Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study

Data available for the read across chemicals was reviewed to determine the reproductive toxicity of

Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate

.Based on the data available for the read across chemical, No Observed Adverse Effect Level (NOAEL) was considered to be above 500 -1000mg/kg bw . Thus, comparing this value with the criteria of CLP regulation

Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate

not likely to classify as reproductive toxicant.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Experimental data of read across substances
Justification for type of information:
Data for the target chemical is summarized based on the structurally similar read across chemicals
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
WoE report is based on two reproductive toxicity studies on rats 1.Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test of test material in Rats.2.Reproductive and developmental toxicity study of test material was performed on wistar rats.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: 1.Crj: CD(SD) 2.Harlan-Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Age at study initiation of dosing: 9 weeks old
Route of administration:
other: 1.oral; gavage 2.oral: feed
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: Study 1.0.5 w/v% CMC-Na solution containing 0.1 w/v% Tween 80
Details on exposure:
1.PREPARATION OF DOSING SOLUTIONS: Test substance suspended in 0.5 w/v% CMC-Na solution containing 0.1 w/v% Tween 80 at 0, 40, 200 and 1000 mg/kg bw DIET PREPARATION - Rate of preparation of diet (frequency): - Mixing appropriate amounts with (Type of food): - Storage temperature of food: VEHICLE - Justification for use and choice of vehicle (if other than water): 0.5 w/v% CMC-Na solution containing 0.1 w/v% Tween 80 - Concentration in vehicle: 0, 40, 200 and 1000 mg/kg bw - Amount of vehicle (if gavage): - Lot/batch no. (if required): - Purity:
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
1.Male: 42 dayFemale: 41 - 48 days (from 14 days before mating to day 4 of lactation)2. upto 3 generation
Frequency of treatment:
Daily
Details on study schedule:
not specified
Remarks:
Study 1.0,40,200,1000mg/kg bw Study 2.0, 5, 50, 150 or 500 mg/kg
No. of animals per sex per dose:
Study 1.Total: 1060 mg/kg/day: 7 male, 12 female 40 mg/kg/day: 12 male, 12 female200 mg/kg/day: 12 male, 12 female1000 mg/kg/day: 7 male, 12 femaleRecory group:0 mg/kg/day: 5 male, 5 female 1000 mg/kg/day: 5 male, 5 femaleStudy 2.10 male and 20 female
Control animals:
yes, concurrent vehicle
Details on study design:
not specified
Positive control:
not specified
Parental animals: Observations and examinations:
Study 1. Survival, clinical sign, body weigth, food consumption and urineanalysis and FOB were examiined.
Oestrous cyclicity (parental animals):
Study 1. Estrous cyclicity, copulation and implantation were examined.
Sperm parameters (parental animals):
not specified
Litter observations:
Study 1. Number of pups, number of live pups, sex ratio on days 0 and 4, clinical signs and body weight were examined.
Postmortem examinations (parental animals):
Study 1. Hematology , clinical chemisrty , Oragn weight, gross pathology and histopathology were examined.
Postmortem examinations (offspring):
Study 1. Gross pathology were examined.
Statistics:
not specified
Reproductive indices:
Study 1. Fertility rat, gestation period, implantation index, live birth index, delivery index, parturition, or maternal behavior were examined.
Offspring viability indices:
Study 1. Viability index on 0 and 4 day were examined.
Clinical signs:
no effects observed
Description (incidence and severity):
Study 1. No clinical signs were observed in treated rats as compared to contorl.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
Study 1. No effect on survival of treated rats were observed at 40, 200 and 1000 mg/kg bw as compared to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Study 1. No change in body weight were observed in treated rats as compared to control.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Study 1. No change in food consumption were observed in treated rats as compared to control.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
Study 1. No changes in hematological parameters were observed in treated male and female rats as compared to control.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Study 1. No changes in clinical chemisrty were observed in treated male and female rats as compared to control.
Urinalysis findings:
no effects observed
Description (incidence and severity):
Study 1. No effect was observed in male rats as compared to control.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Study 1. No changes in behavior test were observed in treated male and female rats as compared to control.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Study 1. Focal necrosis of mucosa and hyperplasia of gastric pits in the glandular stomach were observed in female rat at 200 and 1000 mg/kg bw. The focal necrosis of mucosa is occasionally seen in the mucosa of the glandular stomach when the chemical compounds are administrated. Many of these induced changes have reversibility. focal necrosis of mucosa were not noted at the end of the recovery period, indicating reversibility. The hyperplasia of mucosal epithelium in the glandular stomach was considered to be a regeneration or restoration image against early epithelium disorder. The image of hyperplasia disappeared by complete repairing at the end of the recovery period.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
Study 1. No effect on Estrous cyclicity, copulation and inplantation were observed.
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
Study 1 & 2. No effect on Reproductive performance of treated male and female rats were observed as compared to control.
Dose descriptor:
NOAEL
Effect level:
> 500 - <= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
gross pathology
neuropathology
reproductive function (oestrous cycle)
reproductive performance
other: No effect observed
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
no effects observed
Description (incidence and severity):
Study 1. No Clinical signs were observed in treated pups as compared to control.
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
Study 1. No effect on suvival of pups were observed as compared to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Study 1. No effect on body weight of pups were observed as compared to control.
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
Study 1. No gross pathological changes were observed in treated pups as compared to control.
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 500 - <= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
gross pathology
other: No effect observed
Remarks on result:
other: overall no effects on developmental parameters
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Absolute and relative organ weights in rats treated orally with test material in the combined repeated dose and reproductive/developmental toxicity screening test

