Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
3 October 2007 to 18 January 2008
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Cross-reference
Reason / purpose:
reference to same study
Reference
Endpoint:
skin irritation: in vivo
Remarks:
Dermal Prenatal Developmental Toxicity Study
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
3 October 2007 to 18 January 2008
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Justification for type of information:
This endpoint study record is part of a Weight of Evidence approach comprising a direct observation from RIPT studies, dermal irritation reported during developmental toxicity studies, irritation reported during an LLNA study and the results of an in vitro dermal adsorption study. The data sources are in agreement regarding dermal irritation and are sufficient to fulfil the information requirements as further explained in the provided endpoint summary.
Reason / purpose:
other:
Reason / purpose:
reference to other study
Reason / purpose:
reference to other study
Reason / purpose:
reference to other study
Reason / purpose:
reference to other study
Reason / purpose:
reference to same study
Guideline:
other: equivalent to: OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
Only dermal irritation observations reported
Principles of method if other than guideline:
An OECD Guideline 414 (Prenatal Developmental Toxicity Study) dermal exposure equivalent study was completed. The skin irritation observations are reported.
GLP compliance:
no
Remarks:
The study was not commissioned with compliance with REACH as a goal, rather the study was commissioned during early product development.
Specific details on test material used for the study:
Purity: 99%
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Covance Research Products, Inc., Kalamazoo, Michigan
- Age at study initiation: The animals were approximately 5.5 months old upon receipt.
- Weight at study initiation: Body weight values ranged from 2947 g to 4279 g on gestation day 0.
- Fasting period before study: Not reported
- Housing: housed individually
- Diet: The basal diet was offered in 25 g increments 3 times per day on the day of arrival and in increased amounts over the next few days, until the animals gradually achieved ad libitum status prior to the dose administration period; basal diet was offered ad libitum thereafter.
- Water: ad libitum
- Acclimation period: Prior to the initiation of dose administration, the animals were acclimated to wearing Elizabethan restraint collars. The collars were affixed to each rabbit on gestation days 3, 4, 5 and 6 for approximately 1, 2, 4 and 6 hours, respectively.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19±3°C
- Humidity (%): 50±20%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 4 November 2007 (first gestation day 0) To: 27 November 2007 (Last laparohysterectomy)
Type of coverage:
occlusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Amount / concentration applied:
The dosage level was 1300 mg/kg/day administered at a dosage volume of 0.91 mL/kg.
Duration of treatment / exposure:
6 hours of exposure per day for 14 days (gestation days 7-20)
Observation period:
The application site was scored daily (prior to dose administration and following removal of the dressing) for erythema, edema and other dermal findings.
Number of animals:
22 females per dose
Details on study design:
TEST SITE
- Area of exposure: The hair was clipped from the back of each animal, from the scapula (shoulder) to the wing of the ileum (hipbone) and halfway down the flank of each side of the animal. Doses were evenly applied using a rubber policeman covered glass rod over the clipped, unabraded area. The corners of the application site were marked with indelible ink to allow proper identification of the treated and untreated skin. Elizabethan collars were applied to restrict access to the wrapped dosing site.
- % coverage: approximately 7.9%
- Type of wrap if used: The application site for each animal was covered with 8-ply gauze, covered with an occluded non-porous latex bandage and held in place with non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing: Residual material on the skin was visually estimated and recorded, and the test sites were gently washed twice (the second wash immediately following the first) with a 70:30 isopropanol:water solution and disposable paper towels to remove any residual vehicle or test article.
- Time after start of exposure: After 6-hour exposure period

