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Key value for chemical safety assessment

Effects on fertility

Description of key information

Rat (males and females) reproduction/developmental toxicity screening test: NOEAL = 1000 mg/kg bw/d (OECD 421, GLP; BASF SE, 2012)

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key 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
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
adopted: 27.07.1995
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Landesamt für Umwelt, Wasserwirtschaft und Gebäudeaufsicht, Mainz
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
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
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
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
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.
Duration of treatment / exposure:
51 days F0 females and 44 days F0 males : The treatment lasted up to one day prior to sacrifice.
Frequency of treatment:
daily, at the same time in the morning
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
Parental animals: Observations and 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.
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead.

CLINICAL OBSERVATIONS
The live pups were examined daily for clinical symptoms (including gross-morphological findings) during the clinical inspection of the dams.

BODY WEIGHT DATA
The pups were weighed one day after birth (PND 1) and on day 4 after birth.
Postmortem examinations (parental animals):
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations and assessed by gross pathology, special attention being given to the reproductive organs.

HISTOPATHOLOGY / ORGAN WEIGHTS
Weight assessment was carried out on all animals sacrificed at scheduled dates. The following weights were determined:
1. Anesthetized animals, 2. Epididymides, 3. Ovaries, 4. Testes.
Histopathologycal examination by light microscopy.
Postmortem examinations (offspring):
SACRIFICE
- On PND 4 all pups were sacrificed under isoflurane anesthesia with CO2 and examined macroscopically. Stillborn pups and all pups which died ahead of schedule were examined externally, eviscerated and their organs were assessed macroscopically.

GROSS NECROPSY
- All surviving pups (sacrificed on PND 4 under isoflurane anesthesia with CO2), all stillborn pups and those pups, which died ahead of schedule, were examined externally, eviscerated and their organs were assessed macroscopically.
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.
Reproductive indices:
Male and female mating index
Male and female fertility index

gestation index
Offspring viability indices:
Live birth index
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food efficiency:
no effects observed
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:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): In all male and female animals of test group 3 (1000 mg/kg bw/d) discoloured feces were
observed during premating, gestation and lactation period. No treatment-related findings were observed for all male and female animals of the remaining test groups 1 and 2(100 and 300 mg/kg bw/d). In a single female of test group 0 (0 mg/kg bw/d) no sperm in vaginal smear was detected during the entire mating period, but delivered pups. One female animal of test group 0 (0 mg/kg bw/d) and one female animal of test group 2 (300 mg/kg bw/d) did not deliver. These findings were assessed as being incidental and not related to the test substance administration.
No mortality occurred during the entire study period.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): No treatment-related changes in body weight data were observed in male and female animals of all test groups. The single significantly increased value in body weight change in females of test group 3 (1000 mg/kg bw/d) from day 0 to 7 during gestation (+24%) was assessed as being incidental.
No significant changes in food consumption were observed for male and female animals during the study period.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS). For all F0 parental males mating was confirmed. Thus, the male mating index was 100%.
The female mating index calculated after the mating period for F1 litter was 100%. The mean duration until sperm was detected (GD 0) amounted to 3.9, 2.6, 1.9 and 3.0 days (0, 100, 300 and 1000 mg/kg bw/d, respectively). The differences between the test groups were assessed as being spontaneous in nature and without biological or toxicological relevance. All animals of all test groups (0, 100, 300 and 1000 mg/kg bw/d) delivered pups or had implantations in utero with exception of one animal of test group 0 and one animal of test group 2. The female fertility index was 90% in test group 0 and 2 and 100% in test group 1 and 3. Thus, no treatment-related effect was observed. The mean duration of gestation was similar in all test groups, i.e. between 22.0 and 22.2 days. Implantation was not affected by the treatment in all test groups since the mean number of implantation sites was comparable among all groups. Postimplantation loss was between 1 and 4, these values reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data. The gestation index was 100% in all test groups. The mean number of F1 pups delivered per dam was 11.6, 11.9, 11.9 and 12.2 pups/dam in test groups 0-3 (0, 100, 300 and 1000 mg/kg bw/d, respectively). The rate of liveborn pups was not affected by the test substance as indicated by the live birth indices of 100% in test group 0 and 1. In test group 2 the live birth index was significantly decreased (94%) and in test group 3 slightly decreased (98%). As no dose-response relationship was observed and all respective values were within the range of the historical control data, the lower indices were not assumed to be treatment related.

GROSS PATHOLOGY (PARENTAL ANIMALS): In females of test group 3 (1000 mg/kg bw/d) the contents of the stomach (2/10 females) and rectum (4/10 females) showed an orange discoloration. In a previous study with the same substance (Kaspers, U., et al.) the discoloration of contents occurred without any histopathological correlate. Therefore, stomach and rectum were not examined for histopathology and the discoloration of contents was regarded as non adverse and was considered to respond to the orange color of the test substance.
All other gross lesions observed in the test animals occurred singularly and were considered to be incidental and not related to treatment.

HISTOPATHOLOGY (PARENTAL ANIMALS): One male of the control group showed in the kidneys an unilateral nephroblastoma. This finding, as well as all other histopathological findings were either single observations or biologically equally distributed between control and treatment groups. Such findings were considered to be incidental and/or spontaneous in origin and without any relation to treatment.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: reproductive performance and fertility was not affected by the test substance as no dose-response relationship
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no signs on general, systemic toxicity were observed
Critical effects observed:
no
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
VIABILITY (OFFSPRING): No significant increase of pups that died during lactation was observed for test groups 1-3 (100, 300 and 1000 mg/kg bw/d). The viability index as indicator for pup mortality between PND 0-4 was between 96% and 100% for all test groups.
The mean number of delivered pups per dam and the rate of liveborn pups were evenly distributed among test groups 0-3 (0, 100, 300 and 1000 mg/kg bw/d). The respective values reflect the normal range of biological variation inherent in the strain used in this study.
In test group 2 (300 mg/kg bw/d), the number of liveborn pups was significantly decreased (94%) and the number of stillborn pups was significantly increased. Due to the lack of a dose-response, this was assessed as being incidental.