Sex                      

Dose level (mg/kg)

Administration period

Recovery period

0

40

200

1000

0

1000

Male

Number of animals

5

5

5

5

5

5

Final body weight(g)

493.1 ± 35.9(7)a)

480.7 ± 33.6(12)

486.2 ± 27.2(12)

466.6 ± 28.1(7)

503.8 ± 12.5

510.0 ± 19.2

Absolute organ weight

 

 

 

 

 

 

Brain(g)

2.154 ± 0.079

2.122 ± 0.136

2.132 ± 0.061

2.064 ± 0.093

2.112 ± 0.030

2.168 ± 0.077

Thymus(mg)

359.2 ± 76.7

359.8 ± 105.9

334.0 ± 53.8

379.0 ± 39.2

368.2 ± 81.3

279.8 ± 52.8

Heart(g)

1.466 ± 0.171

1.528 ± 0.147

1.572 ± 0.156

1.648 ± 0.210

1.636 ± 0.145

1.636 ± 0.193

Liver(g)

12.088 ± 1.724

11.506 ± 0.575

12.304 ± 0.993

11.750 ± 0.792

13.082 ± 0.587

12.634 ± 0.882

Spleen(g)

0.826 ± 0.112

0.802 ± 0.087

0.756 ± 0.078

0.798 ± 0.099

0.782 ± 0.070

0.794 ± 0.145

Kidneys(g)

3.268 ± 0.364

3.172 ± 0.288

3.206 ± 0.320

3.002 ± 0.119

3.218 ± 0.133

3.376 ± 0.285

Adrenals(mg)

72.00 ± 15.34

65.94 ± 7.89

66.40 ± 7.42

66.04 ± 8.25

66.96 ± 7.48

64.50 ± 9.45

Testes(g)

3.339 ± 0.294(7)

3.440 ± 0.291(12)

3.472 ± 0.277(12)

3.554 ± 0.236(7)

3.284 ± 0.252

3.232 ± 0.631

Epididymides(g)

1.350 ± 0.085(7)

1.388 ± 0.083(12)

1.376 ± 0.082(12)

1.406 ± 0.089(7)

1.438 ± 0.121

1.340 ± 0.241

Relative organ weight

Brain(g%)

0.442 ± 0.035

0.452 ± 0.018

0.450 ± 0.032

0.444 ± 0.036

0.418 ± 0.013

0.426 ± 0.009

Thymus(mg%)

72.96 ± 11.71

76.58 ± 21.76

70.04 ± 7.72

81.10 ± 5.48

73.20 ± 16.87

54.90 ± 10.64

Heart(g%)

0.298 ± 0.026

0.328 ± 0.038

0.330 ± 0.016

0.354 ± 0.037

0.324 ± 0.034

0.320 ± 0.027

Liver(g%)

2.460 ± 0.166

2.458 ± 0.149

2.590 ± 0.155

2.520 ± 0.124

2.598 ± 0.134

2.476 ± 0.118

Spleen(g%)

0.170 ± 0.012

0.170 ± 0.019

0.160 ± 0.020

0.172 ± 0.030

0.156 ± 0.011

0.156 ± 0.025

Kidneys(g%)

0.666 ± 0.026

0.676 ± 0.048

0.678 ± 0.080

0.646 ± 0.060

0.638 ± 0.043

0.660 ± 0.042

Adrenals(mg%)

