Antimony nickel titanium rutile

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2000

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

Reference

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2000

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 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crj; CD(SD)

Details on species / strain selection:

This strain was selected because this species is usually used in this kind of test and the laboratory is highly experienced with this strain.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc. Atsugi 6/27 breeding center
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 10 wks
- Weight at study initiation: Males: 335 - 386 g; Females: 208 - 249 g
- Housing: individually (except for acclimatisation and mating period)
- Diet: ad libitum, γ-ray irradiation fixed feed CRF-1 (Oriental Yeast Co., Ltd)
- Water: ad libitum, tap water
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 3 (actual measured range of 20 - 24 °C)
- Humidity (%): 55 ± 10 (actual measured range of 45 - 66 %)
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: 1 % carmellose sodium aqueous solution hereinafter referred to as 1 % CMC-Na aqueous solution

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
After grinding the test substance in a mortar, it was weighed accurately per dose, suspended in 1% CMC-Na aqueous solution to receive a predetermined concentration, and was dispersed using an ultrasonic device.

VEHICLE
- Concentration in vehicle: 10, 100, 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Lot/batch no. : 9318

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

No details on the analytical measurements were given.
The analysis of the stability performed prior to administration for the prepared solutions of concentrations of 10 and 200 mg/mL confirmed that the test substance is stable for 24 hours at room temperature and for 7 days at refrigeration. The prepared solutions were used within 7 days after preparation. Further, the uniformity of the prepared solutions of 10, 100 and 200 mg/mL was confirmed.
The concentration of the test substance in the prepared solutions of each concentration of the initial and final preparation was analysed. The content was 98.3 to 101.7 % of the prescribed concentration and therefore was regarded as appropriate.

Duration of treatment / exposure:

46 days

Frequency of treatment:

Once daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

250 mg/kg bw/day (nominal)

Dose / conc.:

500 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The doses of the test substance were set on the basis of the results of the preliminary test for the Combined Repeated Dose and Reproductive/Developmental Toxicity Screening Test of C.I. Pigment Yellow 53 in Rats (Test No. SR-9984P). In the preliminary test, the test substance was administered once a day for 14 days at doses of 0, 500, 1000, and 2000 mg/kg to five male and five female SD rats per group. No abnormalities except yellow feces were observed. Therefore the high dose in the main test was set to 1000 mg/kg bw/d and the lower doses were set at 500 and 250 mg/kg by dividing by a common ratio of 2, for both males and females.

Observations and examinations performed and frequency:

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

Sacrifice and pathology:

HISTOPATHOLOGY: Yes, for control and high dose animals

Statistics:

Please refer to "Any other information on materials and methods incl. tables"

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

Males: After administration day 2 until the necropsy day, yellowish brown feces in the 500 mg/kg group, and yellow or yellowish brown feces in the 1000 mg/kg group were observed in all of 12 rats of each group. In addition to this, fracture of incisor teeth was observed in one animal of the 250 mg/kg group on administration day 42, but this was considered accidental.

Females: After administration day 2 until the necropsy day, yellowish brown feces in the 500 mg/kg group, and yellow or yellowish brown feces in the 1000 mg/kg group were observed in all 12 rats of each group. In addition, alopecia was observed in one female in the control group after day 12 of pregnancy (5 days after delivery) until the necropsy day. The scab-formation on 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. These effects were considered non-treatment related.

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):

Males: In the 250 and 1000 mg/kg groups, a significant shortening of the activated partial thromboplastin time (APTT) was observed.
Females: In the 250 mg/kg group, significant high values of mean corpuscular hemoglobin (MCH) and platelet were observed, but these changes were not seen in the dose groups of 500 mg/kg or more.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

Males: A significant low value of potassium (K) was observed in the 1000 mg/kg group, but it was considered to have no toxicological significance.
Females: Compared with the control group, 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 organs, they were considered without relevance.