OBSERVATION TIME POINTS
The application site was scored daily (prior to dose administration and following removal of the dressing) for erythema, edema and other dermal findings
4-STEP GRADING SYSTEM (Draize, 1965)
Erythema and Eschar Formation:
- 0: No erythema
- 1: Very slight erythema (barely perceptible, edges of area not well defined)
- 2: Sight erythema (pale read in colour and edges definable)
- 3: Moderate to severe erythema (definite red in colour and area well defined)
- 4: Severe erythema (beet or crimson red) to slight eschar formation (injuries in depth)
Edema Formation:
- 0: No edema
- 1: Very slight edema (barely perceptible, edges of area not well defined)
- 2: Slight edema (edges of area well defined by definite raising)
- 3: Moderate edema (raised approximately 1 mm)
- 4: Severe edema (raised more than 1 mm and extending beyond area of exposure)

Further study design regarding prenatal development toxicity are discussed elsewhere in this dossier.
Irritation parameter:
overall irritation score
Remarks:
on day 1 following 6-hour exposure
Basis:
mean
Time point:
24 h
Score:
0
Max. score:
4
Remarks on result:
probability of weak irritation
Remarks:
following repeated exposure
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not determinable because of methodological limitations
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Remarks on result:
not determinable because of methodological limitations
Irritant / corrosive response data:
No dermal irritation effects were observed following single exposure. Very slight erythema was noted in 4 females from 1 to 3 consecutive days during gestiation days 12-14. Due to the absence of this finding in the vehicle control group, these occurrences of very slight erythema were considered to be test article-related; however, because of the transient nature, limited incidence and minimal severity of this finding, it was not considered to be adverse.
In addition, desquamation was noted in 2 and 7 females in the vehicle control and 1300 mg/kg/day group, respectively, prior to dose application; this finding was observed generally beginning as early as gestation day 11 and continuing through gestation day 16. This finding persisted to the time of unwrap (following 6 hours of exposure) in 3 test article-treated females (nos. 52135, 52137 and 52142) during gestation days 14-16.
Interpretation of results:
study cannot be used for classification
Remarks:
Weight of Evidence classification: GHS criteria not met
Conclusions:
Evidence of minimal dermal irritation (very slight erythema) was noted in 4 females from 1 to 3 consecutive days during gestation days 12-14. In addition, desquamation was noted in 2 and 7 females in the vehicle control and 1300 mg/kg/day group, respectively, prior to dose application; this finding was observed generally beginning as early as gestation day 11 and continuing through gestation day 16. This finding persisted to the time of unwrap (following 6 hours of exposure) in 3 test article-treated females (nos. 52135, 52137 and 52142) during gestation days 14-16.
Executive summary:

As part of a weight of evidence approach, the skin irritation observation reported during a rabbit dermal exposure study equivalent to OECD Guideline 414 (Prenatal Developmental Toxicity Study) were considered. The test article was administered by dermal exposure to clipped dorsum (approximately 8% of total body surface area) to 2 groups of 22 time-mated female New Zealand White rabbits once daily, from gestation days 7-20. The application site for each animal was covered with 8-ply gauze, covered with an occluded non-porous latex bandage and held in place with non-irritating tape. Elizabethan collars were applied to restrict access to the wrapped dosing site. The dosage level was 1300 mg/kg/day administered at a dosage volume of 0.91 mL/kg. A concurrent control group of 22 time-mated females received the vehicle (deionized water) on a comparable regimen at a dose volume of 1.3 mL/kg. The application site was scored daily (prior to dose administration and following removal of the dressing) for erythema, edema and other dermal findings. The prenatal developmental toxicity study continued to determine potential toxicity as described elsewhere within this dossier.

 

Minimal dermal irritation (very slight erythema) was noted in 4 females from 1 to 3 consecutive days during gestation days 12-14.

