Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
other information
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study.
Cross-reference
Reason / purpose:
reference to same study
Reference
Endpoint:
toxicity to reproduction
Remarks:
other: subchronic dermal toxicity study
Type of information:
experimental study
Adequacy of study:
other information
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study.
Reason / purpose:
reference to same study
Principles of method if other than guideline:
Percutaneous 91 day subchronic toxicity study.
GLP compliance:
not specified
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
for details see chapter 7.5.2
Route of administration:
dermal
Vehicle:
other: Mixture of petrolatum and C12-15 alkylbenzoate (Finsolv TN) at differing ratios
Details on exposure:
for details see chapter 7.5.2
Details on mating procedure:
not applicable
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
91 days
Frequency of treatment:
5 days per week, totally 65 applications
Details on study schedule:
for details see chapter 7.5.2
Remarks:
Doses / Concentrations:
130, 264, 534 mg/kg/day
Basis:
other: nominal per unit body weight
No. of animals per sex per dose:
5 males and 5 females per group
Control animals:
yes, concurrent vehicle
Details on study design:
for details see chapter 7.5.2
Positive control:
no
Parental animals: Observations and examinations:
for details see chapter 7.5.2
Oestrous cyclicity (parental animals):
not performed
Sperm parameters (parental animals):
Parameters examined :
epididymal sperm motility, concentration and morphology
Litter observations:
not performed
Postmortem examinations (parental animals):
histopathological evaluations of testes and epididymides
for further details see chapter 7.5.2
Postmortem examinations (offspring):
not performed
Statistics:
for details see chapter 7.5.2
Reproductive indices:
not performed
Offspring viability indices:
not performed
GROSS PATHOLOGY and HISTOPATHOLOGY
Regardless of sex or applied concentration, none of the Octocrylene-treated rabbits showed any evidence of macroscopic or histopathological abnormalities in any organs examined.
In male rabbits, morphological examination of epididymis and testicles showed no signs of Octocrylene-associated abnormalities.

OTHER EXAMINATIONS
Epididymal sperm concentrations were (mean ± SD ; n= 5; sperm/g caudal tissue):
311 ± 57 (control),
380 ± 211 (130 mg/kg/day)
467 ± 301 (264 mg/kg/day)
245 ± 58 (534 mg/kg/day).
Percentage sperm motility in these same groups was (mean ± SD; n= 5):
92 ± 4 (control)
91 ± 5 (130 mg/kg/day)
88 ± 8 (264 mg/kg/day)
86 ± 6 (534 mg/kg/day)


for further details see chapter 7.5.2
Reproductive effects observed:
not specified

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Evaluation of Subchronic (13 Week), Reproductive, and in Vitro Genetic Toxicity Potential of 2-Ethylhexyl-2-cyano-3,3-diphenyl Acrylate (Octocrylene).
Author:
Odio RM et al.
Year:
1994
Bibliographic source:
Fund Appl Toxicol 22: 355-368.
Reference Type:
publication
Title:
Toxicological Profile of 2-ethylhexyl-2-cyano-3,3-diphenylacrylate (Octocrylene).
Author:
Odio MR et al
Year:
1992
Bibliographic source:
Toxicologist 12 (1): 96, abstract no 396.

Materials and methods

Principles of method if other than guideline:
Percutaneous 91 day subchronic toxicity study
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Octocrylene, supplier: BASF
No further data

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
male and female New Zealand White rabbits
- Source: Hazelton Research Products, Denver, PA
- Age at study initiation: no data
- Weight at study initiation: 2.0 to 2.3 kg
- Fasting period before study: no
- Housing: individually in suspended stain less-steel cages
- Diet: Purina No. 5325, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: no data

Administration / exposure

Type of coverage:
open
Vehicle:
other: mixture of petrolatum and C12-15 alkylbenzoate (Finsolv TN) at differing ratios
Details on exposure:
TEST SITE
- Area of exposure: back
- % coverage: open
- Time intervals for shavings or clippings: as needed, no further details

REMOVAL OF TEST SUBSTANCE
- Washing (if done): daily with tepid water
- Time after start of exposure: 7 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 ml/kg bw
- Concentration (if solution): 7.5, 15, 30 % (w/w)
- Constant volume or concentration used: yes

