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Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2003
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: According to or similar to guideline study OECD 410: GLP.
Justification for type of information:
The justification for read across is provided as an attachment in IUCLID Section 13.
Cross-reference
Reason / purpose:
read-across: supporting information
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
2003
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: According to or similar to guideline study OECD 410: GLP.
Justification for type of information:
The justification for read across is provided as an attachment in IUCLID Section 13.
Reason / purpose:
read-across source
Clinical signs:
effects observed, treatment-related
Dermal irritation:
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 examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
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:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
One control male was found in a moribund state and was sacrificed on day 21 of the study. One female control was found dead on day 11 of the study. One 1000 mg/kg/day male was found dead on day 15. A male and a female in the highest dose group were found dead on days 10 and 24 respectively and the authors considered these to be treatment- related. Clinical signs observed in the study that were considered to be treatment- related included: thinness, nasal discharge, lethargy, soiled anal area, anal discharge, wheezing. There were group mean body weight losses in the mid and high dose groups and a smaller increase than controls in the low dose group. The authors judged that the weight losses in the mid dose group were not a direct effect of the test material. They noted that weight losses occurred in the first week of dosing and that after this there were increases in weight. The authors comment that such effects generally occur as a result of the stress of dosing and the dermal irritation that occurred. The skin irritation grades showed that irritation was dose related and was greatest in the highest dose group. The mean irritation score, calculated as the mean sum of all the irritation scores (erythema and edema), for each group are in the table below.

Other dermal findings included cracked, flaky and/or leathery skin, crusts and/or hair loss. These findings only occurred in the treated groups and appeared with greater frequency as the dose level increased. There were no hematological findings in the female groups. In males, a reduction in RBC, hemoglobin and hematocrit was noted. No treatment-related changes were seen in the clinical chemistry data with the following exceptions: total protein reduced by 8% in 200 mg/kg males; SGPT and ALP reduced by 37% and 46% respectively in the 2000 mg/kg females. The authors comment that these values were well within the normal range of historical controls and are not judged to be test material related.

Organ weights and organ/body weight ratios that differed from controls were: Heart, Liver, Spleen, R Kidney, L Kidney, R Adrenal, L Adrenal, Pituitary, and Brain. The authors concluded that the increases in relative heart weights for the mid- and high- dose males and females were treatment-related. Other heart weight changes were within the normal range for control values for the laboratory. Increased absolute and relative spleen weights for males were considered incidental since they fell within the normal range for the laboratory. For the females however, the differences were considered to be treatment-related. In both males and females, differences in absolute and relative adrenal weights were considered to be stress-related and therefore, indirectly related to treatment.

Gross necropsy findings were confined largely to the skin. Enlarged spleens in the female groups were also noted. Slight to moderate proliferative and slight to moderately severe inflammatory changes were present in the treated skin of all male and female animals in the high dose group. These changes were accompanied by an increase in granulopoiesis of the bone marrow in 5/6 males and 3/4 females. 4/6 high dose group males also had multifocal or diffuse tubular hypoplasia of a few of the seminiferous tubules of both testes. The degree of spermatogenesis was similar to controls in one animal, was absent in two animals and was slightly reduced in three animals. These testicular changes were considered by the authors to be secondary to the skin and/or weight changes. All other lesions observed were considered to be incidental and unrelated to treatment.
Key result
Dose descriptor:
NOAEL
Remarks:
dermal irritation
Effect level:
200 mg/kg bw/day
Sex:
male/female
Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Critical effects observed:
not specified

Irritation Scores
Group/sex MIS Classification
Control Male 0 Non-irritant
Control Female 0 Non-irritant
200 mg/kg/day Male 1.3 Slight irritant
200 mg/kg/day Female 1.7 Slight irritant
1000 mg/kg/day Male 3.7 Moderate irritant
1000 mg/kg/day Male 3.5 Moderate irritant
2000 mg/kg/day Male 4.1 Moderate irritant
2000 mg/kg/day Male 3.6 Moderate irritant
Conclusions:
The NOAEL was determined to be 200 mg/kg based on skin irritation. The systemic NOAEL was determined to be 1000 mg/kg bw based on the treatment related deaths noted at 2000 mg/kg/day.
Executive summary:

This data is being read across from the source study that tested straight run kerosene based on analogue read across.