In addition, desquamation was noted in 2 and 7 females in the vehicle control and 1300 mg/kg/day group, respectively, prior to dose application; this finding was observed generally beginning as early as gestation day 11 and continuing through gestation day 16. This finding persisted to the time of unwrap (following 6 hours of exposure) in 3 test article-treated females (nos. 52135, 52137 and 52142) during gestation days 14-16.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report Date:
2008

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Only 8% of the body surface was covered, acclimatization was not at least 5 days
GLP compliance:
no
Remarks:
The study was not commissioned with compliance with REACH as a goal, rather the study was commissioned during early product development.
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Lot no. Q14A-14
- Purity: 99%

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Covance Research Products, Inc., Kalamazoo, Michigan
- Age at study initiation: The animals were approximately 5.5 months old upon receipt.
- Weight at study initiation: Body weight values ranged from 2947 g to 4279 g on gestation day 0.
- Fasting period before study: Not reported
- Housing: Housed individually
- Diet: The basal diet was offered in 25 g increments 3 times per day on the day of arrival and in increased amounts over the next few days, until the animals gradually achieved ad libitum status prior to the dose administration period; basal diet was offered ad libitum thereafter.
- Water: ad libitum
- Acclimation period: Prior to the initiation of dose administration, the animals were acclimated to wearing Elizabethan restraint collars. The collars were affixed to each rabbit on gestation days 3, 4, 5 and 6 for approximately 1, 2, 4 and 6 hours, respectively.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19±3°C
- Humidity (%): 50±20%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 4 November 2007 (first gestation day 0) To: 27 November 2007 (Last laparohysterectomy)

Administration / exposure

Route of administration:
dermal
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: the hair was clipped from the back of each animal, from the scapula (shoulder) to the wing of the ileum (hipbone) and halfway down the flank of each side of the animal.
- % coverage: ~8.0% and 7.9% for the control and 1300 mg/kg/day group, respectively
- Type of wrap if used: The application site for each animal was covered with 8-ply gauze, covered with an occluded non-porous latex bandage and held in place with non-irritating tape. Elizabethan collars were applied to restrict access to the wrapped dosing site.
- Time intervals for shavings or clipplings: On the day prior to the initiation of dose administration (9 October 2007), and as often as needed thereafter (only after a dermal evaluation), the hair was clipped.

REMOVAL OF TEST SUBSTANCE
- Washing: yes - Residual material on the skin was visually estimated and recorded, and the test sites were gently washed twice (the second wash immediately following the first) with a 70:30 isopropanol:water solution (septihol sterile; lot no. 24286715C7; exp. date: 1 Mar 2009; received from the sponsor) and disposable paper towels to remove any residual vehicle or test article.
- Time after start of exposure: After 6-hour exposure period

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): The dosage level was 1300 mg/kg/day administered at a dosage volume of 0.91 mL/kg. A concurrent control group of 22 time-mated females received the vehicle (deionized water) on a comparable regimen at a dose volume of 1.3 mL/kg. Density of the test article was 1.432 g/mL.
- Concentration (if solution): neat
- Constant volume or concentration used: yes

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes
Analytical verification of doses or concentrations:
yes
Remarks:
The test article was administered as supplied by the sponsor.
Details on analytical verification of doses or concentrations:
2 samples (50 μL each) of the test article were collected [1 following the first day of dosing (10 October 2007) and 1 following the last day of dosing (24 October 2007)] and shipped on blue ice to the sponsor.
Details on mating procedure:
Time-mated female New Zealand White rabbits were received in good health from Covance Research Products, Inc., Kalamazoo, Michigan, on 5 October 2007. The time-mated rabbits were received on gestation days 1 or 2. Each female was examined by a qualified technician on the day of receipt and gestation day 4 or 5. Each rabbit was uniquely identified by a color-coded plastic ear tag displaying the animal number. The rabbits were observed twice daily for mortality and general changes in appearance and behavior prior to the start of dose administration. Body weights were recorded by the supplier on gestation day 0.
Duration of treatment / exposure:
The vehicle or test article was applied evenly to the clipped, intact dorsal skin of each animal on gestation days 7-20.
Frequency of treatment:
The vehicle or test article was applied evenly to the clipped, intact dorsal skin of each animal once daily for a minimum of 6 hours.
Duration of test:
Gestation days 7-20
Doses / concentrations
Dose / conc.:
1 300 mg/kg bw/day (nominal)
No. of animals per sex per dose:
22 females per dose
Control animals:
yes
Details on study design:
- Dose selection rationale: Dosage levels were selected based on the results of previous studies conducted by the sponsor.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All rabbits were observed twice daily, once in the morning and once in the afternoon, for moribundity and mortality.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Individual detailed clinical observations were recorded from the day of receipt through gestation day 29 (prior to dose administration during the treatment period).

