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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: According to OECD 421
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2009-12-10 to 2010-06-15
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was conducted with a similar substance according to standard methods and GLP, therefore it is considered reliable and relevant, but as it is only a screening study, not adequate for classification. Various anchor points demonstrated a similar structural and physicochemical characteristics and comparable toxicological profile ( acute toxicity, genotoxicity and local tolerance endpoints), showing that read-across can be considered adequate.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
adopted by the Council on July 27th 1995
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): Tin Sulfide
- Molecular formula (if other than submission substance): SSn
- Molecular weight (if other than submission substance): 150.776
- Smiles notation (if other than submission substance): [SnH2]=S
- InChl (if other than submission substance): 1S/S.Sn
- Substance type: Inorganic monoconstituent
- Physical state: Dark grey powder
- Analytical purity: ca. 97.6% (77.5% Sn, 20.1% S)
- Lot/batch No.: CH S80774
- Expiration date of the lot/batch: Till 08/2011
- Stability under test conditions: In the time period used for the handling with suspension in this study, Tin sulfide was stable and not decomposed. ( The application form of Tin sulfide was prepared daily in the morning and it was immediately administered to animals.)
- Storage condition of test material: In supplied glass container in the dark and in dry room, at the ambient temperature

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: SPF Breeding, VELAZ s.r.o., Koleč
- Age at study initiation: 10 weeks
- Weight at study initiation: Males average 317.67 g; Females average 212.17 g
- Fasting period before study: Not provided
- Housing: In SPF animal room, 2 rats of the same sex in one plastic cage (40x25x20 cm) containing sterilized clean shavings of soft wood. During mating period-one male and one female in one cage, pregnant females-individually, offspring-with mother.
- Diet (e.g. ad libitum): Complete pelleted diet for rats and mice in SPF breeding –ST 1 BERGMAN (Mlýn Kocanda, Výroba krmných smesi, Kocanda No. 19, 252 42 Jesenice u Prahy. Diet was sterilized before using.
- Water (e.g. ad libitum): Water was sterilized before using, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): 30-70%
- Air changes (per hr): 15/h
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% methylcellulose in water for injection
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The concentrations of the suspensions at all dose levels were adjusted to ensure the administration of 1 mL per 100 g of body weight. The vehicle control group was administered by 0.5% methylcellulose in water for injection in the same volume. The application form (test susbstance suspension in 0.5% methylcellulose in water for injection) was prepared daily just before administration. This suspension was mixed for 10 minutes by magnetic stirrer (ca. 1000 rpm).


VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:
- Amount of vehicle (if gavage):
- Lot/batch no. (if required): methylcellulose: DT223712; water for injection: 0204101109, 0101011209
- Purity:

Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: until day 0 of pregnancy
- 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:
Analytical report includes the results of testing a homogeneity of Tin sulfide application form.
The application form for "Tin sulfide- Reproduction/Developmental Toxicity Screening Test" is the suspension of test substance in 0.5% methylcellulose. The test purpose was found out whether the application form prepared is homogenous.
Homogeneity of the application form was checked by determination of a concentration of the test subs tance in three levels of solution (at the bottom, in the middle and at the surface ).
The measurement was performed on two concentration levels (50 mg / 10 mL and 1000 mg / 10 mL).
The application form was prepared in a way that is conformable with "Tin sulfide – Reproduction/Developmental Toxicity Screening Test" (the similar equipment: container, mixing stirrer). The analyses were performed by ICP - OE spectrophotometric method.
From the results of analyses follows that the Tin sulfide application form in vehicle at defined laboratory conditions (laboratory temperature, preparation of solution by defined manner) is homogeneous.
The differences in concentrations detected on the single levels of measurement to average are less then uncertainty of measurement.
Duration of treatment / exposure:
The treated groups were administered daily for the following periods:
-males and females : 2 weeks prior to the mating period and during the mating period
-pregnant females: during pregnancy and till the 3rd day of lactation
-males: after mating period; totally for 42 days
-non-pregnant females (mated females without parturition): for 25 days after the confirmed mating
Frequency of treatment:
once per day, 7 days per week
Details on study schedule:
- Age at mating of the mated animals in the study: 12 weeks (10 weeks at start of study; mating from
the 15th day of study)
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The dose levels for study- 100, 300 and 1000 mg/kg/day -were chosen with respect to the results of the dose-range finding experiment and on request of the sponsor.
The DRF experiment with 14-day application period was performed with 4 groups of treated rats.
The doses for the DRF experiment were chosen with respect to the literature data : 125, 250, 500 and 1000 mg/kg/day. In the DRF experiment with Tin sulfide, the body weight increments and haematological parameters were relatively well-balanced at all dose levels during the 14-day application
period. The pathological examination did not reveal any pathological changes. No animal died during the 14-day application period.
- Rationale for animal assignment (if not random): random
Positive control:
no

