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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline Study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report date:
2005

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: U.S. Food and Drug Administration (FDA), Guideline on detection of toxicity to reproduction for medicinal products. Federal Register, Sept. 22, 1994, Vol. 59, No. 183
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
425-950-7
EC Name:
-
Cas Number:
187393-00-6
Molecular formula:
C38-H49-N3-O5
IUPAC Name:
5-[(2-ethylhexyl)oxy]-2-(4-{4-[(2-ethylhexyl)oxy]-2-hydroxyphenyl}-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl)phenol
Details on test material:
- Name of test material (as cited in study report): Tinosorb S (FAT 76'884)
- Substance type: organic
- Physical state: yellow powder
- Analytical purity: >97.9%
- Purity test date: 29-Nov-2004
- Lot/batch No.: 06484CL2
- Expiration date of the lot/batch: 3-Dec-2007

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Covance Research Products, Inc., Denver, Pennsylvania
- Age at study initiation: 5 months
- Weight at study initiation: 2.5 - 4.3 kg (at study assignment)
- Fasting period before study: no
- Housing: units of six stainless steel cages
- Diet (e.g. ad libitum):
^ Approximately 150 g of Certified Rabbit Chow® #5322 (PMI® Nutrition International) was offered to each rabbit until day of first dosage
^ Approximately 180 to 185 g of the chow offered to each rabbit from day of first dosage.
- Water (e.g. ad libitum): Local water passed through Reverse Osmosis filter (R.O. water) then chlorinated.
- Acclimation period: 1 day

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 - 22
- Humidity (%): 30 - 70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 30 Apr 2004 To: 28 May 2004

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% (w/v) carboxymethylcellulose (CMC) in 0.1% (w/v) Tween® 80
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Suspensions of test article and vehicle were prepared at least once weekly at the Testing Facility. Prepared suspensions were stored refrigerated.

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Concentration in vehicle: 0, 10, 30, 100 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg-bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis performed to dermine the test article concentration at the start of the study and at the end of the study. Analysis by HPLC.
Details on mating procedure:
The female rabbits were naturally bred by breeder male rabbits of the same source and strain before shipment to the Testing Facility. The rabbits were mated on four consecutive days and shipped to the Testing Facility to arrive on DGs 1, 2, 3 or 4. The day of mating was considered to be DG 0.
Duration of treatment / exposure:
Gestation days 6 through 19
Frequency of treatment:
Daily
Duration of test:
23 days (animals were Caesarean-sectioned on gestation day 29).
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 300, & 1000 mg/kg-bw
Basis:
other: dose administered by gavage
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection rationale: Dosages were selected on the basis of a dosage-range study conducted at the Testing Facility. In that study, dosages of 0 (Vehicle), 100, 300, or 1000 mg/kg/day were administered orally by stomach tube to groups of six timed mated rabbits on DGs 6 through 19. There were no test article-related deaths, clinical signs, or alterations at necropsy. Body weight changes and food consumption values were increased in the does given Tinosorb S in these small samples; however, there was minimal impact on the average body weights. Caesarean-sectioning and litter observations were comparable among the groups or within the ranges observed historically, and no fetal gross external alterations were observed. Based on the results of this study, dosages of 100, 300, and 1000 mg/kg/day were selected for the developmental toxicity study of Tinosorb S in rabbits.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily during study, and once daily during the post-dosage stage

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: approx. 60 minutes after dosage

