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Repeated dose toxicity: dermal

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Administrative data

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

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

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

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

Growth rates were unaffected by treatment.

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

Haematological and serum clinical parameters were unaffected by treatment.

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

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

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

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
yes

Test material

Constituent 1
Reference substance name:
Kerosine (petroleum), hydrodesulfurized
EC Number:
265-184-9
EC Name:
Kerosine (petroleum), hydrodesulfurized
Cas Number:
64742-81-0
IUPAC Name:
Kerosine (petroleum), hydrodesulfurized
Constituent 2
Reference substance name:
hydrodesulphurised kerosine
IUPAC Name:
hydrodesulphurised kerosine
Test material form:
other: dilution in mineral oil
Details on test material:
Hydrodesulfurized kerosine

The Hydrodesulfurized kerosine had the following properties.
Boiling point 148.9 °C (300 °F)
Specific gravity 0.825 @ 60 °F
Melting point Not applicable
% volatile 100
Vapour pressure 0.4 mm Hg @ 68 °F
Evaporation rate
(water = 1) Slower
Vapour density (air = 1) 4.7
Viscosity 1.3 - 2.2 cSt @ 100 °F
% solubility in water Negligible
Pour point -34.4 °C (-30 °F)
pH Not determined
Appearance/odour Clear liquid with hydrocarbon odour


The vehicle used was Squibb mineral oil.

For dosing, mixtures of hydrodesulfurized kerosine were
prepared in the mineral oil at concentrations of 20, 40 and
60% (v/v)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Type of coverage:
other: open with elizabethan collars
Vehicle:
other: mineral oil
Details on exposure:
Route of Administration: dermal
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Six hours each day
Frequency of treatment:
Daily, five days per week for 13 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
165, 330 & 495 mg/kg/day
Basis:

No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
Test material was applied at concentrations of 20, 40 or 60% (v/v) at a rate of 1 ml/kg/day to the shorn intrascapular region of the rats. This was equivalent to doses of test material of 165, 330 or 495 mg/kg/day. Dosing was continued daily for five consecutive days each week, five days a week for 13 weeks. In addition a group of 12 male and 12 female rats of similar age were administered mineral oil at a dose rate of 1 ml/kg/day; these animals served as vehicle controls. An additional 12 rats/sex/group in the vehicle controls and high dose group were maintained for a 4-week recovery period following dosing for 13 weeks. All animals were fitted with collars to prevent ingestion and these were removed six hours after dosing and any residual test or control material was wiped from the skin. Animals were observed for clinical signs prior to dosing and 1, 6 and 24 hours after the first dose. Subsequently, observations were made prior to each dose being applied.

Examinations

Sacrifice and pathology:
A complete necropsy was performed on six rats/sex/group following 13 weeks dosing, and on 6 rats/sex/group of the recovery animals (high dose and controls) at week 18. A limited necropsy was performed on the remaining six animals and their organs were not weighed (see below). Each full necropsy included an examination of the external surface of the body, all orifices, cranial, thoracic, abdominal and pelvic cavities and their contents. Gross observations were recorded and the following organs were weighed: Adrenal glands, brain, epididymides, heart, kidneys, liver, ovaries, prostate, spleen, testes, thymus and uterus.
The following tissues were collected, processed and then examined microscopically. Adrenal glands                   Nose (nasal cavity & turbinates) Animal identification               Ovaries Bone marrow (from sternum)        Oviducts Brain                               Pancreas Epididymides                       Parathyroid glands Oesophagus                       Pituitary gland Exorbital lacrimal glands       Prostate Eyes with optic nerve               Salivary glands Femur (incl. articular surface)       Seminal vesicles Gross lesions                       Skin (application site) Harderian gland                       Skin (inguinal) Heart and aorta                       Spinal cord (3 levels) Intestine (3 levels)               Spleen Kidneys                               Stomach Larynx and pharynx               Testes Liver                               Thymus Lungs with mainstream bronchi       Thyroid gland Lymph nodes (mandibular/mesenteric) Urinary bladder Mammary glands with adjacent skin  Uterus Muscle (thigh)                       Vagina Nerve (sciatic) The remaining six rats of each group were anesthetized with an intraperitoneal injection of Pentothal ® and transcardially perfused in-situ using 10% neutral-buffered formalin and given a limited necropsy. For these rats, no organs were weighed and the following tissues were collected: Head/skull       Sural nerve Brain               Tibial nerve Spinal cord       Gross lesions Sciatic nerve The following tissues were examined microscopically in these animals: Brain (forebrain, cerebrum, midbrain, cerebellum, pons and medulla obligata) Gasserian ganglia Dorsal root ganglia Dorsal and ventral root fibers Sural nerve Tibial nerve Spinal cord (cervical and lumbar areas) Sciatic nerve.
Other examinations:
At the 14 week necropsy, blood samples were collected from 12 animals/sex/group and at the week 18 necropsy from the recovery rats (vehicle and high dose groups). The following haematological and clinical chemical parameters were measured. Haematology Erythrocyte count Haemoglobin Haematocrit Mean corpuscular volume Mean corpuscular haemoglobin Mean corpuscular hemoglobin concentration Platelet count Reticulocyte count Total leukocyte count Differential leukocyte count Morphological examination of erythrocytes and platelets Coagulation determinations (prothrombin time & activated partial thromboplastin time) were also carried out on six animals from each group at week 14 and from the recovery groups at the week 18 necropsy.

Results and discussion

Effect levels

Key result
Dose descriptor:
NOEL
Effect level:
>= 495 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: test material

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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

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

Growth rates were unaffected by treatment.

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

Haematological and serum clinical parameters were unaffected by treatment.

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

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

Applicant's summary and conclusion

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

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