14.62 ± 2.23

14.12 ± 1.84

14.08 ± 2.48

14.18 ± 2.11

13.26 ± 1.28

12.60 ± 1.36

Testes(g%)

0.676 ± 0.030(7)

0.718 ± 0.079(12)

0.717 ± 0.075(12)

0.764 ± 0.077(7)

0.654 ± 0.039

0.634 ± 0.118

Epididymides(g%)

0.276 ± 0.022(7)

0.291 ± 0.025(12)

0.284 ± 0.019(12)

0.301 ± 0.032(7)

0.284 ± 0.024

0.262 ± 0.041

Female

Number of animals

5

5

5

5

5

5

Final body weight(g)

305.2 ± 26.7

314.4 ± 13.2

318.0 ± 22.2

314.2 ± 20.1

294.2 ± 31.1

299.0 ± 17.1

Absolute organ weight

Brain(g)

1.958 ± 0.044

1.940 ± 0.059

1.972 ± 0.052

2.008 ± 0.052

1.952 ± 0.048

1.990 ± 0.066

Thymus(mg)

223.2 ± 71.3

323.4 ± 54.4

303.6 ± 74.3

356.6 ± 46.3*

377.0 ± 111.5

335.2 ± 99.4

Heart(g)

1.028 ± 0.082

1.030 ± 0.037

1.078 ± 0.073

1.094 ± 0.070

0.912 ± 0.053

0.962 ± 0.040

Liver(g)

11.058 ± 0.861

10.332 ± 0.882

10.618 ± 0.689

10.824 ± 0.585

7.354 ± 0.986

7.922 ± 0.804

Spleen(g)

0.768 ± 0.094

0.624 ± 0.041

0.794 ± 0.063

0.902 ± 0.141

0.594 ± 0.065

0.522 ± 0.078

Kidneys(g)

2.212 ± 0.196

2.118 ± 0.151

2.386 ± 0.240

2.186 ± 0.222

1.986 ± 0.123

1.938 ± 0.075

Adrenals(mg)

81.30 ± 9.55

82.64 ± 4.70

79.46 ± 12.12

75.76 ± 16.53

77.86 ± 19.32

73.22 ± 10.90

Relative organ weight

Brain(g%)

0.646 ± 0.059

0.618 ± 0.026

0.618 ± 0.036

0.642 ± 0.039

0.668 ± 0.070

0.670 ± 0.056

Thymus(mg%)

72.96 ± 22.82

102.52 ± 13.98*

94.82 ± 18.35

113.64 ± 14.99**

127.10 ± 26.70

113.00 ± 35.65

Heart(g%)

0.336 ± 0.034

0.328 ± 0.011

0.338 ± 0.008

0.346 ± 0.009

0.314 ± 0.026

0.322 ± 0.008

Liver(g%)

3.632 ± 0.195

3.286 ± 0.249*

3.344 ± 0.180

3.444 ± 0.075

2.494 ± 0.086

2.646 ± 0.166

Spleen(g%)

0.254 ± 0.038

0.200 ± 0.014*

0.250 ± 0.020

0.286 ± 0.043

0.202 ± 0.008

0.176 ± 0.025

Kidneys(g%)

0.728 ± 0.033

0.672 ± 0.036

0.750 ± 0.043

0.694 ± 0.040

0.680 ± 0.060

0.650 ± 0.039

Adrenals(mg%)

26.70 ± 2.88

26.30 ± 1.17

25.08 ± 4.44

23.94 ± 3.94

26.52 ± 6.48

24.50 ± 3.87

a) Number of animals examied.

Values are expressed as Mean ± S.D.

Significantly different from 0 mg/kg group; * p <0.05, ** p <0.01

Histopathological findings in rats treated orally with test material in the combined repeated dose and reproductive/developmental toxicity screening test

Sex

Organ Finding

Dose level (mg/kg)

Number of animals

Administration period

Recovery period

0

40

200

1000

0

1000

7

12

12

7

5

5

Male                          (Grade)

 Urinary bladder

<5>

<0>

<0>

<5>

<0>

<0>

Testis

<5>

<0>

<0>

<5>

<0>

<1>

Degeneration, seminiferous tubular epithelium, focal

1+

1

 

 

0

 

0

Degeneration, seminiferous tubular epithelium, diffuse

1+

0

 

 

0

 

1

Epididymis

<5>

<0>

<0>

<5>

<0>

<1>

Decrease, sperm

 