Examinations

Parental animals: Observations and examinations:
Health condition control: daily - during the acclimatization and the experimental part;
Body weight: males - the first day of administration and then weekly,females - the first day of administration and then weekly in prematingand mating period; during pregnancy: 0., 7th, 14th, 20th day; during lactation: 0. or 1st and 4th day;
Food consumption: males- weekly (except the mating period), females - weekly during premating period and after mating period, during pregnancy and lactation on the same days as body weight;
Clinical observations: males and females - daily during the administration period;
Mortality control: daily.
Oestrous cyclicity (parental animals):
The oestrous cycle length and pattern was not evaluated before mating but the phases of oestrous
cycle were recorded during histopathological examination.
Sperm parameters (parental animals):
In all males of all groups surviving to scheduled necropsy the sperm parameters were examined: sperm motility and sperm morphology. Sperm specimens were prepared and examined according to the SOP No. M/45.
Sperm motility:
Sperm samples were taken from one epididymis and sperm motility was assessed from these samples. The motility of sperm was determined by microscopic examination of the prepared sperm suspension (mixture of one epididymis cutted into pieces and 5 ml of 0.9% NaCl). The result of obser
vation was evaluated subjectively according to following grades: 1 - fast progressive motility, 2 - slow progressive motility, 3 -no progressive motility, 4- nonmotile sperm.
Sperm morphology:
Sperm samples (taken from one epididymis) and sperm morphology was assessed from these samples. A smear from the sperm suspension was prepared and stained (Giemsa staining). The morphology of sperm was determined by microscopic examination. All deviations - e.g. broken tail,
abnormal form of tail, double head, amorphous head and abnormal form of neck - were recorded.
Litter observations:
All pups were observed in natural conditions in their cages daily during the lactation period. Changes in behavioural abnom1alities were recorded. Detailed examination of each litter was performed as soon as possible after delivery (day 0 or 1 post-partum) and the 4th day of lactation. The number and sex of pups, stillbirths, live births and presence of gross anomalies were recorded.
Postmortem examinations (parental animals):
Parental males were killed at the end of the administration period after 42 days of administration.
Parental females were killed on the 4th day of lactation. Mated females without delivery was killed 26th day after confirmed mating. Then they were macroscopically examined for any pathological changes with special attention to the organs of the reproductive systems. All macroscopic abnormalities were recorded. The absolute weights of testes, one epididymis, prostate gland and pituitary gland were recorded in males and absolute weight of ovaries; uterus (incl. uterine tube and cervix) and pituitary gland were recorded in females. Afterwards the relative weight of the organ was computed according to the following formula: weight of organ x 100/ body weight.
Postmortem examinations (offspring):
Dead pups were sexed and externally examined; the stomach was examined for the presence of milk. Pups killed on the 4th day of lactation were sexed and subjected to external examination of the cranium, and to macroscopic examination of the thoracic and abdominal tissues and organs. All ma croscopic changes were recorded.
Statistics:
The ANOVA test –Analysis of Variance (QC. Expert 2.5) at significance level 0.05 was used for the statistical analysis. This statistical analysis was used for the results of body weight –necropsy weight in males, body weight of females on the 20th day of pregnancy, necropsy weight of females; biometry of organs of males and females; number of live pups on the 0/1st day and 4th day of lactation period and average weight of pup on the 0/1st day and 4th day of lactation period. Control group with vehicle was compared with the three treated groups.
The results statistically significant on probability level 0.05 are indicated by figures with asterisk in the summary tables (no findings at probability level 0.01 and 0.001).
Reproductive indices:
Reproduction parameters: number of females achieving pregnancy, number of females bearing live pups and number of females with live pups at day 4 after parturition in treated groups were similiar to the control or higher than the control groups. Duration of mating and pregnancy were similar in the control and treated females. Pre-implantation, post-implantation and postnatal losses were relatively well balanced at the treated groups and control group.
Offspring viability indices:
Pre-implantation loss, post-implantation loss, post-natal loss, mating index, fertility index, conception index, gestation index, percentage of postnatal loss days 0-4 post partum and viability index were calculated.