VEHICLE
mixture of petrolatum and C12-15 alkylbenzoate (Finsolv TN) at differing ratios
- Justification for use and choice of vehicle (if other than water): no data
- Amount(s) applied (volume or weight with unit): 2 ml/kg bw
- Lot/batch no. (if required): no data
- Purity: no data

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes
To prevent ingestion a restraining collar was placed around the neck of each animal before application.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
91 days
Frequency of treatment:
5 days per week, totally 65 applications
Doses / concentrations
Remarks:
Doses / Concentrations:
130, 264, 534 mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5 males and 5 females per group
Control animals:
yes, concurrent vehicle
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: daily
The skin at the site of compound application was examined in each animal for the presence of erythema, edema, desquamation, atonia, fissuring, eschar, and exfoliation.

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: No data

FOOD EFFICIENCY: No

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: within 3 days after the last dose
- Anaesthetic used for blood collection: Yes (sodium pentobarbital)
- Animals fasted: No data
- How many animals: all animals
- Parameters examined:
erythrocyte count, leukocyte count, platelet count, differential leukocyte count, cell morphology, hematocrit, hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin concentration

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
Within 3 days after the last dose, animals were terminated by exsanguination under pentobarbital anesthesia.

GROSS PATHOLOGY: Yes
examination of external surfaces and all internal organs
determination of liver and kidney weight

HISTOPATHOLOGY: Yes
All internal organs and samples of the treated skin areas were preserved in 10 % neutral buffered formalin. Preserved tissues were trimmed, embedded in paraffin, sectioned, stained with hematoxylin and eosin, and examined microscopically. To evaluate Octocrylene effects on male reproductive status, histopathological evaluations of testicles and epididymis were conducted. In addition, epididymal sperm motility, concentration, and morphology were examined.
Statistics:
Bartlett's Test
ANOVA
Dunnett's Test
Wilcoxon-Mann-Whitney test
analysis of covariance
Cochran-Armitage Test

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
No clinical signs were observed, with exception of local findings at the application area (see below). All animals survived until scheduled sacrifice.

SKIN IRRITATION
Octocrylene-treated rabbits presented dose-dependent hindlimb alopecia and skin irritation at the site of compound application. Macroscopically, the predominant dermal effects were erythema and desquamation in all dose groups. Edema and fissuring were observed sporadically, but these events were not consistent or prevalent enough to merit further discussion. Eschar and exfoliation were not observed.
In terms of histopathological effects, Octocrylene-treated rabbits showed consistently greater incidence of skin abnormalities than control counterparts. In this instance, a dose-related pattern was less evident than that noted for macroscopical observations, but this could reflect the all-or-nothing nature of the observation, which did not incorporate a quantitative evaluation of severity.

BODY WEIGHT AND WEIGHT GAIN
In both sexes, mid- and high-dose treatments significantly depressed body weight gain relative to the corresponding controls. At the low dose, no significant body weight effect was noted in females (NOEL = 130 mg/kg bw), whereas in male animals, a statistically significant depression of body weight gain was still observed (NOEL not established). The ratio of final to initial weights shows a pattern similar to that noted for skin irritation effects. The magnitude of the irritant or body weight effects was generally comparable for males and females treated with 264 and 534 mg/kg/day Octocrylene. By contrast, both the weight and the irritation effects were of lesser magnitudes for males and females treated with the low dose of the compound

HAEMATOLOGY
Clinical hematology values were within historical control limits for this strain of rabbit.

ORGAN WEIGHTS
No significant effects in kidney weights of male or female rabbits at any of the Octocrylene doses tested.

GROSS PATHOLOGY and HISTOPATHOLOGY
Regardless of sex or applied concentration, none of the Octocrylene-treated rabbits showed any evidence of macroscopic or histopathological abnormalities in any organs examined.
In male rabbits, morphological examination of epididymis and testicles showed no signs of Octocrylene-associated abnormalities.

OTHER EXAMINATIONS
Epididymal sperm concentrations were (mean ± SD ; n= 5; sperm/g caudal tissue):
311 ± 57 (control),
380 ± 211 (130 mg/kg/day)
467 ± 301 (264 mg/kg/day)
245 ± 58 (534 mg/kg/day).
Percentage sperm motility in these same groups was (mean ± SD; n= 5):
92 ± 4 (control)
91 ± 5 (130 mg/kg/day)
88 ± 8 (264 mg/kg/day)
86 ± 6 (534 mg/kg/day)

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion