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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2000
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Remarks:
(Peer review was conducted by a Japanese toxicological expert group at March 5, 2001; However only secondary source material available)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
Mar 1996
Deviations:
no
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Antimony nickel titanium oxide yellow
EC Number:
232-353-3
EC Name:
Antimony nickel titanium oxide yellow
Cas Number:
8007-18-9
Molecular formula:
(Ti, Sb, Ni) O2
IUPAC Name:
Antimony nickel titanium rutile
Details on test material:
Purity: 100%
Lot/batch no: 4879

Test animals

Species:
rat
Strain:
other: Crj; CD(SD)
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: 4 d
- Proof of pregnancy: vaginal plug or sperm in vaginal smear
Duration of treatment / exposure:
Exposure period: male: 46 days from 14 days prior to mating; female: 41-45 days from 14 days prior to mating to day 4 postpartum throughout mating and pregnancy
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: male: 47 days; female: 42-46 days
Frequency of treatment:
Once daily
Doses / concentrationsopen allclose all
Dose / conc.:
250 mg/kg bw/day
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: 1, 2, 3, 5, 7, 10 and 14 d; then weekly

BODY WEIGHT: Yes
- Time schedule for examinations: 1, 2, 3, 5, 7, 10 and 14 d; then weekly

Oestrous cyclicity (parental animals):
Estrous cycle was determined before mating
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, viability index, body weight and necroscopy

Postmortem examinations (parental animals):
GROSS NECROPSY
ORGAN WEIGHTS
Reproductive indices:
Estrous cycle, copulation index (number of pairs with successful copulation/number of pairs mated X 100), fertility index (number of pregnant animals/number of pairs with successful copulation X 100), gestation index (number of females with live pups/number of living pregnant females X 100), gestation length, nursing index, number of pregnant females, corpora lutea and implantation sites, implantation index (number of implantation sites/number of corpora lutea X 100), delivery index (number of pups born/number of implantation sites X 100),
Offspring viability indices:
number of live pups on day 4/number of live pups on day 0 X 100

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
At 500 and 1000 mg/kg bw/day: yellow or yellowish brown feces in all of 12 male and female rats of each group
The scab-formation in the back in the 250 mg/kg group and the trauma and scab-formation in the lower eyelid in the 500 mg/kg group were observed each in one female, but they were not considered to be affected by treatment
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
250 and 1000 mg/kg bw/day: a significant shortening of the activated partial thromboplastin time (APTT) was observed in males
250 mg/kg bw/day: In females, significant high values of mean corpuscular hemoglobin (MCH) and platelet were observed, but they were changes that cannot be seen in the dose groups of 500 mg/kg or more.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
A significant low value of potassium (K) was observed in the 1000 mg/kg group males, but it was considered to have no toxicological significance.
In females, significant low value of cholinesterase (ChE) in the 250 mg/kg group, significant low value of sodium (Na) in the 500 mg/kg group, and significant low value of GPT in the 1000 mg/kg group were observed, but, since there were no changes found in the related items, they were considered to have no relevance to the administration
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
250 mg/kg bw/day: In males, a significant increase was observed in urine specific gravity, but it was a change that cannot be seen in the dose groups of 500 mg/kg or more.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
1000 mg/kg bw/day: myocardial degeneration of heart in three males, eosinophilic bodies of the proximal tubule epithelium in one male, atrophy of the seminiferous tubules of testes in three males, intraluminal cell debris of the epididymis in one male, and lymphocyte infiltration of the prostate in four males were observed.
As for all the above changes, no significant difference was observed in the frequency of appearance, as compared to the control group.
In females, in the 1000 mg/kg group, erosion of the tongue was observed in one animal, and mineralization in the cortico-medullary junction of the kidney was observed in three females. In addition, the atresia of vagina and the inflammation of the uterine horn were observed in one animal in which the atresia of vagina was seen at necropsy (infertility example), and the atresia of vagina was a congenital anomaly and it was considered as the cause of infertility.
As for all the above changes, no significant difference was observed in the frequency of appearance, as compared to the control group.
Histopathological findings: neoplastic:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
As for the incidence of females with normal estrus interval, copulation index, fertility index, gestation index, length of gestation, and nursing index on lactation day 4, there was no significant difference observed in each dose group. Unsuccessful copulation was observed in the 250 and 500 mg/kg groups, each in one pair. In the estrous cycle inspection of females of these pairs, continuous diestrus was observed, but from the fact that it was not observed in the 1000 mg/kg group, it was not considered as the effect due to treatment. One non-pregnant female was observed in the 1000 mg/kg group. As for this female, the atresia of vagina that is a congenital anomaly was observed in the pathological examination and it was considered to be the cause of infertility.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
As for the live pups, there was nothing except for the trauma in the abdominal region observed in one female in the 500 mg/kg group.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
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
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Except for the scab observed in one male of the 1000 mg/kg group, there was no abnormality observed in any of the dead pups. As for the pups necropsied on day 4 of lactation, yellowish white portion of the liver was observed in one male of 250 mg/kg group and in one male of 1000 mg/kg group, and trauma found in the observation of general condition was observed in one female of 500 mg/kg group, but there was no other abnormality observed.
Histopathological findings:
not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Details on results (F1)

No effects observed in the offspring.

Effect levels (F1)

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 effects observed

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
In conclusion, the effects of the test substance's administration on the male and female reproduction and on the newborns were not observed in each dose group. Therefore, the no-observed-effect level (NOEL) of the test substanc's administration with repeated dose in this test conditions for the reproduction of parent animals and the no-observed-effect level (NOEL) for the development of newborns were considered to be 1000 mg/kg/day or more.