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related effects were found in treated males during the health condition control.
No relevant clinical changes were observed in males at all dose levels after application of the test substance.
Slight fall of weight ( one male at the dose level of 100 mg/kg/day in the 6th week) and thinner excrements ( one male at the dose of 1000 mg/kg/day in the 1 st week) were observed sporadically in treated males.
Females:
Slight decreases in body weights were sporadically (in 1 or 2 females from the group) recorded in the 3rd week at all groups including control.
In treated females of all dose levels, no signs of disease were found during the check-in, acclimatisation and application period. Treatment-related effects were not detected during health condition control and clinical observation of females ( except of vocalisation in one female at the dose level of 1000 mg/kg/day in the 5th week).
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The average animal body weights at all dose levels were relatively balanced with the control group during the whole application period. No statistically significant differences were detected.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Males: Average food consumption values of males at all treated close levels were slightly increased against the control group during the whole study. These differences were not dependent on the dose level and therefore not considered relevant.
Females:
Pre-mating period
Average food consumption of treated females was analogous to food consumption of control females.
Pregnancy
Females without parturition (non pregnant or aborted females) were not included in the evaluation of food consumption during pregnancy. Average food consumption of treated females was wellbalanced with control females.
Lactation
Only mothers (females with live pups) were included in evaluation of food consumption during lactation period. Average food consumption of treated females was similar to consumption of control females.
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:
effects observed, treatment-related
Description (incidence and severity):
Absolute weight of pituitary gland was increased in males at 1000 mg/kg bw/day. In absence of any changes of microscopic structure the effect was considered not to be of toxicological importance.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Males: Examination of the external surface of the body, thoracic and cranial cavity revealed no macroscopic changes in treated and control animals. In the abdominal cavity, decrement of prostate gland was detected in one control male, one male at the dose level of 100 mg/kg/day and one male at the dose level of 300 mg/kg/day. These changes were not treatment related.
Females: The incidence of affected females is expressed in numeric form and ranged in sequence of the dose levels of 0-100-300-1000 mg/kg/day further in the text. Examination of the external surface of the body revealed no changes. In the thoracic and abdominal cavities, no changes were observed. In the pelvic area, dilatation of uterine horns by clear liquid was detected in 3-1-1-0 females. No other macroscopic findings were recorded.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The effect on the microscopical structure of the testes (sporadic degeneration and/or atrophy of germ epithelium, residual bodies in germ epithelium and vacuolation of cytoplasm of spermiogonia) had no effect on spermiogenesis, thus, were not relevant.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

Body weight, food consumption, clinical status and macroscopic structure of reproductive organs of treated parental males were unaffected by treatment of the test substance. An absolute weight of pituitary gland was statistically significantly incrased in males at the dose level of 1000 mg/kg/day. In absence of any changes of microscopic structure of the pituitary gland, the effect could be considered not to be of toxicological importance. The test substance had effect on the microscopical structure of the tests without damage of spermiogenesis. Histopathological examination of tests of parental males showed increased incidence of irrelevant changes: degenerations and/or atrophies of germ epithelium and vacuolations of cytoplasm of spermiogonia in males of the dose level 1000 mg/kg/ day. Food consumption, clinical observations, weight and structure of reproductive organs of treated parental females were not significantly affected by treatment of the test substance. Growth of parental females was slightly but insignificantly influenced by the test substance administration: the body weight of females at the dose levels of 300 and 1000 mg/kg/day were slightly decreased during the pregnancy and lactation period.
Reproduction parameters - number of females achieving pregnancy, number of females bearing live pups and number of females with live pups at day 4 after parturition in treated groups were similar to the control or higher than the control groups. Duration of mating and pregnancy were similar in the control and treated females. Pre-implantation, post-implantation and postnatal losses were relatively well balanced at the treated groups and control group.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Remarks:
for the REPRODUCTION
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: See full study report
Dose descriptor:
NOEL
Remarks:
toxic effect on reproduction organs
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
organ weights and organ / body weight ratios
histopathology: non-neoplastic
Dose descriptor:
NOEL
Remarks:
toxic effect on reproductive organs
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive performance