Urinalysis findings:

effects observed, non-treatment-related

Description (incidence and severity):

Males: In the 250 mg/kg group, a significant increase was observed in urine specific gravity, but it was a change that could not be seen in the dose groups of 500 mg/kg or more. As for each of the other items, there were no significant differences between the pigment administration groups and the control group.
Females: No effects obeserved

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Males: Yellowish green contents of the cecum were observed in one male of the 500 mg/kg group and in all the 12 males of the 1000 mg/kg group. Other abnormalities were not observed.
Females: In the control group, dilatation of the renal pelvis and alopecia were observed each in one female. Yellowish green contents of the cecum were observed in four females of the 500 mg/kg group. In the 1000 mg/kg group, yellow contents of the stomach and the cecum in one female and yellowish green contents of the cecum in eight females were observed. For the female in which yellow contents of the stomach and the cecum were observed no evidence of pregnancy was obtained. Moreover, in this animal yellowish-white liquid retention in the uterus as well as vaginal closure and yellowish-white liquid retention were observed.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Males: In the control group, myocardial degeneration of the heart, hyaline cast of the kidney, eosinophilic bodies of the proximal tubule epithelium, atrophy of the seminiferous tubules of testes and sperm granuloma of the epididymis were observed, each in one male, and lymphocyte infiltration of the prostate was found in six males. In the 1000 mg/kg group, 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.
No other significant differences were observed compared to the control group.
Females: In the control group, erosion of the tongue was observed in three animals, and focal necrosis of the liver, kidney cysts, dilatation of the renal pelvis, dilatation of the renal tubules, focal fibrosis of the kidney, mineralization in the cortico-medullary junction of the kidney, granuloma of the cervix, atrophy of the thymus, atrophy of the skin hair follicles and inflammation of the mammary gland were observed each in one case. 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.
For all the above changes, no significant difference was observed in the frequency of appearance, when compared to the control group.

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Details on results:

The substance did not cause any significant effect on growth, food consumption, clinical signs, hematology, biochemistry, organ weight and pathology.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed

Key result

Critical effects observed:

no

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Antimony nickel titanium rutile

EC Number:

701-459-6

Cas Number:

8007-18-9

Molecular formula:

Ni(x/3)Sb(2x/3)Ti(1-x)O2 0,1≤x≤0,3

IUPAC Name:

Antimony nickel titanium rutile

Test material form:

solid

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- lot No. of test material: 4879

Test animals

Species:

rat

Strain:

Sprague-Dawley

Remarks:

Crj; CD(SD)

Details on species / strain selection:

This strain was selected because this species is usually used in this kind of study and the laboratory has a high experience with this rat strain.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc. Atsugi 6/27 breeding center
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 10 wks
- Weight at study initiation: Males: 335 - 386 g; Females: 208 - 249 g
- Housing: individually (except for acclimatisation and mating period)
- Diet: ad libitum, γ-ray irradiation fixed feed CRF-1 (Oriental Yeast Co., Ltd)
- Water: ad libitum, tap water
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 3 (actual measured range of 20 - 24 °C)
- Humidity (%): 55 ± 10 (actual measured range of 45 - 66 %)
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 1% carmellose sodium aqueous solution

Remarks:

hereinafter referred to as 1% CMC-Na aqueous solution

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
After grinding the test substance in a mortar, it was weighed accurately per dose, suspended in 1% CMC-Na aqueous solution to have a predetermined concentration, and was dispersed using an ultrasonic device.

VEHICLE
- Concentration in vehicle: 10, 100, 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Lot/batch no. : 9318

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: 1 d
- Proof of pregnancy: vaginal plug or sperm in vaginal smear
- M/F ratio per cage: 1/1
- Length of cohabitation: 14 d
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individually

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

No details on the analytical measurements were given.
The analysis of the stability performed prior to administration for the prepared solutions of concentrations of 10 and 200 mg/mL, confirmed that the test substance is stable for 24 hours at room temperature and for 7 days at refrigeration. The prepared solutions were used within 7 days after preparation. Further, the uniformity of the prepared solutions of 10, 100 and 200 mg/mL was confirmed.
The concentration of the test substance in the prepared solutions of each concentration of the initial and final preparation was analysed. The content was 98.3 to 101.7 % of the prescribed concentration, and therefore was regarded as appropriate.