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #29
- Organs examined: gross examination of the thoracic, abdominal and pelvic viscera, including liver, lungs, and kidneys.
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 fetuses
- Soft tissue examinations: Yes: all fetuses
- Skeletal examinations: Yes: all fetuses
- Head examinations: Yes: all fetuses
Statistics:
Data generated during the course of this study were recorded either by hand or using the Argus Automated Data Collection and Management System and the Vivarium Temperature and Relative Humidity Monitoring System. All data were tabulated, summarized and/or statistically analyzed using the Argus Automated Data Collection and Management System, The Vivarium Temperature and Relative Humidity Monitoring System, Microsoft® Excel (part of Microsoft® Office 97/2000/XP), Quattro Pro 8 and/or The SAS System (version 6.12). Averages and percentages were calculated. Litter values were used where appropriate. Clinical observations and other proportional data were analyzed using the Variance Test for Homogeneity of the Binomial Distribution. Continuous data (e.g., maternal body weights, body weight changes, feed consumption values and litter averages for percent male fetuses, percent resorbed conceptuses, fetal body weights, fetal anomaly data and fetal ossification site data) were analyzed using Bartlett’s Test of Homogeneity of Variances and the Analysis of Variance, when appropriate [i.e., Bartlett’s Test was not significant (p>0.001)]. If the Analysis of Variance was significant (p≤0.05), Dunnett’s Test was used to identify the statistical significance of the individual groups. If the Analysis of Variance was not appropriate [i.e., Bartlett’s Test was significant (p≤0.001)], the Kruskal-Wallis Test was used, when less than or equal to 75% ties were present. In cases where the Kruskal-Wallis Test was statistically significant (p≤0.05), Dunn’s Method of Multiple Comparisons was used to identify the statistical significance of the individual groups. If there were greater than 75% ties, Fisher’s Exact Test(18) was used to analyze the data. Count data obtained at Caesarean-sectioning of the does were evaluated using the procedures described above for the Kruskal-Wallis Test.
Historical control data:
January 2002 thru 2004 from 74 studies representing 967 rabbits (932 pregnant).

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The maternal no-observable-adverse-effect-level (NOAEL) of Tinosorb S (FAT 76’884) is was determined to be at least 1000 mg/kg/day; the highest dosage tested. The developmental NOAEL is also at least 1000 mg/kg/day and there were no adverse effects on embryo-fetal development. Based on these data, the test substance should not be identified as a developmental toxicant.
Executive summary:

Eighty timed-mated female Hra:(NZW)SPF rabbits were randomly assigned to four dosage groups, 20 rabbits per dosage group. The test article, Tinosorb S, and/or vehicle, 0.5% (w/v) carboxymethylcellulose in 0.1% (w/v) aqueous Tween® 80, were administered once daily on days 6 through 19 of gestation (DGs 6 through 19) at dosages of 0 (Vehicle), 100, 300 and 1000 mg/kg/day. The dosage volume was 10 mL/kg, adjusted daily on the basis of the individual body weights recorded before intubation. 

Rabbits were observed for viability at least twice each day of the study. Observations for clinical signs, abortions, premature deliveries and deaths were made before and approximately 60 ± 10 minutes after dosage administration and once daily during the postdosage period. Body weights were recorded on DG 0, the day of arrival at the Testing Facility and daily during the dosage and postdosage periods. Feed consumption values were recorded daily after arrival at the Testing Facility.

Rabbits were sacrificed on DG 29, Caesarean-sectioned and a gross necropsy of the thoracic, abdominal and pelvic viscera was performed. The number and distribution of corpora lutea were recorded. The uterus of each rabbit was excised, weighed and examined for pregnancy, number and distribution of implantation sites, live and dead fetuses and early and late resorptions. Placentae were examined for size, color and shape. Fetuses were individually identified, weighed and examined for gross lesions. All fetuses were examined internally to identify sex. Cavitated organs were evaluated in all fetuses by dissection. A single cross-section was made between the parietal and the frontal bones, and the brain was examined in situ. All fetuses were examined for skeletal alterations.

No deaths were caused by Tinosorb S. One doe in the 1000 mg/kg/day dosage group was sacrificed on day 19 of gestation (DG 19) due to its moribund condition as the result of an intubation accident. All other rabbits survived until scheduled Caesarean-sectioning. All clinical and necropsy observations were considered unrelated to Tinosorb S. Body weights, body weight gains, gravid uterine weights, and absolute and relative feed consumption values were unaffected by dosages of Tinosorb S as high as 1000 mg/kg/day. No Caesarean-sectioning or litter parameters were affected by dosages of Tinosorb S as high as 1000 mg/kg/day, nor were any gross external, soft tissue or skeletal fetal alterations (malformations or variations) caused by dosages of Tinosorb S as high as 1000 mg/kg/day.