Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD guideline 421 (Reproduction/Developmental Toxicity Screening Test); Adopted: 27.07.1995
GLP compliance:
yes (incl. QA statement)
Remarks:
Landesamt für Umwelt, Wasserwirtschaft und Gebäudeaufsicht, Mainz
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
485-430-0
EC Name:
-
Cas Number:
923954-49-8
Molecular formula:
SnxZnyTi2Oz with x = 0,5 – 1,7 y = 0,5 – 1,7 z = 5,5 – 7,5
IUPAC Name:
Tin Titanium Zinc kegginite B
Details on test material:
- Name of test substance: Tin titanium zinc oxide
- Test substance No.: 07/0285-1
- Batch identification GV 33900-66
- Purity: 99.61g / 100g (Analytical report: 07L00144)
- Homogeneity: given
- Stability: Unlimited. The stability under storage conditions over the prospective administration period was guaranteed.
- Physical state/appearance: solid/orange
- Storage conditions: room temperature

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: 10-11 weeks (males/females)
- Weight at study initiation: (P) Males: 316.6-342.8 g; Females: 184.4-216.0 g
- Housing: During the study period, the rats were housed individually in Makrolon type M III cages (Becker & Co., Castrop-Rauxel, Germany), with the following exceptions: • During overnight mating, male and female mating partners were housed together in Makrolon type M III cages. • Pregnant animals and their litters were housed together until PND 4 (end of lactation).
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr): 15 times per hour
- Photoperiod (hrs dark / hrs light): 12 hours / 12 hours

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1% in water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Concentration in vehicle: 1% carboxymethylcellulose in drinking water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical investigations of the test substance preparations was carried out at Competence Center Analytics, Department of BASF SE, Ludwigshafen, Germany, as a separate GLP study.
At the beginning of the administration period samples were taken from the lowest and highest concentration for homogeneity analysis (were also used for concentration control). From the mid concentration a concentration control analysis was carried out. At the end of the administration period concentration control analyses of the test substance preparations were performed in samples of all concentrations.
Details on mating procedure:
- M/F ratio per cage: 1:1 ratio
- Length of cohabitation: Each of the male and female animals was mated overnight for a maximum of 2 weeks. The animals were paired by placing the female in the cage of the male mating partner from about 16.00 h until 07.00-09.00 h of the following morning.
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
50 days F0 females and 40 days F0 males: The treatment lasted up to one day prior sacrifice.
Frequency of treatment:
daily, at the same time in the morning
Duration of test:
51 days
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 300, 1000 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily

BODY WEIGHT: Yes
- Time schedule for examinations: once a week at the same time of the day (in the morning). During gestation and lactation period, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20, on the parturition day (postnatal day [PND] 0) and on PND 4.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption was determined once a week (in a period of 7 days) for male and female parental animals, with the following exceptions:
• Food consumption was not determined after the 2nd premating week (male parental animals) and during the mating period (male and female F0 animals). • Food consumption of the F0 females with evidence of sperm was determined on GD 0, 7, 14 and 20. • Food consumption of F0 females, which gave birth to a litter, was determined on PND 1 and 4.
Food consumption was not determined in females without positive evidence of sperm and females without litter.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No
Fetal examinations:
- External examinations: Yes: Stillborn pups and all pups which died ahead of schedule
- Soft tissue examinations: Yes: Stillborn pups and all pups which died ahead of schedule
- Skeletal examinations: No
- Head examinations: No
Statistics:
Statistics of clinical examinations:
Food consumption (parental animals), body weight and body weight change (parental animals and pups; for the pup weights, the litter means were used), number of mating days, duration of gestation, number of pups delivered per litter, implantation sites, post implantation loss: Simultaneous comparison of all dose groups with the control group using the DUNNETT-test (two-sided) for the hypothesis of equal means.
Male and female mating index, male and female fertility index, gestation index, females with liveborn pups, females with stillborn pups, females with all stillborn pups, live birth index, pups stillborn, pups died, pups cannibalized, pups sacrificed moribund, viability index, number of litters with affected pups at necropsy: Pairwise comparison of each dose group with the control group using FISHER'S EXACT test for the hypothesis of equal proportions.
Proportions of affected pups per litter with necropsy observations: Pairwise comparison of each dose group with the control group using the WILCOXON-test (one-sided) for the hypothesis of equal medians.
Statistics of pathology:
Non-parametric one-way analysis using KRUSKAL-WALLIS test (two-sided). If the resulting pvalue was equal or less than 0.05, a pair wise comparison of each dose group with the control group was performed using WILCOXON-test (two-sided) for the equal medians.
Indices:
Live birth index
Historical control data:
Historical control data from the testing laboratory were available and used to assess the biological relevance of any observed effect.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food efficiency:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
see cross reference 7.8.1 Toxicity to reproduction: Key. BASF.80R0285/07C029 Reproduction/Developmental Screening Study. 421

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
see cross reference 7.8.1 Toxicity to reproduction: Key. BASF.80R0285/07C029 Reproduction/Developmental Screening Study. 421

Effect levels (fetuses)

Dose descriptor:
NOAEC
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed.

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Table 1: Live birth index

Test group (mg/kg bw/d)

Live birth index (%)

0

100

100

100

300

94 (significantly decreased)

1000

98

Applicant's summary and conclusion