Duration of treatment / exposure:

Males: 46 days
Females: 42-46 days

Frequency of treatment:

Once daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

250 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

500 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The doses of the test substance were set on the basis of the results of the preliminary test for the Combined Repeated Dose and Reproductive/Developmental Toxicity Screening Test of C.I. Pigment Yellow 53 in Rats (Test No. SR-9984P). In the preliminary test, the test substance was administered once a day for 14 days at doses of 0, 500, 1000, and 2000 mg/kg to five male and five female SD rats per group. No abnormalities beside yellow feces were observed. Therefore the high dose in the main test was set to 1000 mg/kg bw/d and the lower doses were set at 500 and 250 mg/kg by dividing by a common ratio of 2, for both males and females.

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: mortality, behaviour, external appearance

BODY WEIGHT: Yes
- Time schedule for examinations:
Males: administration days 1, 2, 3, 5, 7, 10 and 14; then weekly until necropsy
Females: administrations days 1, 2, 3, 5, 7, 10 and 14; pregnancy days 0, 1, 3, 5, 7, 10, 14, 17 and 20 and lactation days 0, 1 and 4

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necropsy
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: all male animals; 6 lactating females per dosing group
- Parameters examined: Number of red blood cells (RBC), Hematocrit (Ht), Hemoglobin (Hb), Mean corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin concentration (MCHC), Reticulocyte count (Ret), Platelet count (Plat), White blood cell count (WBC), White blood cell percentage (Hemogram of WBC), Prothrombin time (PT), Activated partial thromboplastin time (APTT)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at necropsy
- Animals fasted: Yes
- How many animals: all male animals; 6 lactating females per dosing group
- Parameters examined: GOT, GPT, Alkaline phosphatase (ALP), γ-GTP, Glucose (Glu), Choline esterase (ChE), Total cholesterol (T-Cho), Phospholipid (PL), Triglyceride (TG), Total bilirubin (T-Bil), Urea nitrogen (UN), Creatinine (Crea), Sodium (Na), Potassium (K), Chloride (Cl), Calcium (Ca), Inorganic phosphorus (IP), Total protein (TP), A/G ratio (A/G)

URINALYSIS: Yes
- Time schedule for collection of urine: on administration days 44 - 45
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No
- Parameters examined: pH, protein, glucose, ketone bodies, urobilinogen, bilirubin, occult blood, sediment, color, volume, specific gravity

Oestrous cyclicity (parental animals):

For all females, every day from 10 days prior to dosing until successful copulation, vaginal smear samples with Giemsa staining were prepared and their estrous cycle phases (proestrus, estrus, metestrus, diestrus) were determined under an optical microscope and a cycle of repeating each phase of estrous cycle two or more times at an interval of 4 to 5 days was regarded as normal. Continuation of diestrus for 7 days or more was judged to be an abnormal estrous cycle. Estrus interval was calculated from estrous cycle of each female.

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):

SACRIFICE
- Male animals: All surviving animals (on the day after administration Day 46)
- Maternal animals: All surviving animals (until Day 5 post partum)

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated below were prepared for microscopic examination:
Brain (cerebrum, cerebellum), pituitary, thymus, thyroid (left and right), parathyroid (left and right), adrenal gland (left and right), spleen, heart, thoracic aorta, tongue, esophagus, stomach (forestomach and glandular stomach), liver, pancreas, duodenum, jejunum, ileum (including Peyer's patches), cecum, colon, rectum, larynx, trachea, lung (including bronchial), kidney (left and right), bladder, testes (left and right), epididymis (left and right), prostate, seminal vesicles (including coagulation glands, left and right), eye (left and right), harderian gland (left and right), skin (right abdomen), sternum (including bone marrow), femur (including bone marrow, right), spinal cord (neck), skeletal muscle (right thigh), mesenteric lymph node, mandibular lymph nodes (left and right), submandibular gland (left and right), sublingual gland (left and right), parotid gland (left and right) and the sciatic nerve (right).

