposures.

CLINICAL CHEMISTRY: There were no differences between exposed and control animals for any of the biochemistry parameters which could be ascribed to the test material exposures.

URINALYSIS: There were a few statistically significant differences between exposed and control animals, but since all values were within the normal range, none of the differences were considered exposure related.

ORGAN WEIGHTS: At the terminal sacrifice, test article related organ weight changes were observed in the liver and kidney of male and female rats.

GROSS PATHOLOGY: No test article related macroscopic changes were observed in any of the male and female rats that were sacrificed after a 13 weeks exposure period.

HISTOPATHOLOGY: NON-NEOPLASTIC: There were test article related changes observed in the livers of male anf female rats and in the kidneys of male rats from the high-dose level.

HISTOPATHOLOGY: NEOPLASTIC: The liver change consisted of centrilobular hepatocellular hypertrophy involving scatted lobules. The liver cell enlargement was minimal. The incidence was slightly higher in male rats than in females (10/20 in males and 5/20 in females). The kidney changes in males consisted of: (a) granular casts within tubules located in the outer zone of the medulla, (b) tubular degeneration and regeneration, particularly in the proximal convoluted tubules, and (c) an increased incidence of chronic interstitial inflammatory recation. The severity of these changes varied from trace to mild and the distribution was multifocal. Most of the tubules that contained the granular casts appeared dilated with some degree of flattening and/or pressure necrosis of the lining epithelia. Degeneration of tubular epithelium was minimal, but regeneration was comparatively more prominent. Around some of these tubules there was infiltration with chronic inflammatory cells, primarily mononuclear cells. These changes occurred in other areas as well.
Dose descriptor:
NOAEC
Effect level:
ca. 21 792 mg/m³ air (analytical)
Sex:
female
Basis for effect level:
clinical signs
organ weights and organ / body weight ratios
Dose descriptor:
NOAEC
Effect level:
ca. 12 528 mg/m³ air (analytical)
Sex:
male
Basis for effect level:
body weight and weight gain
clinical signs
organ weights and organ / body weight ratios
Critical effects observed:
not specified
Conclusions:
Exposure to light catalytically cracked naphtha (API 81-03) for 13 weeks produced mild but significant toxic responses in males, depressed body weights and typical hydrocarbon induced nephropathy. Female rats were essentially unaffected by the test material. Therefore, the male NOAEL was determined to be 12528 mg/m3 and the female NOAEL was concluded to be 21792 mg/m3.
Executive summary:

The purpose of this study was to evaluate the subchronic toxicity of light catalytically cracked naphtha when administered to Sprague-Dawley rats by whole body inhalation exposure for thirteen consecutive weeks at the analytical concentrations of 7248 mg/m3, 12528 mg/m3, and 21792 mg/m3. Very few responses were observed in male or females rats at the high-dose with the exception of red nasal discharge. Decreased body weight gain was observed in male rats of the mid- and high-dose groups. There were no exposure-related differences for either males or females in any of the hematologic, serum biochemical or urinalysis parameters evaluated. Exposure-related increases in the liver weights of male and female rats and the kidney weights of male rats were observed. Therefore, the male NOAEL was determined to be 12528 mg/m3 and the female NOAEL was concluded to be 21792 mg/m3.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
12 528 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report similar or equivalent to OECD 413 TG under GLP conditions performed on an analogue substance.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes (incl. QA statement)
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Scott Model 216 THA
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours per day five days per week
Remarks:
Doses / Concentrations:
7248 mg/m3
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
12528 mg/m3
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
21792 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
20 males and 20 females per dose
Control animals:
yes, sham-exposed
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
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:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY: High-dose males and females exhibited red material around the nose. Other clinical signs seen did not show any treatment-related trends. All animals survived to termination of the study.

BODY WEIGHT AND WEIGHT GAIN: Statistically significant decreases in mean body weights were noted in study weeks 2 through 13 for high-dose males and during weeks 4 and 5 for mid-dose males, when compared with control males. Group mean body weights were similar between control and treated females.

HAEMATOLOGY: There were no differences between exposed and control animals for any of the hematologic parameters which could be ascribed to the test material exposures.

CLINICAL CHEMISTRY: There were no differences between exposed and control animals for any of the biochemistry parameters which could be ascribed to the test material exposures.

URINALYSIS: There were a few statistically significant differences between exposed and control animals, but since all values were within the normal range, none of the differences were considered exposure related.

ORGAN WEIGHTS: At the terminal sacrifice, test article related organ weight changes were observed in the liver and kidney of male and female rats.

