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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1977

Materials and methods

Principles of method if other than guideline:
Two dose levels applied for 21 days.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
4-methylstyrene
EC Number:
210-762-8
EC Name:
4-methylstyrene
Cas Number:
622-97-9
Molecular formula:
C9H10
IUPAC Name:
1-methyl-4-vinylbenzene
Test material form:
liquid
Details on test material:
- Name as cited in study report: MCTR-243-77
Specific details on test material used for the study:
Lot Nr.: 145070177-2

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
New Zealand White rabbits: weight 2.05 to 2.55 Kg acclimatised for 7 days and housed individually in a laminar flow room. Diet (Purina Rabbit Chow) and water ad libitum.

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
Application site of approximately 25 % of total body surface was clipped free of hair prior to study and once weekly. One rabbit per group/sex abraded at the test site with a clipper head before each application.
The test substance was delivered from a glass syringe and spread evenly over the test site and left for 6 hours before the area was rinsed with water and dried. Rabbits were maintained in a harness during the exposure period to prevent oral ingestion.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
6 hours
Frequency of treatment:
daily for 21 days
Doses / concentrationsopen allclose all
Dose / conc.:
0.5 other: mL/kg
Remarks:
nominal per unit body weight
Dose / conc.:
0.2 other: mL/kg
Remarks:
nominal per unit body weight
No. of animals per sex per dose:
3 males and 3 females
Control animals:
other: 2.0 mL/kg distilled water
Details on study design:
Eighteen New Zeeland rabbits (nine males and nine females) weighing from 2.05 kg to 2.55 kg were randomized by weight into three groups of three males and three females each. Animals were dosed daily, for 21 days at dose volumes of 0.5 or 2.0 mL/kg of the test substance and 2.0 mL/kg distilled water (controls).

Examinations

Observations and examinations performed and frequency:
Observations: daily
Skin irritation scores: twice daily, before and after application
Clinical pathology: prior to treatment and at the end of treatment. Blood collected from the ear artery.
Haematology: PCV, Haemoglobin, MCV, RBC, WBC (total and differential)
Clinical chemistry: glucose, BUN, alkaline phosphatase, SGOT, SGPT, bilirubin, total protein, calcium and phosphorus

Sacrifice and pathology:
At the end of the 21-day period, all rabbits were weighed, anesthetized with sodium pentobarbital and exsanguinated. A necropsy to observe gross lesions was performed and the following tissues were fixed in 10% buffered formalin and evaluated histomorphologically: skin, heart, lung, adrenals, brain, gonads, liver, kidney, spleen, stomach, du odenum, bone marrow, bladder, pancreas, pituitary, unusual lesions, mesentery lumph node.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
All rabbits experienced pain when the test substance was applied.
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
The test substance was a skin irritant at both dose levels. Observation at skin site included thickening of the epidermins, congestion, edema, inflammatory cellular infiltration, serum exudates and necrotic cellular debris on the surface.

After the first application there was very slight erythema and edema, by day 4 the severity was slight and coriaceious skin and atonia were apparent. After the 5th application moderate to marked fissuring of the skin was noted eventually leading to slight bleeding from the fissures. By day nine the surface layer of skin sloughed or peeled off and the underlying skin was golden to black colour. The severity of skin response was similar in both test groups.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was a dose related decrease in body weight, considered to be a consequence of the pain and irritation at the skin application site.
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
Description (incidence and severity):
Effects on WBC due to irritation: elevated WBC and increase in segmented and non-segmented neutrophils.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Elevated SGOT and considered to be related to skin cell damage.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
No evidence of systemic pathology. The renal collecting tubules of some of the rabbits were more visible than normally observed and they were white and the renal medulla was brownish – pink (pale) olor rather than a normal red colour.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
not specified

Effect levels

Key result
Dose descriptor:
NOAEL
Sex:
male/female
Basis for effect level:
other: Skin irritation at both dose levels
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Applicant's summary and conclusion

Conclusions:
Under the study conditions, there were no results to suggest systemic toxicity. However, the test substance caused moderate to severe skin irritation. Further, the irritation resulted in pain, reduced body weight, elevated WBC and increase in segmented and non-segmented neutrophils. By day nine the surface layer of skin sloughed or peeled off and the underlying skin was golden to black colour. The severity of skin response was similar in both test groups. The only effect on the clinical chemistry parameters was an elevation in the serum glutamic oxaloacetic transaminase(SGOT) ezyme which probably is related to the skin cell damage at the application site. The renal collecting tubules of some of the rabbits were more visible than normally observed and they were white and the renal medulla was brownish – pink (pale) colour rather than a normal red colour. No NOAEL was established for the study (Adamik, 1977).
Executive summary:

A study was conducted to determine the toxicity of the test substance when applied to the skin of albino rabbits during a period of 21 consecutive days. The test substance was applied dermally to groups of 3 male and 3 female New Zealand rabbits, daily, at dose volumes of 0.5 or 2.0 mL/kg bw/day. Controls received 2.0 mL/kg bw/day of distilled water. The test substance was in contact with the skin, non-occluded, for 6 h each day. Clinical signs were recorded daily and body weight weekly. Blood samples for haematology and clinical chemistry were taken prior to treatment and at termination. All rabbits were subject to necropsy and limited histopathology. Under the study conditions, there were no results to suggest systemic toxicity. However, the test substance caused moderate to severe skin irritation. Further, the irritation resulted in pain, reduced body weight, elevated white blood cells and increase in segmented and non-segmented neutrophils. By Day 9, the surface layer of skin sloughed or peeled off and the underlying skin was golden to black colour. The severity of skin response was similar in both test groups. The only effect on the clinical chemistry parameters was an elevation in the serum glutamic oxaloacetic transaminase (SGOT) enzyme which was probably related to the skin cell damage at the application site. The renal collecting tubules of some of the rabbits were more visible than normally observed and they were white and the renal medulla was brownish – pink (pale) colour rather than a normal red colour. No NOAEL was established for the study (Adamik, 1977).

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