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Description (incidence and severity):
One pup of control group and one pup of the dose level 300 mg/kg/day died after birth – in the period 0/1st day - 4th day.
No differences in development of pups were observed at the control group and at all treated groups.
Statistical evaluation was performed on the number of live pups.The total numbers of live pups (on the day of parturition/1st day after parturition and the 4th day after parturition) were similar at the control and the dose level 1000 mg/kg. At the dose level 100 mg/kg/day the number was higher, and vice versa at the dose level 300 mg/kg/day, it was slightly lower.
Average numbers of pups per litter were well-balanced at the control and the dose level 100 mg/kg/day. At the dose levels 300 and 1000 mg/kg/day, the average number of pups per litter was decreased compared to the control, however they fell within the normal range of historical control data.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The average weights of the litters and pups at the dose level 100 mg/kg/day were slightly increased against control. At the dose levels of 300 and 1000 mg/kg/day, the average weight of the litter was lower compared to control, but the average body weights of pups were slightly higher compared to control group. No statistically significant changes were found.
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:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
The macroscopical examination was performed in all pups. Sporadic pathologic findings were recorded in pups of the treated and control groups. The number of pups with macroscopic changes was comparable in the control and 100 and 300 mg/kg dosed groups; an increase in livers with
marked structure was noted in the 1000 mg/kg dose group.
Histopathological findings:
no effects observed
Description (incidence and severity):
The microscopical examination was performed in the pups with macroscopic changes: susp. hydrocephalus (litter No. 142 at the dose level 300) - no histopathological changes in cranial cavity; dark spot on testis (litter No. 167 at the dose level 1000) - no histopathological changes on testis and epididymis; oversized teeth (litter No. 127 at the dose level 100) – no histopathological changes and marked structure of liver (litter No. 164 and 171 at the dose level 1000) – extramedullary haemopoiesis was recorded (it is a physiological finding in pups).

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Details on results (F1)

The number of corpora lutea, implantations, number of pups and accompanied weight of litter were slightly but insignificantly influenced by the administration of the test substance (decrease esp. at dose levels 300 and 1000 mg/kg/day). Sex ratio, average weight of pups and postnatal development of pups were unaffected. Macroscopic abnormalities were described sporadically in pups of all treated and the control groups.

Effect levels (F1)

Dose descriptor:
NOAEL
Remarks:
for the development
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
gross pathology

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Table 1. Observation of sperm-Males

Observation of sperm – MALES(average)

Observed parameters

Dose level (mg/kg/day)

0

100

300

1000

Sperm motility (grade)

1.4

1.5

1.5

1.6

Sperm motility(grade/number of males)

1/8

2/4

 1/8

 2/3

 3/1

1/8

2/3

3/1

1/7

2/4

3/1

Sperm morphology

(percentage of affected sperms)

10.58 %

6.17 %

10.92 %

6.00 %

- Flattened head

7.25 %

3.83 %

8.25 %

4.25 %

- Bent neck

2.25 %

1.33 %

1.42 %

1.25 %

- Bent tail

1.08 %

1.00 %

1.25 %

0.50 %

Note: Sperm motility: 1 - fast progressive motility, 2 - slow progressive motility,

                                   3 - no progressive motility, 4 - non-motile sperm.