The NOAEL was determined to be 200 mg/kg based on skin irritation. The dermal irritation noted is primarily due to use of an occlusive dressing that prevented evaporation of the volatile elements. The systemic NOAEL was determined to be 1000 mg/kg bw based on the treatment related deaths noted at 2000 mg/kg/day.

Data source

Referenceopen allclose all

Reference Type:
other: HPV Summary
Title:
Robust Summary of Information for Substance Group Kerosene.
Author:
American Petroleum Institute
Year:
2003
Report Date:
2003
Reference Type:
study report
Title:
Unnamed
Year:
1985

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
Occlusive dressing used
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
Undiluted test material was applied to the shorn dorsal skin of each of five male and five female rabbits at doses of 200, 1000 and 2000 mg/kg/day, three times weekly until 12 doses had been applied. Five rabbits of each sex served as sham treated controls. Dosing was carried out on alternate days. Each treated site was covered with a gauze pad and an occlusive dressing. The occluded dressing was then removed after six hours and any residual test material was removed from the skin with a clean, dry, absorbent gauze pad.
Analytical verification of doses or concentrations:
no
Doses / concentrations
Remarks:
Doses / Concentrations:
200, 1000 and 2000mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
Undiluted test material was applied to the shorn dorsal skin of each of five male and five female rabbits at doses of 200, 1000 and 2000 mg/kg/day, three times weekly until 12 doses had been applied. Five rabbits of each sex served as sham treated controls. Dosing was carried out on alternate days.
Control animals:
yes, sham-exposed
Details on study design:
Undiluted test material was applied to the shorn dorsal skin of each of five male and five female rabbits at doses of 200, 1000 and 2000 mg/kg/day, three times weekly until 12 doses had been applied. Five rabbits of each sex served as sham treated controls. Dosing was carried out on alternate days. Each treated site was covered with a gauze pad and an occlusive dressing. The occluded dressing was then removed after six hours and any residual test material was removed from the skin with a clean, dry, absorbent gauze pad. Each animal was observed twice daily for clinical signs of toxicity and pharmacological effects. Body weights were recorded prior to dosing and then weekly throughout the study. The test site was examined daily and dermal reactions were graded using the Draize scale and recorded. At termination, blood samples were collected for the following clinical chemical and hematological determinations.

Examinations

Observations and examinations performed and frequency:
Each animal was observed twice daily for clinical signs of toxicity and pharmacological effects. Body weights were recorded prior to dosing and then weekly throughout the study. The test site was examined daily and dermal reactions were graded using the Draize scale and recorded. At termination, blood samples were collected for the following clinical chemical and hematological determinations.
Sacrifice and pathology:
At termination, blood samples were collected for the following clinical chemical and hematological determinations.

Hematology: Erythrocyte count, Total leukocyte count, Differential leukocyte count, Hemoglobin, Hematocrit.

Clinical chemistry: Glucose, Blood urea nitrogen, Total protein, SGOT, SGPT.