GROSS PATHOLOGY: No test article related macroscopic changes were observed in any of the male and female rats that were sacrificed after a 13 weeks exposure period.

HISTOPATHOLOGY: NON-NEOPLASTIC: There were test article related changes observed in the livers of male anf female rats and in the kidneys of male rats from the high-dose level.

HISTOPATHOLOGY: NEOPLASTIC: The liver change consisted of centrilobular hepatocellular hypertrophy involving scatted lobules. The liver cell enlargement was minimal. The incidence was slightly higher in male rats than in females (10/20 in males and 5/20 in females). The kidney changes in males consisted of: (a) granular casts within tubules located in the outer zone of the medulla, (b) tubular degeneration and regeneration, particularly in the proximal convoluted tubules, and (c) an increased incidence of chronic interstitial inflammatory recation. The severity of these changes varied from trace to mild and the distribution was multifocal. Most of the tubules that contained the granular casts appeared dilated with some degree of flattening and/or pressure necrosis of the lining epithelia. Degeneration of tubular epithelium was minimal, but regeneration was comparatively more prominent. Around some of these tubules there was infiltration with chronic inflammatory cells, primarily mononuclear cells. These changes occurred in other areas as well.
Dose descriptor:
NOAEC
Effect level:
ca. 21 792 mg/m³ air (analytical)
Sex:
female
Basis for effect level:
clinical signs
organ weights and organ / body weight ratios
Dose descriptor:
NOAEC
Effect level:
ca. 12 528 mg/m³ air (analytical)
Sex:
male
Basis for effect level:
body weight and weight gain
clinical signs
organ weights and organ / body weight ratios
Critical effects observed:
not specified
Conclusions:
Exposure to light catalytically cracked naphtha (API 81-03) for 13 weeks produced mild but significant toxic responses in males, depressed body weights and typical hydrocarbon induced nephropathy. Female rats were essentially unaffected by the test material. Therefore, the male NOAEL was determined to be 12528 mg/m3 and the female NOAEL was concluded to be 21792 mg/m3.
Executive summary:

The purpose of this study was to evaluate the subchronic toxicity of light catalytically cracked naphtha when administered to Sprague-Dawley rats by whole body inhalation exposure for thirteen consecutive weeks at the analytical concentrations of 7248 mg/m3, 12528 mg/m3, and 21792 mg/m3. Very few responses were observed in male or females rats at the high-dose with the exception of red nasal discharge. Decreased body weight gain was observed in male rats of the mid- and high-dose groups. There were no exposure-related differences for either males or females in any of the hematologic, serum biochemical or urinalysis parameters evaluated. Exposure-related increases in the liver weights of male and female rats and the kidney weights of male rats were observed. Therefore, the male NOAEL was determined to be 12528 mg/m3 and the female NOAEL was concluded to be 21792 mg/m3.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
12 528 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report similar or equivalent to OECD TG 411 performed on an analogue substance.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
not specified
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
Dermal exposures
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 days per week
Remarks:
Doses / Concentrations:
30 mg/kg/day
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
125 mg/kg/day
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
300 mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
15 male and 15 female rats per dose
Control animals:
yes, sham-exposed
Clinical signs:
effects observed, treatment-related
Dermal irritation:
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 specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY: All rats survived to the end of the study and were euthanized after thirteen weeks of treatment. Moderate erythema, slight edema (in males only), and flaking of the skin were observed in the treated groups during the dosing phase of the study.

BODY WEIGHT AND WEIGHT GAIN: Final body weight data did not show any treatment-related effects.

CLINICAL CHEMISTRY: The results suggest that 13 weeks of dermal treatment with LCCN marginally affected normal serum chemistry of male Sprague-Dawley rats without affecting female rats.

ORGAN WEIGHTS: Final organ weight date did not show any treatment-related effects.

GROSS PATHOLOGY: Findings included various skin lesions - scabs, erosion, scratches, scaling, dry skin and red-brown spots - were observed in fifty percent or more of the treated rats and in none of the controls.