BODY WEIGHT: Yes
- Time schedule for examinations: Individual maternal body weights were recorded on gestation days 0 (by supplier), 4 or 5, 7-21 (daily), 24 and 29. Mean body weight changes were calculated for each corresponding interval and also for gestation days 7-10, 10-13, 13-21, 7-21 and 21-29.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes (not feeding study)
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #: Day 29
- Organs examined: uterus, ovaries

OTHER: The application site was scored daily (prior to dose administration and following removal of the dressing) for erythema, edema and other dermal findings using the 4-step grading system (Draize, 1965). In addition, the amount of residual material present on the skin following the 6-hour exposure period was visually estimated and recorded following the removal of the dressing. All significant findings were recorded.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: Yes: [all per litter]
Statistics:
All statistical tests were performed using appropriate computing devices or programs.
Historical control data:
WIL Research Laboratories, LLC has historical control data on the background incidence of fetal malformations and developmental variations in the New Zealand White rabbit.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test article-related clinical findings noted in the 1300 mg/kg/day group. Clinical findings noted in the test article treated-group, including hair loss around the right ear, soft stool and small feces, occurred infrequently, at similar frequencies in the vehicle control group and/or prior to or following cessation of the treatment period.
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
During the observations of the application sites (prior to each application and following the 6-hour exposure period), evidence of minimal dermal irritation (very slight erythema) was noted in 4 females in the 1300 mg/kg/day group from 1 to 3 consecutive days during gestation days 12-14. Due to the absence of this finding in the vehicle control group, these occurrences of very slight erythema were considered to be test article-related; however, because of the transient nature, limited incidence and minimal severity of this finding, it was not considered to be adverse. In addition, desquamation was noted in 2 and 7 females in the vehicle control and 1300 mg/kg/day group, respectively, prior to dose application; this finding was observed generally beginning as early as gestation day
11 and continuing through gestation day 16. This finding persisted to the time of unwrap (following 6 hours of exposure) in 3 test article-treated females (nos. 52135, 52137 and 52142) during gestation days 14-16.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Female no. 52113 in the 1300 mg/kg/day group was found dead on gestation day 16; a single clinical observation (red material in cage pan) was noted for this female prior to death. In addition, 1 female (no. 52107) in the vehicle control group was euthanized in extremis on gestation day 14; clinical findings noted prior to euthanasia (gestation days 13-14), included hypoactivity, brown material around the anogenital area and decreased defecation. This female had marked body weight losses and food consumption was 3 g/animal/day or less from gestation day 9 through euthanasia. Due to the moribundity observed in this vehicle control group female and the lack of other indications of maternal toxicity, the death of the female in the 1300 mg/kg/day group was not considered to be test article-related.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Relative to the vehicle control group, there were no statistically significant effects on mean body weights or body weight gains in the 1300 mg/kg/day group during the treatment (gestation days 7-21) or post-treatment (gestation days 21-29) periods. In addition, mean net body weight, net body weight change and gravid uterine weight in this same group were unaffected by test article administration. Differences from the vehicle control group were slight and not statistically significant
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption, evaluated as g/animal/day and g/kg/day, in the 1300 mg/kg/day group was unaffected by test article administration. Differences from the vehicle control group were slight and not statistically significant.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
One female (no. 52113) in the 1300 mg/kg/day group was found dead on gestation day 16; this female had dark red uterine contents, 7 normally developing implantations and 3 early resorptions noted in the uterus. Additionally, female no. 52107 in the vehicle control group was euthanized in extremis on gestation day 14; cystic kidney, slightly distended ureter (right) were noted for this female at necropsy. This female had a single early resorption noted in the uterus. Female no. 52128 in the vehicle control group aborted 1 late resorption with no apparent external malformations on gestation day 28. Findings for this female at necropsy included a cystic oviduct, red matting around the urogenital area and an absent uterus (left horn); 3 late resorptions with no apparent malformations were noted in utero.
At the scheduled necropsy on gestation day 29, no test article-related internal findings were observed at 1300 mg/kg/day. Macroscopic findings observed in surviving animals occurred infrequently and/or at similar frequencies in the control group. With the exception of 3 females (nos. 52098, 52116 and 52131) in the 1300 mg/kg/day group, all females were gravid.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
Female no. 52128 in the vehicle control group aborted on gestation day 28. Prior to abortion, clinical observations for this female included brown material around the
anogenital area, red material around the right ear and excreta-related findings (decreased defecation, soft stool and small feces). All remaining females survived to the scheduled necropsy on gestation day 29.
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
The mean litter proportion of postimplantation loss (primarily early resorptions) in the 1300 mg/kg/day group (9.6% per litter) was higher than the vehicle control group value (5.4% per litter) and higher than the maximum mean in the WIL historical control data (7.3% per litter).