All animals were sacrificed and necropsied whether they had died or had survived throughout the study. Organs from animals found dead were not weighed but for animals surviving to the end of the study, the following organs were weighed and organ/body weight ratios were determined: Heart, liver, spleen, kidneys, adrenals, thyroid, pituitary, testes, ovaries and brain. The following tissues were collected and preserved and were prepared for subsequent histological examination. Heart, Sacculus rotundus, Urinary bladder, lungs, colon, adipose tissue, bronchi, thymus, mammary gland, trachea, spleen, brain (cerebellum, cerebrum, pons), thyroid, liver, parathyroids, pancreas, pituitary, cervical lymph nodes, kidneys, spinal cord (two sections), salivary gland, adrenals, skeletal muscle, tongue, vagina, sciatic nerve, esophagus, seminal vesicles, testes/ovaries, skin (treated and untreated), stomach, bone, duodenum, epididymis, bone marrow (smear), jejunum, ileum, prostate/uterus, eyes, mesenteric lymph nodes and any gross lesions.
Statistics:
A two-tailed student's t-test was used to determine the significance of any differences between treated and control groups for body weights, clinical pathology and absolute and relative organ weights.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Dermal irritation:
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 examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
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:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
One control male was found in a moribund state and was sacrificed on day 21 of the study. One female control was found dead on day 11 of the study. One 1000 mg/kg/day male was found dead on day 15. A male and a female in the highest dose group were found dead on days 10 and 24 respectively and the authors considered these to be treatment- related. Clinical signs observed in the study that were considered to be treatment- related included: thinness, nasal discharge, lethargy, soiled anal area, anal discharge, wheezing. There were group mean body weight losses in the mid and high dose groups and a smaller increase than controls in the low dose group. The authors judged that the weight losses in the mid dose group were not a direct effect of the test material. They noted that weight losses occurred in the first week of dosing and that after this there were increases in weight. The authors comment that such effects generally occur as a result of the stress of dosing and the dermal irritation that occurred. The skin irritation grades showed that irritation was dose related and was greatest in the highest dose group. The mean irritation score, calculated as the mean sum of all the irritation scores (erythema and edema), for each group are in the table below.

Other dermal findings included cracked, flaky and/or leathery skin, crusts and/or hair loss. These findings only occurred in the treated groups and appeared with greater frequency as the dose level increased. There were no hematological findings in the female groups. In males, a reduction in RBC, hemoglobin and hematocrit was noted. No treatment-related changes were seen in the clinical chemistry data with the following exceptions: total protein reduced by 8% in 200 mg/kg males; SGPT and ALP reduced by 37% and 46% respectively in the 2000 mg/kg females. The authors comment that these values were well within the normal range of historical controls and are not judged to be test material related.

Organ weights and organ/body weight ratios that differed from controls were: Heart, Liver, Spleen, R Kidney, L Kidney, R Adrenal, L Adrenal, Pituitary, and Brain. The authors concluded that the increases in relative heart weights for the mid- and high- dose males and females were treatment-related. Other heart weight changes were within the normal range for control values for the laboratory. Increased absolute and relative spleen weights for males were considered incidental since they fell within the normal range for the laboratory. For the females however, the differences were considered to be treatment-related. In both males and females, differences in absolute and relative adrenal weights were considered to be stress-related and therefore, indirectly related to treatment.

Gross necropsy findings were confined largely to the skin. Enlarged spleens in the female groups were also noted. Slight to moderate proliferative and slight to moderately severe inflammatory changes were present in the treated skin of all male and female animals in the high dose group. These changes were accompanied by an increase in granulopoiesis of the bone marrow in 5/6 males and 3/4 females. 4/6 high dose group males also had multifocal or diffuse tubular hypoplasia of a few of the seminiferous tubules of both testes. The degree of spermatogenesis was similar to controls in one animal, was absent in two animals and was slightly reduced in three animals. These testicular changes were considered by the authors to be secondary to the skin and/or weight changes. All other lesions observed were considered to be incidental and unrelated to treatment.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
dermal irritation
Effect level:
200 mg/kg bw/day
Sex:
male/female
Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
1 000 mg/kg bw/day
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Irritation Scores
Group/sex MIS Classification
Control Male 0 Non-irritant
Control Female 0 Non-irritant
200 mg/kg/day Male 1.3 Slight irritant
200 mg/kg/day Female 1.7 Slight irritant
1000 mg/kg/day Male 3.7 Moderate irritant
1000 mg/kg/day Male 3.5 Moderate irritant
2000 mg/kg/day Male 4.1 Moderate irritant
2000 mg/kg/day Male 3.6 Moderate irritant

Applicant's summary and conclusion

Conclusions:
The NOAEL was determined to be 200 mg/kg based on skin irritation. The systemic NOAEL was determined to be 1000 mg/kg bw based on the treatment related deaths noted at 2000 mg/kg/day.
Executive summary:

The NOAEL was determined to be 200 mg/kg based on skin irritation. The dermal irritation noted is primarily due to use of an occlusive dressing that prevented evaporation of the volatile elements. The systemic NOAEL was determined to be 1000 mg/kg bw based on the treatment related deaths noted at 2000 mg/kg/day.