 Sperm morphology: flattened head, bent neck, bent tail

Table 2. Microscopic findings-Males

Microscopic findings – MALES (numberof affected animals)

Histopathological findings

Dose level(mg/kg/day)

0

100

300

1000

 Number of examined animals

12

12

12

12

 Without pathologic changes

6

6

2

0

Epididymides:interstitium and epithelium - slight lymphocyte infiltration (non-pathological finding)

12

12

12

12

Epididymides:cell detritus in sporadic tubules

1

0

0

0

Pituitary gland:cyst

0

1

0

0

Prostate gland:atrophy of alveolar epithelium

0

0

3

0

Prostate gland:functional hyperplasia

0

0

4

3

Prostate gland:lymphocyte infiltration

4

4

0

1

Seminal vesicles:atrophy of epithelium

0

0

2

0

Testes:alteration of germinative epithelium

0

1

0

0

Testes -sporadic tubules: degeneration and/or atrophy of germinative epithelium

0

2

2

5

Testes-less than 10% of tubules: degeneration and atrophy of germinative epithelium

0

0

0

2

Testes:residual bodies in germinative epithelium (stage IX) 

0

0

0

9

Testes:sloughing of germinative epithelium into lumen of some tubules

0

2

0

0

Testes -sporadic tubules:vacuolation of cytoplasm of sporadic spermiogonia

1

0

4

12

 

Table 3. Microscopic findings-Females

Microscopic findingsFEMALES(number of affected animals)

Pathological findings

Dose level

0

100

300

1000

 Number of examined animals

12

12

12

12

 Without pathologic changes

6

9

7

6

 Uterus:hydrometra

2

2

1

0

 Uterus:fibrosis of endometrial stroma

1

0

0

0

 Uterus:hyalinization of arteria wall

0

0

0

1

 Ovaries:hyperplasia of interstitial glands

3

0

4

5

 Ovaries:follicular cyst

1

1

0

1

 Ovaries:tubular structures in medulla and hillus

0

0

0

1

 

Table 4. Number of live pups and sex

Number of live pups and sex(average per litter)

Dose level

0

100

300

1000

Day of study

Number of males and females

Number of males and females

Number of males and females

Number of males and females

0/1 - parturition

(first check of litter)

44 M

51 F

59 M

54 F

 47 M

 39 F

50 M

45 F

4thday of lactation

43 M

51 F

59 M

54 F

 46 M

 39 F

50 M

45 F

 

Table 5. Average body weight-Pups

Average body weight- PUPS(grams)

Dose level

0

100

300

1000

Day of study

Pup

Pup

Pup

Pup

0/1 – parturition (first check of litter)

6.04

6.25

6.08

6.17

4thday of lactation

8.74

8.90

9.24

9.57

Note: No statistically significant changes were found on probability level 0.05 (ANOVA test).

Table 6. Reproduction data

Reproduction data

                                            Observed parameters

Dose level

0

100

300

1000

 Pairs started (N)

12

12

12

12

 Females showing evidence of copulation (N)

11*

12*

12

12

 Females achieving pregnancy (N)

8

10

8

9

 Conceiving days 1 – 5 (N)

11*

11*

12

11

 Conceiving days 6 – 13 (N)

0

0

0

1

 Pregnancy ≤ 21 days (N)

3

3

4

2

 Pregnancy = 22 days (N)

2

5

2

3

 Pregnancy ≥ 23 days (N)

2

0

1

3

 Females with live pups born (N)

7

8

7

8

 Females with live pups at day 4 after parturition (N)

7

8

7

8

 Corpora lutea (average)

15.13

13.20

13.00

13.11

 Implantations (average)

13.00

12.40

11.25

11.89

 Live pups/mother at birth (average)

13.57

14.13

12.29

11.88

 Live pups/mother at day 4 after parturition (average)

13.43

14.13

12.14

11.88

 Sex ratio (M/F) at birth (average in %)

46/54

52/48

55/45

53/47

 Sex ratio (M/F) at day 4 after parturition (average in %)

46/54

52/48

54/46

53/47

 Litter weight at birth (g-average)

81.23

88.25

73.46

71.00

 Litter weight at day 4 after parturition (g - average)

115.63

125.51

110.77

109.79

 Pup weight at birth (g - average)

6.04

6.25

6.08

6.17

 Pup weight at day 4 after parturition (g - average)