HISTOPATHOLOGY: NON-NEOPLASTIC: Microscopic examination of the skin indicated mild to moderate epidermal hyperplasia, mild inflammation of the superficial dermic, and ulceration. The degree of skin reaction was surprising since the material was not covered and appeared to evaporate from the skin within minutes.
Dose descriptor:
NOEL
Remarks:
dermal irritation
Effect level:
< 30 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
dermal irritation
Dose descriptor:
NOEL
Remarks:
systemic effects
Effect level:
> 300 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical biochemistry
gross pathology
histopathology: non-neoplastic
Critical effects observed:
not specified
Conclusions:
Repeated dose dermal applications of light catalytically cracked naphtha at 30 mg/kg, 125 mg/kg, and 300 mg/kg resulted in slight to moderate dose-dependent dermal irritation effects. Based on these findings, the dermal irritation NOEL was determined to be less than 30 mg/kg/day. The systemic NOEL was determined to be greater than 300 mg/kg.
Executive summary:

Light catalytically cracked naphtha was administered dermally to rats (15 males and 15 females per group) at concentrations of 30, 125, and 300 mg/kg five days per week for 13 weeks to evaluate the subchronic toxicity of the test material. Slight to moderate dose-dependent dermal irritation in all dose groups was seen during the study. No animals died. There were no effects on body weight gain or organ weights. Statistically significant results were concluded from the gross pathological and histopathological examinations and the serum chemistry analyses. Based on these findings, the dermal irritation NOEL was determined to be less than 30 mg/kg/day. The systemic NOEL was determined to be 300 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report similar or equivalent to OECD 410 TG performed under GLP conditions on an analogue substance.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
GLP compliance:
yes
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
Source: Hazleton Dutchland, Inc. (Denver, PA)
Housing: Stainless steel cages with grid bottoms
Diet: Purina Laboratory Rabbit Chow #5321 ad libitum
Water: ad libitum
Acclimation period: 2.5 weeks

ENVIRONMENTAL CONDITIONS
Temperature (°C): 23 ± 3
Humidity (%): 20-70%
Air changes (per hr): 10-15
Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
Area of exposure: 15 X 20 cm
% coverage: 10 %
Type of wrap if used: sheet of polyethylene material and secured by hypoallergenic tape
Time intervals for shavings or clipplings: The exposure site was reclipped as necessary

REMOVAL OF TEST SUBSTANCE
Time after start of exposure: Occlusion lasted for six hours, after which time the tape, wrap and gauze pad were removed, and any residual test article was gently wiped from the test site with a dry, clean absorbent gauze pad.

TEST MATERIAL
Amount(s) applied (volume or weight with unit): Doses were based on the weekly body weight taken for each animal and the specific gravity (0.6985 g/ml) of API 81-04.
Constant volume or concentration used: no
Duration of treatment / exposure:
6 hours
Frequency of treatment:
three times per week for four weeks for a total of 12 applications
Remarks:
Doses / Concentrations:
200 mg/kg/day
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
1000 mg/kg/day
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
2000 mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5 rabbits per sex per dose
Control animals:
yes, sham-exposed
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
Time schedule: Twice daily, at least six hours apart

DETAILED CLINICAL OBSERVATIONS: Yes
Time schedule: Twice daily, at least six hours apart

DERMAL IRRITATION (if dermal study): Yes
Time schedule for examinations: Examinations were done just prior to test article application on the days of treatment and in the mornings on no-treatment days.

BODY WEIGHT: Yes
Time schedule for examinations:At the end of the quarantine period, then weekly for the remainder of the study, and at termination.

HAEMATOLOGY: Yes
Time schedule for collection of blood: Prior to initiation of dosing and at termination
Anaesthetic used for blood collection: No data
Animals fasted: No data
How many animals: All animals

CLINICAL CHEMISTRY: Yes
Time schedule for collection of blood: Prior to initiation of dosing and at termination
Animals fasted: No data
How many animals: All animals
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Body weights, clinical pathology, and absolute and relative organ body weight data of the control groups were statistically compared to the treated group data of the same sex, using a two-tailed Student's t-test at the 5% probability level.
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
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 specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY: Five animals died. All deaths were considered as incidental spontaneous deaths. In the surviving statements, wheezing and thinness were observed at the 2000 mg/kg dose level.

DERMAL IRRITATION
A moderate to severe dose-dependent dermal irritation in the mid- and high-dose groups was seen during the study.

BODY WEIGHT AND WEIGHT GAIN: Statistically significantly lower mean body weights observed for high-dose males and mid- and high-dose females were considered treatment-related. Also the statistically significantly lower than control mean weight gain for mid-dose males and high-dose femaleswere considered treatment-related.

HAEMATOLOGY: No treatment-related findings.

CLINICAL CHEMISTRY: No treatment-related findings.

ORGAN WEIGHTS: The statistical differences are considered to be incidental in nature and were not related to treatment with the test articles.

GROSS PATHOLOGY: Treatment-related gross pathology findings were confined to the treated skin and consisted of thickened, reddened, flaky, fissured, cracked and/or dry skin.