The following organs were weighed:
Brain, heart, liver, kidney (left and right), spleen, adrenal glands (left and right), thymus, testis (left and right) and epididymis (left and right), ovary (left and right)

Postmortem examinations (offspring):

SACRIFICE
- The offspring was sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of external examination (including the inside of the mouth) and internal examinations including the cervical, thoracic, and abdominal viscera

Statistics:

Please refer to "Any other information on materials and methods incl. tables"

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, non-treatment-related

Description (incidence and severity):

Males: After administration day 2 until the necropsy day, yellowish brown feces in the 500 mg/kg group, and yellow or yellowish brown feces in the 1000 mg/kg group were observed in all of 12 rats of each group. In addition to this, fracture of incisor teeth was observed in one animal of the 250 mg/kg group on administration day 42, but this was considered accidental.

Females: After administration day 2 until the necropsy day, yellowish brown feces in the 500 mg/kg group, and yellow or yellowish brown feces in the 1000 mg/kg group were observed in all 12 rats of each group. In addition, alopecia was observed in one female in the control group after day 12 of pregnancy (5 days after delivery) until the necropsy day. The scab-formation on 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. These effects were considered non-treatment related.

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):

Males: In the 250 and 1000 mg/kg groups, a significant shortening of the activated partial thromboplastin time (APTT) was observed.
Females: Significant high values of mean corpuscular hemoglobin (MCH) and platelet were observed in the 250 mg/kg group, but not in the higher dosing groups.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

Males: A significant low value of potassium (K) was observed in the 1000 mg/kg group, but it was considered to have no toxicological significance.
Females: Compared with the control group, a significant low value of cholinesterase (ChE) in the 250 mg/kg group, a significant low value of sodium (Na) in the 500 mg/kg group, and a significant low value of GPT in the 1000 mg/kg group were observed, but, since there were no changes found in the related organs, this was considered as non treatment related.

Urinalysis findings:

effects observed, non-treatment-related

Description (incidence and severity):

In the 250 mg/kg group, significant increase was observed in urine specific gravity in the 250 mg/kg group, but not in the higher dosing groups. No other urine parameter was altered compared to the control group.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Males: In the control group, myocardial degeneration of the heart, hyaline cast of the kidney, eosinophilic bodies of the proximal tubule epithelium, atrophy of the seminiferous tubules of testes and sperm granuloma of the epididymis were observed each in one male. Lymphocyte infiltration of the prostate was found in six other males. In the 1000 mg/kg group, 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.
No other significant differences were observed compared to the control group.
Females: In the control group, erosion of the tongue was observed in three animals, and focal necrosis of the liver, kidney cysts, dilatation of the renal pelvis, dilatation of the renal tubules, focal fibrosis of the kidney, mineralization in the cortico-medullary junction of the kidney, granuloma of the cervix, atrophy of the thymus, atrophy of the skin hair follicles and inflammation of the mammary gland were observed each in one case. 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). The atresia of vagina was a congenital anomaly and it was considered as the cause of infertility.
For all the above changes, no significant difference was observed in the frequency of appearance, when compared to the control group.

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Reproductive performance:

effects observed, non-treatment-related

Description (incidence and severity):

As for the incidence of females with normal estrous cycle, 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, compared to the control 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 substance related. One non-pregnant female was observed in the 1000 mg/kg group. For this female, the atresia of vagina was observed in the pathological examination. This was assumed to cause infertility and it was considered to be the cause of infertility.
As for the number of corpora lutea, number of implantation sites, implantation index, total number of pups born, the sex ratio of pups born, number of live pups on lactation day 0, live birth index, number of live pups on lactation day 4, newborn viability index, there was no significant difference observed in each administration group, compared with the control group. Delivery index was significantly decreased in the 250 mg/kg group, but this was considered as an incidental variation since there was no significant difference observed in the dose groups of 500 mg/kg or more.

Effect levels (P0)

Key result

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 in the parental generation.

Target system / organ toxicity (P0)

Key result

Critical effects observed:

no

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

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

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

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.
Yellowish white portion of the liver was observed in one male of 250 mg/kg group and in one male of the 1000 mg/kg group, for the pups necropsied on day 4 of lactation. Trauma was noted for one female of the 500 mg/kg group. But no other abnormalities were 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)

Key result

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 in the offspring.

Target system / organ toxicity (F1)

Key result

Critical effects observed:

no

Overall reproductive toxicity

Key result

Reproductive effects observed:

no