Mean numbers of corpora lutea and implantation sites and the mean litter proportions of preimplantation loss were similar between the vehicle control group and the 1300 mg/kg/day groups.
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Other effects:
not specified

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
1 300 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: Based on lack of maternal toxicity
Remarks on result:
other: Limit test

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were no test article-related effects on mean fetal weight at 1300 mg/kg/day.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
effects observed, non-treatment-related
Description (incidence and severity):
A lower mean litter proportion of viable fetuses (90.4% per litter) was observed in this group when compared to the vehicle control group value (94.6% per litter). However, these differences were not statistically significant when compared to the concurrent control group and were primarily attributed to 1 female (no. 52097) with 100% postimplantation loss, and therefore, not considered to be test article-related.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
There were no test article-related effects on sex fetal ratios at 1300 mg/kg/day.
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Description (incidence and severity):
The numbers of fetuses (litters) available for morphological evaluation were 178(20) and 168(17) in the vehicle control and 1300 mg/kg/day groups, respectively. There were no external malformations or developmental variations observed for fetuses in this study.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
A vertebral anomaly with associated rib anomaly (absent arches and centra and fused ribs) was noted in fetus no. 52125-06 in the 1300 mg/kg/day group. In addition, a rib anomaly (left ribs nos. 9-10 fused) was observed in fetus no. 52135-10 in this same group. The mean litter proportions of these findings (0.6% per litter for both) were within the range of the WIL historical control data (0.0% to 1.2% per litter for the rib anomaly and 0.0% to 1.3% per litter for the vertebral anomaly) and the differences were not statistically significant when compared to the vehicle control group. Therefore, these findings were not attributed to test article administration.

Skeletal developmental variations, consisting primarily of 13th rudimentary ribs, 13th full ribs, 27 presacral vertebrae, sternebrae nos. 5 and/or 6 unossified and bent hyoid arches, were noted at similar frequencies in the vehicle control group, were not statistically significant and/or were within the ranges of the WIL historical control data.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Visceral malformations were noted in 2 fetuses in the 1300 mg/kg/day group. Fetus no. 52122-04 had an absent kidney and ureter and fetus no. 52100-11 had a stenotic pulmonary trunk. The finding absent kidney and ureter was not observed in the 14 studies that comprise the WIL historical control data (Kalamazoo, Michigan facility). However, absent kidney and ureter has been observed in the 40 studies that comprise the WIL historical control data (Denver, Pennsylvania facility), and the mean litter proportion of this finding (0.5% per litter) was within the range of this historical control data (0.0%-0.9% per litter). The mean litter proportion of stenotic pulmonary trunk (0.5% per litter) was within the range of the WIL historical control data (0.0% to 0.5% per litter; Kalamazoo, Michigan facility). Additionally, these findings were not statistically significant compared to the vehicle control group, and therefore, were not considered to be test article-related.

