Menthane, monohydroperoxy derivative

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: standard NTP test protocol, not all standard parameters assessed The nature of the effects (local at the application site) allows conclusions on the NOAEL

Data source

Reference

Reference Type:

other: website data

Title:

Unnamed

Year:

2004

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)

Deviations:

yes

Remarks:

no biochemistry, urinalysis, behavioural effects

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

α,α-dimethylbenzyl hydroperoxide

EC Number:

201-254-7

EC Name:

α,α-dimethylbenzyl hydroperoxide

Cas Number:

80-15-9

IUPAC Name:

1-methyl-1-phenylethyl hydroperoxide

Constituent 2

Reference substance name:

cumene hydroperoxide

IUPAC Name:

cumene hydroperoxide

Test material form:

not specified

Details on test material:

cumene hydroperoxide

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Administration / exposure

Type of coverage:

not specified

Vehicle:

ethanol

Details on exposure:

- Area of exposure: 10% of total surface (based on an average BW of 200 g and a conversion factor of 5.9 (Kg to m2)*: 0.1 times 0.034 m2 = 34 cm2)

TEST MATERIAL: no detailed data

VEHICLE: ethanol (indicated in the result section of the micronucleus test) 0.5 mL/ kg


* Freireich, EJ, et al. Quantitative comparison of toxicity of anticancer agents in mouse, rat, dog, monkey and man. Cancer Chemother Rep.1966;50(4):219-244

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

93 days

Frequency of treatment:

daily on week days

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.75, 1.5, 3.0, 6.0 and 12 mg/kg bw
Basis:
nominal per unit body weight

No. of animals per sex per dose:

10/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

After a 10- to 14-day quarantine period, animals are assigned at random to treatment groups. The study includes five treatment groups each administered a different concentration of the test article plus a control group. Each group contains 10 animals per sex per species. The animals receive the subject chemical by a designated route of exposure. Controls receive vehicle alone.Animals are exposed five times per week, weekdays only until the day prior to necropsy. All rats are housed individually.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once weekly

BODY WEIGHT: Yes
- Time schedule for examinations: on day 1 and weekly thereafter

FOOD CONSUMPTION: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
on day 93: Erythrocyte count, Mean corpuscular volume, Hemoglobin, Packed cell volume, Mean corpuscular haemoglobin, Mean corpuscular hemoglobin concentration, Erythrocyte morphologic assessment, Leukocyte count, Leukocyte differential, Reticulocyte count, Platelet count and morphologic assessment

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

ORGAN WEIGHTS:
Liver, thymus, right kidney, right testis, heart, and lung

GROSS PATHOLOGY: Yes
Adrenal glands, Oral cavity, larynx and pharynx, Brain Ovaries, Clitoral glands, Pancreas, Esophagus, Parathyroid glands, Eyes, Pituitary gland, Femur, Preputial glands, Prostate, Gross lesions, Salivary glands, Harderian glands, Seminal vesicles, Heart and aorta, Skin, site of application (dermal studies), Large intestine (cecum, colon, rectum), Spinal cord, Small Intestine (duodenum, jejunum, ileum), Spleen, Kidneys, Stomach (forestomach and glandular), Liver, Testes, epididymides and vaginal tunics of testes, Lungs and mainstem bronchi, Thymus, Lymph nodes - mandibular and mesenteric, Thyroid gland , Tissue masses, Tongue, Mammary gland with adjacent skin, Trachea, Muscle (thigh), Urinary bladder, sciatic Nerve, Uterus, Nasal cavity and nasal turbinates, Vagina, Zymbal gland

HISTOPATHOLOGY: Yes
A complete histopathologic evaluation inclusive of treatment-related gross lesions on all early death animals regardless of dose group, all control animals and all animals in the highest treatment group. In addition all gross lesions irrespective of the dose group.

Statistics:

not yet performed

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

1 moribund

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

at 6 mg/kg bw and above

Mortality:

mortality observed, treatment-related

Description (incidence):

1 moribund

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

slightly decreased in high dose males

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:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

primary effect on skin at application site

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

skin lesions

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
1 male died at 6 mg/kg bw on day 33 (reduced bodyweight(gain) and hyperplasia at application site), no mortality in females

BODY WEIGHT AND WEIGHT GAIN
males: slightly decreased at 12 mg/kg bw
females: no treatment related effects

HAEMATOLOGY
males: no treatment related effects
females: increased platelets numbers at 6 and 12 mg/kg bw

ORGAN WEIGHTS
males: slightly decreased absolute liver, lung, testis and thymus weights at 12 mg/kg bw (not relative to bodyweight)
females: no treatment related effects

HISTOPATHOLOGY: NON-NEOPLASTIC
epididymus:
inflammation and/or cellular infiltration of lymphocytes in 3/10 males at 12 mg/kg bw

at the application site
sebaceous glands:
hyperplasia in all males and females at 12 mg/kg bw and in 1 male at 6 mg/kg bw

dermis:
inflammation in 10 males and 9 females at 12 mg/kg bw; in 2/10 males at 6 mg/kg bw; in 1/10 males at 1.5 mg/kg bw

epidermis:
degradation, exudate, ulcer, necrosis, hyperkeratosis and and squamous hyperplasia in males and females at 12 mg/kg bw
minimal hyperkeratosis and squamous hyperplasia in males at 6 mg/kg bw

Effects increased in incidence and severity with increasing dose levels

Effect levels

Dose descriptor:

NOAEL

Effect level:

3 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: local effects on the application site due to the corrosive nature of the test substance

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

No treatment related systemic effects were identified.

Applicant's summary and conclusion

Conclusions:

The NOAEL under the conditions of the study is 3 mg/kg bw

Executive summary:

Ten rats per sex/dose and 10/sex for controls were treated dermally with the test substance for 13 weeks

at 0, 0.75, 1.5, 3.0, 6.0 and 12 mg/kg bw/day. One male died in the 6 mg/kg bw group. Body weights were slightly decreased in males at 12 mg/kg bw. Treatment related effects were found at the application site which included, hyperplasia of the sebaceous glands inflammation of the dermis and degeneration, exudate, ulcer, necrosis, hyperkeratosis and squamous hyperplasia of the epidermis. The effects increased in severity with increasing dose. No treatment related systemic effects were found. The NOAEL is 3.0 mg/kg bw/day (0.6% or 0.018 mg/cm2 per day).