HISTOPATHOLOGY: NON-NEOPLASTIC: Findings were confined to the treated skin and consisted of slight to moderately severe proliferative and inflammatory changes. These inflammatory changes were accompanied by an increased granulopoiesis of the bone marrow, probably related to the stress or other factors associated with the skin irritation. Other findings were considered spontaneous and incidental to treatment.
Dose descriptor:
NOEL
Remarks:
dermal irritation
Effect level:
< 200 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
dermal irritation
Dose descriptor:
NOEL
Remarks:
systemic effects
Effect level:
> 2 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
gross pathology
histopathology: non-neoplastic
Critical effects observed:
not specified
Conclusions:
Repeated dose dermal applications of light catalytic cracked naphtha (API 81-04) at 200 mg/kg/day, 1000 mg/kg/day, and 2000 mg/kg/day resulted in moderate to severe dose-dependent dermal irritation effects. The dermal irritation NOEL was determined to be less than 200 mg/kg and the systemic NOEL was determined to be greater than 2000 mg/kg.
Executive summary:

Light catalytically cracked naphtha (API 81-04) was administered dermally to rats (5 males and 5 females per group) at the concentrations of 200, 1000, and 2000 mg/kg three days per week for four weeks to evaluate the subacute toxicity of the test material. A moderate to severe dose-dependent dermal irritation in the mid- and high-dose groups was seen during the study. Five animals died; all deaths were considered treatment-unrelated. No clinical signs or effects on organ weight gain, hematology, and clinical chemistry were observed. Statistically significant results included: body weight gain, gross pathology, and non-neoplastic histopathology results. Based on these findings, the systemic NOEL was determined to be greater than 2000 mg/kg/day and the dermal irritation NOEL was determined to be less than 200 mg/kg/day.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
30
Study duration:
subchronic
Species:
rat

Additional information

The Light Oxo Fraction (LOF, Alkenes, C6-10, hydroformylation products, low-boiling) is a by-product from C6-C8 alcohol formation. In the hydroformylation process olefins (alkenes) are catalytically reacted with carbon monoxide and hydrogen, resulting in a range of products including primary alcohols. Alcohols are separated from the reaction mixture by distillation, with the remaining LOF containing unreacted olefins (alkenes) and paraffins (alkanes). Compositional analysis indicates LOF is approximately a 50/50% mixture of olefins and paraffins with a boiling point range of 102 – 182 ºC. While toxicity data are not available for LOF, based on composition and physical chemical characteristics it is appropriate to use data from naphtha petroleum streams with low levels of aromatic groups and carbon number ranges similar to C6-10. Naphtha streams are derived from the same original feedstock (crude petroleum) Light Catalytic Cracked Naphtha (LCCN; CAS No. 64741-55-5, consisting of hydrocarbons derived from a catalytic cracking process in the range of 4 to 11 carbons with a boiling range of approximately 65 to 230 degrees centigrade;) or Light Straight Run Naphtha (LSRN; CAS No. 64741-46-4, 64741-46-4, consisting predominantly of aliphatic [paraffinic and isoparaffinic] hydrocarbons in the range of 4 to 10 carbons and boiling between -20 to 180 degree centigrade) as read-across. 

 

LCCN is a gasoline blending stream derived from refined petroleum. LCCN has a carbon range between C5-C10, a boiling point range from 37-168 ºC, and consists of approximately 30% paraffins, 45% olefins, 10% naphthenics, and 13% aromatics. A substantial dataset is available for LCCN and due to its similar composition to LOF, is suitable for use as read-across to fulfill the required REACH endpoints. 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Repeated oral exposure results in hydrocarbon-induced alpha-2-u globulin mediated nephropathy in male rats, but this effect is not considered relevant because there is no alpha-2-u globulin expression in humans.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
No adverse effects for highest dose tested in male rats

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Red nasal discharge in the absence of any adverse histopathological findings at highest dose tested was used in development of DNEL values.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
No adverse effects with highest dose tested in male and female rats

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Dermal irritation observed at lowest dose tested (30 mg/kg/day) in male and female rats.

Justification for classification or non-classification

Dermal exposures indicate irritation as a potential effect, for which classification is already recommended in the appropriate section.

No human relevant systemic effects were observed following repeated oral, dermal, or inhalation exposure in subchronic studies. Therefore no classification is indicated according to the general classification and labeling requirements for dangerous substances and preparations (Directive 67-548-EEC) or the classification, labeling and packaging (CLP) regulation (EC) No 1272/2008.