8.74

8.90

9.24

9.57

Note:  (N)number of animals *presence of sperms was not found in females No. 106 (control) and 128 (100 mg/kg/day), female No. 106 - probably nonmated, female No. 128 mated and aborted (during necropsy implantations in uterus were found); in females No. 106 and 128 the duration of mating (conceiving days) was not determined 

 

Table 7. Fertility parameters

Fertility parameters

Calculated parameters

Dose level

0

100

300

1000

 Mating index

91.67

100.00

100.00

100.00

 Fertility index

72.73

83.33

66.67

75.00

 Conception index

66.67

83.33

66.67

75.00

 Gestation index

87.50

80.00

87.50

88.89

 Percentage of postnatal loss

1.05

0.00

1.16

0.00

 Viability index

98.95

100.00

98.84

100.00

Loss of offspring

 

 Pre-implantation

(corpora lutea minus implants)

 

 Pregnant females with 0 (N)

4

4

2

5

 Pregnant females with 1 (N)

1

5

4

2

 Pregnant females with 2 (N)

1

0

0

1

 Pregnant females with ≥ 3 (N)

2

1

2

1

 Post-implantation

(implants minus live births)

 

 Pregnant females with 0 (N)

3

6

6

3

 Pregnant females with 1 (N)

3

1

0

3

 Pregnant females with 2 (N)

1

2

2

2

 Pregnant females with ≥ 3 (N)

1

1

0

1

 Post-natal

 (live births minus alive at post-natal day 4)

 

 Pregnant females with 0 (N)

6

8

6

8

 Pregnant females with 1 (N)

1

0

1

0

 Pregnant females with 2 (N)

0

0

0

0

 Pregnant females with ≥ 3 (N)

0

0

0

0

Applicant's summary and conclusion

Conclusions:
A reproduction and development toxicity screening study according to OECD guideline 421 in rats with tin sulfide revealed the following values:
NOAEL for the Reproduction: 1000 mg/kg bw/day
NOEL for the toxic effect on reproduction organs of males: 300 mg/kg bw/day
NOEL for the toxic effect on reproduction organs of females: 1000 mg/kg bw/day
NOAEL for the Development of pups: 1000 mg/kg bw/day
Executive summary:

This OECD Screening Test Guideline 421 can be used to provide initial information on possible effects on reproduction and/or development, either at an early stage of assessing the toxicological properties. Males were dosed for a minimum of four weeks and up to and including the day before scheduled kill (this includes a minimum of two weeks prior to mating, during the mating period and, approximately, two weeks post-mating). Females were dosed for a minimum of two weeks prior to mating, during mating and pregnacy and till the third day of lactation. In view of the limited pre-mating dosing period in males, the combination of a pre-mating dosing period of two weeks and subsequent mating/fertility observations, followed by detailed histopathology of the male gonads, is considered sufficient to enable detection of the majority of effects on male fertility and spermatogenesis.

Body weight, food consumption, clinical status and macroscopic structure of reproductive organs of treated parental males were unaffected by treatment of the test substance. An absolute weight of pituitary gland was statistically significantly increased in males at the dose level of 1000 mg/kg/day, however in absence of any changes of microscopic structure of the pituitary gland, the effect could be considered not to be of toxicological importance. The test substance had effect on the microscopical structure of the testes without damage of spermiogenesis. Histopathological examination of tests of parental males showed increased incidence of irrelevant changes: degenerations and/or atrophies of germ epithelium and vacuolations of cytoplasm of spermiogonia in males of the dose level 1000 mg/kg/ day. Food consumption, clinical observations, weight and structure of reproductive organs of treated parental females were not significantly affected by treatment of the test substance. Growth of parental females was slightly but insignificantly influenced by the test substance administration: the body weight of females at the dose levels of 300 and 1000 mg/kg/day were slightly decreased during the pregnancy and lactation period.

In conclusion, NOAEL for the Reproduction was 1000 mg/kg bw/day, NOEL for the toxic effect on reproduction organs of males was 300 mg/kg bw/day, NOEL for the toxic effect on reproduction organs of females was 1000 mg/kg bw/day.