0

 

 

0

 

1

Seminal vesicle

<5>

<0>

<0>

<5>

<0>

<0>

Prostate

<5>

<0>

<0>

<5>

<0>

<0>

Cell infiltration, lymphocyte, interstitium

1+

1

 

 

2

 

 

Coagulating gland

<5>

<0>

<0>

<5>

<0>

<0>

Pituitary

<5>

<0>

<0>

<5>

<0>

<0>

Cyst, anterior lobe

1+

1

 

 

0

 

 

Cyst-like lesion, anterior lobe

1+

0

 

 

1

 

 

Thyroid

<5>

<0>

<0>

<5>

<0>

<0>

Ectopic thymic tissue

1+

0

 

 

1

 

 

Ultimobrancheal remnant

1+

1

 

 

1

 

 

Parathyroid

<5>

<0>

<0>

<5>

<0>

<0>

Adrenal

<5>

<0>

<0>

<5>

<0>

<0>

Brain

<5>

<0>

<0>

<5>

<0>

<0>

Spinal cord

<5>

<0>

<0>

<5>

<0>

<0>

Sciatic nerve

<5>

<0>

<0>

<5>

<0>

<0>

< > : Number of animals examined.

Grade; 1+ : Minimal, 2+ : Mild, 3+ : Moderate, 4+ : Severe,

Significantly different from 0 mg/kg group; * p <0.05, ** p <0.01

Sex

Organ Finding

Dose level (mg/kg)

Number of animals

Administration period

Recovery period

Non-pregnant

0

40

200

1000

0

1000

1000

12

11

12

11

5

5

1

Female                                  (Grade)

 Heart

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Lymph node, mandibular

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Lymph node, mesenteric

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Thymus

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Cyst

1+

3

 

 

1

 

 

 

Spleen

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Prostate

<5>

<0>

<0>

<5>

<0>

<0>

 

Extramedullary hematopoiesis, erythrocytic

1+

2

 

 

2

 

 

 

Bone marrow, femur

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Trachea

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Lung (and bronchus)

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Accumulation, foam cell, alveolus

1+

1

 

 

1

 

 

 

Mineralization, arterial wall, focal

1+

1

 

 

1

 

 

 

Stomach

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Cyst, mucosa, glandular stomach

1+

0

1

0

0

0

0

 

Hyperplasia, foveola, glandular stomach

1+

0

0

1

3

0

0

 

Necrosis, mucosa, glandular stomach, focal

1+

0

0

1

3

0

0

 

Small intestine, duodenum

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Small intestine, jejunum

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Small intestine, ileum

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Large intestine, cecum

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Large intestine, colon

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Large intestine, rectum

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Liver

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Proliferation, bile duct

1+

1

 

 

0

 

 

 

Kidney

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Basophilic tubule

1+

0

 

 

1

 

 

 

Cell infiltration, inflammatory, pelvis, focal

1+

0

 

 

1

 

 

 

Cell infiltration, lymphocyte, interstitium, focal

1+

1

 

 

0

 

 

 

Fibrosis, focal

1+

1

 

 

0

 

 

 

Urinary bladder

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Ovary

<5>

<0>

<0>

<5>

<0>

<0>

<1>

Uterus

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Vagina

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Pituitary

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Cyst, Rathke's pouch

1+

0

 

 

1

 

 

 

Thyroid

<5>

<0>

<0>

<5>

<0>

<0>

<0>

Ultimobrancheal remnant

1+

3

 

 

2

 

 

 

< > : Number of animals examined.

Grade; 1+ : Minimal, 2+ : Mild, 3+ : Moderate, 4+ : Severe,

Significantly different from 0 mg/kg group; * p <0.05, ** p <0.01

Fertility and pregnancy data in rats treated orally with test material in the combined repeated dose and reproductive/developmental toxicity screening test

Dose level(mg/kg)

Administration period

0

40

200

1000

Number of pairs examined

12

12

12

12

Estrous cycle

4.18 ± 0.34

4.03 ± 0.09

4.00 ± 0.00

4.08 ± 0.29

Irregular estrous cycle

1/12

1/12

1/12

1/12

Number of pairs with successful mating

12

12

12

12

Mating index (%)a)

100.0

100.0

100.0

100.0

Number of pregnant females

12

12

12

12

Fertility index (%)b)

100.0

100.0

100.0

91.7

Pairing days until mating

3.0 ± 1.3

3.4 ± 1.8

2.8 ± 1.1

2.8 ± 1.1

Number of estrous stages without mating

0.0 ± 0.0

0.3 ± 0.5*

0.0 ± 0.0

0.0 ± 0.0

a) Mating index (%) = (Number of pairs with successful mating/number of pairs examined)×100

b) Fertility index (%) = (Number of pregnant animals/number of pairs with successful mating)×100

Values are expressed as Mean ± S.D.