CLINICAL SIGNS (OFFSPRING): All F1 pups did not show adverse clinical signs up to scheduled sacrifice on PND 4.

BODY WEIGHT (OFFSPRING): Mean pup body weights/pup body weight changes of all pups in test groups 1-3 (100, 300 and 1000 mg/kg bw/d) were comparable to the concurrent control group (0 mg/kg bw/d). The observable differences between the groups were assessed as being spontaneous in nature and without biological relevance.
One runt was seen in female pups of test group 1 (100 mg/kg bw/d). This was within the normal range inherent of this strain and not related to treatment.

SEXUAL MATURATION (OFFSPRING): The sex distribution and sex ratios of live F1 pups on the day of birth and on PND 4 did not show biologically relevant differences between all test groups.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no developmental toxicity was observed
Remarks on result:
other: Observed up to postnatal day 4
Critical effects observed:
no
Reproductive effects observed:
no

Table 1: Female fertility index

Test groups

Fertility index (%)

0mg/kg bw/d

90

100mg/kg bw/d

100

300mg/kg bw/d

90

1000mg/kg bw/d

100

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In a screening study conducted according to OECD 421 (GLP conform) the substance was administered by gavage (vehicle: 1% carboxymethylcellulose in drinking water) to groups of 10 male and 10 female Wistar rats at dose levels of 0, 100, 300, and 1000 mg/kg bw/d (BASF SE, 2012). The duration of treatment covered a premating period of 2 weeks and a mating period (max. of 2 weeks) in both sexes, approximately 2 weeks post-mating in males, and the entire gestation period as well as 4 days of lactation in females. F0 animals were examined for their reproductive performance including determination of the number of implantation sites and the calculation of postimplantation loss for all F0 females. All surviving F0 parental animals were sacrificed and assessed by gross pathology. Sex organ weights were recorded and a histopathological examination was performed when required.

Regarding clinical examinations, reproductive performance and fertility in male and female Wistar rats was not affected by the test substance as no dose-response relationship was observed. Therefore no signs of toxicity were observed for male and female animals up to a dose level of 1000 mg/kg bw/d. Regarding pathology, the administration of the test substance to parental male and female

rats at a dose level of 100, 300 and 1000 mg/kg bw/d revealed no adverse findings.

Under the conditions of this reproduction/developmental toxicity screening test the no observed adverse effect level (NOAEL) for reproductive performance and fertility in male and female Wistar rats was 1000 mg/kg bw/d.



Effects on developmental toxicity

Description of key information

Rat (males and females) reproduction/developmental toxicity screening test: NOAEL = 1000 mg/kg bw/d (OECD 421, GLP; BASF SE, 2012)

According to REACH Annex XI, part 1, testing of developmental toxicity does not appear scientifically necessary. For further information please refer to the respective study record.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key 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
Reason / purpose for cross-reference:
reference to same study
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
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
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
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
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.
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
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
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
Abnormalities:
no effects observed
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
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.
Abnormalities:
no effects observed
Developmental effects observed:
no

Table 1: Live birth index

Test group (mg/kg bw/d)

Live birth index (%)

0

100

100

100

300

94 (significantly decreased)

1000

98

Endpoint:
developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and there is no or no significant human exposure
other:
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
Please refer to the attached justification for further information.
Reason / purpose for cross-reference:
exposure-related information
Reason / purpose for cross-reference:
data waiving: supporting information
Species:
rat
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

The above described reproduction/developmental screening study, performed according to OECD guideline 421, pups were sexed on PND 0 and weighed one PND1 and on PND 4. Their viability was recorded twice daily on each workday or only in the morning on Saturday and Sunday. On PND 4 all pups were sacrificed under isoflurane anesthesia with CO2 and examined macroscopically for external and visceral findings. The mean number of delivered pups per dam and the rate of liveborn pups reflect the normal range of biological variation inherent in the strain used in this study. In test group 2 (300 mg/kg bw/d), the number of liveborn pups was significantly decreased (94%) and the number of stillborn pups was significantly increased. Due to the lack of a dose-response, this was assessed as being incidental. No significant increase of pups that died during lactation was observed for test groups 1-3 (100, 300 and 1000 mg/kg bw/d). The viability index as indicator for pup mortality between PND 0-4 was between 96% and 100% for all test groups. The sex distribution and sex ratios of live F1 pups on the day of birth and on PND 4 did not show biologically relevant differences between all test groups. All F1 pups did not show adverse clinical signs up to scheduled sacrifice on PND 4. Mean pup body weights/pup body weight changes of all pups in test groups 1-3 (100, 300 and 1000 mg/kg bw/d) were comparable to the concurrent control group (0 mg/kg bw/d). The observable differences between the groups were assessed as being spontaneous in nature and without biological relevance. One runt was seen in female pups of test group 1 (100 mg/kg bw/d). This was within the normal range inherent of this strain and not related to treatment. It can be concluded that no treatment-related findings were observed.

Under the conditions of this reproduction/developmental toxicity screening test the no observed adverse effectv level (NOAEL) for developmental toxicity in Wistar rats was 1000 mg/kg bw/d.

Justification for classification or non-classification

Based on available data, Tin Titanium Zinc oxide does not need to be classified for effects of fertility and developmental toxicity according to Annex I of Directive 67/548/EEC and according to GHS criteria Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Additional information