Soft tissue developmental variations noted in the 1300 mg/kg/day group consisted primarily of pale or accessory spleen(s), extra papillary heart muscle, major blood vessel variations, small lungs and absent or small gallbladder. The mean litter proportions of these developmental variations were noted at similar frequencies in the vehicle control group, were not statistically significant and/or were within the ranges of the WIL historical control data.

Oviduct cysts noted in fetus nos. 52109-06 and 52142-13 in the 1300 mg/kg/day group was not classified as malformations or variations and was not included in any tabulation.
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
The numbers of fetuses (litters) available for morphological evaluation were 178(20) and 168(17) in the vehicle control and 1300 mg/kg/day groups, respectively. Malformations were observed in 0(0) and 4(4) fetuses (litters) in these same respective dosage groups and were considered spontaneous in origin. When the total malformations and developmental variations were evaluated on a proportional basis, no statistically significant differences from the vehicle control group were noted. Fetal malformations and developmental variations, when observed in the 1300 mg/kg/day group, occurred infrequently or at a frequency similar to that in the control group and/or were within the WIL historical control data ranges. Based on these data, no fetal malformations or developmental variations were attributed to the test article.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
1 300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Lack of embryo/fetal developmental toxicity
Remarks on result:
other: Limit test

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Based on the lack of maternal and embryo/fetal developmental toxicity observed in this study, a dosage level of 1300 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity and for embryo/fetal development when 2,2,3,3,4,4,5,5-Octafluoropentyl Methacrylate was administered by dermal exposure to pregnant New Zealand White rabbits.
Executive summary:

The test article, 2,2,3,3,4,4,5,5-Octafluoropentyl Methacrylate (OFPMA), was administered by dermal exposure to clipped dorsum (approximately 8% of total body surface area) to 2 groups of 22 time-mated female New Zealand White rabbits once daily, from gestation days 7-20. The application site for each animal was covered with 8-ply gauze, covered with an occluded non-porous latex bandage and held in place with non-irritating tape. Elizabethan collars were applied to restrict access to the wrapped dosing site. The dosage level was 1300 mg/kg/day administered at a dosage volume of 0.9 mL/kg. A concurrent control group of 22 time-mated females received the vehicle (deionized water) on a comparable regimen at a dose volume of 1.3 mL/kg. All animals were observed twice daily for mortality and moribundity. Clinical observations, body weights and food consumption were recorded at appropriate intervals. On gestation day 29, a laparohysterectomy was performed on the surviving females. The uteri, placentae and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. The fetuses were weighed, sexed and examined for external, visceral and skeletal malformations and developmental variations.

 

There were no test article-related mortalities observed in this study. In addition, there were no test article-related clinical observations noted at the daily examinations in the 1300 mg/kg/day group.

 

Erythema (very slight) was observed in the 1300 mg/kg/day group prior to and following the 6-hour exposure period. The incidence and severity of this dermal observation was contributed to the test article but was not considered to be adverse due to the transient occurrence. In addition, desquamation was noted in the vehicle control group (prior to daily application) and the 1300 mg/kg/day group (prior to and following the 6-hour exposure period).

 

Mean body weights, body weight gains, net body weight, net body weight change, gravid uterine weight and food consumption in the 1300 mg/kg/day group were unaffected by test article administration.

 

There were no effects on intrauterine growth and survival at 1300 mg/kg/day. In addition, no fetal malformations or developmental variations observed in the 1300 mg/kg/day group were attributed to test article administration.

 

Based on the lack of maternal and embryo/fetal developmental toxicity observed in this study, a dosage level of 1300 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity and for embryo/fetal development when 2,2,3,3,4,4,5,5-Octafluoropentyl Methacrylate was administered by dermal exposure to pregnant New Zealand White rabbits.