Significantly different from 0 mg/kg group; * p <0.05, ** p <0.01

Delivery and litter data in rats treated orally with test material in the combined repeated dose and reproductive/developmental toxicity screening test

Dose level(mg/kg)

Administration period

0

40

200

1000

Number of females examined

12

11

12

11

Number of females with live pups

12

11

12

11

Gestation index (%)a)

100.0

100.0

100.0

100.0

Gestation length (days)

22.4 ± 0.5

22.4 ± 0.5

22.3 ± 0.5

22.3 ± 0.5

Number of corpora lutea

16.3 ± 1.4

16.5 ± 1.8

17.3 ± 1.2

15.8 ± 1.9

Number of implantation sites

15.2 ± 1.4

15.2 ± 1.5

15.9 ± 1.0

14.8 ± 1.9

Implantation index (%)b)

92.94 ± 4.90

92.47 ± 5.65

91.98 ± 5.40

93.83 ± 6.46

Delivery index (%)c)

97.25 ± 3.41

94.67 ± 7.56

91.88 ± 10.99

92.85 ± 7.84

Number of pups delivered

14.8 ± 1.5

14.4 ± 1.7

14.6 ± 1.7

13.8 ± 2.6

Number of live pups on day 0

14.6 ± 1.6

14.4 ± 1.7

14.6 ± 1.7

13.6 ± 2.7

Number of live pups on day 4

14.5 ± 1.7

13.1 ± 3.1

14.5 ± 1.8

13.2 ± 2.6

Live birth index (%)d)

98.84 ± 2.72

100.00 ± 0.00

100.00 ± 0.00

98.55 ± 3.24

Viability index on day 4 (%)e)

99.31 ± 2.40

91.58 ± 19.79

99.36 ± 2.22

96.68 ± 4.03

Sex ratio of total number of offspring at birth (M/Total)

0.46(81/177)

0.50(79/158)

0.49(85/175)

0.45(68/152)

Sex ratio of total number of live

offspring at birth (M/Total)

0.46(80/175)

0.50(79/158)

0.49(85/175)

0.44(66/150)

Sex ratio of total number of live

offspring on day 4 (M/Total)

0.46(80/174)

0.51(73/144)

0.48(84/174)

0.44(64/145)

Sex ratio of total number of offspring at birth (M/Total, litter)

0.457 ± 0.112

0.505 ± 0.141

0.505 ± 0.141

0.453 ± 0.153

Sex ratio of total number of liveoffspring at birth (M/Total, litter)

0.456 ± 0.120

0.505 ± 0.141

0.484 ± 0.093

0.444 ± 0.157

Sex ratio of total number of live offspring on day 4 (M/Total, litter )

0.458 ± 0.117

0.506 ± 0.142

0.481 ± 0.094

0.444 ± 0.146

Body weight of pups (g)

on day 0 male

female

 

on day 4 male

female

6.9 ± 0.6

6.4 ± 0.5

 

10.7 ± 1.4

10.2 ± 1.3

6.6 ± 0.7

6.3 ± 0.8

 

10.4 ± 1.6

9.9 ± 1.5

6.8 ± 0.5

6.5 ± 0.6

 

10.2 ± 1.1

9.8 ± 1.1

6.8 ± 0.5

6.4 ± 0.5

 

10.7 ± 1.4

10.3 ± 1.4

a) Gestation index (%) = (Number of females with live pups/number of pregnant females)×100

b) Implantation index (%) = (Number of implantation sites/number of corpora lutea)×100

c) Delivery index (%) = (Number of pups delivered/number of implantation sites)×100

d) Live birth index (%) = (Number of live pups on day 0/number of pups delivered)×100

e) Viability index (%) = (Number of live pups on day 4/number of live pups on day 0)×100

Values are expressed as Mean±S.D.

Significantly different from 0 mg/kg group; * p <0.05, ** p <0.01

 

 

Conclusions:
NOAEL was considered to be above 500- 1000 mg/kg/day for P and F1 generation when male and female rats treated with test material orally by gavage.
Executive summary:

Data available from different studies were reviewed to determine the reproductive toxicity of Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate.The studies are as mentioned below:

Study 1.

In a Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test,Crl:CD (SD) male and female rats treated with test material in the concentration of0, 40, 200 and 1000 mg/kg/day orally by gavage in0.1 w/v% Tween 80 added 0.5 w/v% CMC-Na solution. No efect on survival, clinical signs, body weight, food consumption, behavior test, hematology, blood chemistry, urinalysis, organ weight and gross pathology were observed in treated male and female rats as compared to control. Focal necrosis of mucosa and hyperplasia of gastric pits in the glandular stomach were observed in female rat at 200 and 1000 mg/kg bw. The focal necrosis of mucosa is occasionally seen in the mucosa of the glandular stomach when the chemical compounds are administrated. Many of these induced changes have reversibility. Focal necrosis of mucosa were not noted at the end of the recovery period, indicating reversibility. The hyperplasia of mucosal epithelium in the glandular stomach was considered to be a regeneration or restoration image against early epithelium disorder. The image of hyperplasia disappeared by complete repairing at the end of the recovery period. In addition no reproductive effect such as Estrous cyclicity, copulation and implantation, Fertility rat, gestation period, implantation index, live birth index, delivery index were observed in treated rats as compared to control. No effect on viability, clinical signs, body weights, development and growth of pups and gross pathological changes were observed in treated rats as compared to control. Therefore, NOAEL was considered to be 1000 mg/kg/day for P and F1 generation whenCrl:CD (SD)male and female rats treated with test material orally by gavage.

Study 2.

Reproductive and development toxicity study oftestmaterial was performed on male and femaleHarlan-Wistar rats. Test material administered in diet for up to 3 generation. 10 male and 20 females were used. Asno indications of any influence on reproductive parameters and No developmental toxic effects were seen up to the highest dose of 500 mg/kg bw, Hence No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 500 mg/kg/day.When male and female wistar rats were treated withtest materialorally up to 3 generation.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from authoritative database
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity study

Data available from different studies were reviewed to determine the reproductive toxicity of Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate.The studies are as mentioned below:

Study 1.

In a Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test,Crl:CD (SD) male and female rats treated with test material in the concentration of0, 40, 200 and 1000 mg/kg/day orally by gavage in0.1 w/v% Tween 80 added 0.5 w/v% CMC-Na solution. No efect on survival, clinical signs, body weight, food consumption, behavior test, hematology, blood chemistry, urinalysis, organ weight and gross pathology were observed in treated male and female rats as compared to control. Focal necrosis of mucosa and hyperplasia of gastric pits in the glandular stomach were observed in female rat at 200 and 1000 mg/kg bw. The focal necrosis of mucosa is occasionally seen in the mucosa of the glandular stomach when the chemical compounds are administrated. Many of these induced changes have reversibility. Focal necrosis of mucosa were not noted at the end of the recovery period, indicating reversibility. The hyperplasia of mucosal epithelium in the glandular stomach was considered to be a regeneration or restoration image against early epithelium disorder. The image of hyperplasia disappeared by complete repairing at the end of the recovery period. In addition no reproductive effect such as Estrous cyclicity, copulation and implantation, Fertility rat, gestation period, implantation index, live birth index, delivery index were observed in treated rats as compared to control. No effect on viability, clinical signs, body weights, development and growth of pups and gross pathological changes were observed in treated rats as compared to control. Therefore, NOAEL was considered to be 1000 mg/kg/day for P and F1 generation whenCrl:CD (SD)male and female rats treated with test material orally by gavage.

Study 2.

Reproductive and development toxicity study oftestmaterial was performed on male and femaleHarlan-Wistar rats. Test material administered in diet for up to 3 generation. 10 male and 20 females were used. Asno indications of any influence on reproductive parameters and No developmental toxic effects were seen up to the highest dose of 500 mg/kg bw, Hence No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 500 mg/kg/day.When male and female wistar rats were treated withtest materialorally up to 3 generation.

.Based on the data available for the read across chemical, No Observed Adverse Effect Level (NOAEL) was considered to be above 500 -1000mg/kg bw . Thus, comparing this value with the criteria of CLP regulation

Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate

not likely to classify as reproductive toxicant.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation

Reaction mass of 3H-Indolium, 2-[2-[4-[(2-cyanoethyl)methylamino]phenyl]ethenyl]-1,3,3-trimethyl- & acetate is not likely to classify as reproductive toxicant.

Additional information