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Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data from secondary source

Data source

Reference
Reference Type:
other: authoritative database
Title:
Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422) of 2-Naphthalenecarboxamide,3-hydroxy-N-phenyl in rats
Author:
National Institute of Health Sciences
Year:
2018
Bibliographic source:
Japan Chemicals Collaborative Knowledge Database, 2018

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test (OECD TG422) of test chemical in rats
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data avaiable

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
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):2-Naphthalenecarboxamide,3-hydroxy-N-phenyl
- Molecular formula: C17H13NO2
- Molecular weight : 263.29 g/mole
- Substance type: Organic
- Physical state:Smoky and very light yellow powder
- Impurities (identity and concentrations): No data available

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on species / strain selection:
No data avaiable
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation:9 weeks old

Administration / exposure

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: 1 w/v% Tween 80 solution
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Test material dissolved in 1 w/v% Tween 80 solution

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):
- Concentration in vehicle: 0, 40, 200, 1000 mg/kg
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity:
Details on mating procedure:
No data avaiable
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data avaiable
Duration of treatment / exposure:
Male: 42 days
Female: 42 – 48 days (from 14 days before mating to day 4 of lactation)
Frequency of treatment:
Daily
Details on study schedule:
Recovery period: Males, 14 days
Females (satellite), 14 days

Sacrifice : Males, day 43 of treatment and day 15 of recovery
Females, day 5 of lactation
Females (satellite), day 15 of recovery
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 40, 200, 1000 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
No of animals Total: 116
0 mg/kg bw/day:12 male , 12 female
40 mg/kg bw/day:12 male , 12 female
200 mg/kg bw/day:12 male , 12 female
1000 mg/kg bw/day:12 male , 12 female

Recovery:
0 mg/kg bw/day: 5 male , 5 female
1000 mg/kg bw/day: 5 male , 5 female
Control animals:
yes, concurrent vehicle
Details on study design:
No data avaialble
Positive control:
No data avaialble

Examinations

Parental animals: Observations and examinations:
Clinical signs, FOB, Body weight, Food consumption, Urinalysis, Hematology and clinical chemistry were observed.
Oestrous cyclicity (parental animals):
Estrous cycle, numbers of corpora lutea or Implantations were observed
Sperm parameters (parental animals):
No data avaialble
Litter observations:
Viability, Clinical signs and Body weight were observed
Postmortem examinations (parental animals):
Gross pathology and Histopathology were observed
Postmortem examinations (offspring):
Gross pathology and Histopathology were observed
Statistics:
No data avaialble
Reproductive indices:
Copulation index, fertility index, delivery index, gestation length, implantation index and gestation index were observed
Offspring viability indices:
Viability on day 4 were observed.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
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
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Details on results (P0)

Clinical signs: No clinical signs of toxicity was observed in treated rats.

Body weight: No effect on body weight of treated rats was observed as compared to control.

Reproductive function: estrous cycle: No effects estrous cycle, numbers of corpora lutea or Implantations were observed in treated rats as compared to control.

Reproductive performance: No effects on copulation index, fertility index, delivery index, gestation length, implantation index and gestation index were observed in treated rats as compared to control.

Organ weights : No effect on organ weight of treated rats were in treated rats as compared to control.

Gross pathology: No gross pathological changes were observed in treatd rats as compared to control.

Histopathology: No histopathological changes were observed in treatd rats as compared to control.

other findings No effect on food consumption, hematology, blood chemistry, urinalysis of treated rats were observed as compared to contorl.

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 effect on Clinical signs, FOB, Body weight, Food consumption, Urinalysis, Hematology, Blood chemistry, organ weights, reproductive performance and Histopathology
Remarks on result:
other: overall no effects on reproductive parameters

Target system / organ toxicity (P0)

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

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
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
Histopathological findings:
no effects observed
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Details on results (F1)

Viability: No effect on viability on day 4 were observed in offsprings to treated rats.

Clinical signs: No clinical signs of toxicity was observed in treated rats

Body weight: No effect on body weight of treated rats was observed in offsprings to treated rats as compared to control.

Gross pathology: No gross pathological changes were observed in offsprings of treated rats as compared to control.

Histopathology: No histopathological changes were observed in offsprings of treated rats as compared to control.

other findings: No effect on number of offspring or live offspring at birth, sex ratio and live birth index of offsprings of treated rats as compared to control.

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 effect on number of offspring or live offspring at birth, sex ratio, live birth index, or viability index , gross pathology and Histopathology
Remarks on result:
other: overall no effects on developmental parameters

Target system / organ toxicity (F1)

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

Overall reproductive toxicity

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

Any other information on results incl. tables

 

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

 

Administration period

Dose level (mg/kg)

0

40

200

1000

Number of pairs examined

12

12

12

12

Estrous cycle

4.08 ±

0.19

4.00 ±

0.00

4.09 ±

0.30

4.04 ±

0.14

Irregular estrous cycle

0/12

0/12

1/12

0/12

Number of pairs with successful mating

12

11

11

12

Mating index (%) a)

100.0

91.7

91.7

100.0

Number of pregnant females

12

11

11

12

Fertility index (%) b)

100.0

100.0

100.0

100.0

Pairing days until mating

2.1 ±

1.1

2.7±

1.2

3.4 ±

1.2

2.6 ±

1.0

Number of estrous stages without mating

0.0 ±

0.0

0.3±

0.9

0.2 ±

0.4

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.

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

 

Administration period

Dose level(mg/kg)

0

40

200

1000

Number of females examined

12

11

11

12

Number of females with live pups

12

11

11

12

Gestation index (%) a)

100.00

100.00

100.00

100.00

Gestation length (days)

22.3±0.5

22.5 ±0.5

22.5±0.5

22.4±0.5

Number of corpora lutea

17.8 ±1.5

17.2±1.6

16.5±1.9

17.2±2.9

Number of implantation sites

16.8±1.2

16.1±1.4

15.5±2.0

15.7±3.0

Implantation index (%) b)

95.00 ±4.37

93.78 ±4.34

94.43 ±4.34

90.88 8.66

Delivery index (%) c)

95.23 ± 6.29

95.36  ±4.25

94.50 ±5.25

95.00 4.75

Number of pups delivered

16.0 ±1.1

15.4±1.6

14.7±2.3

14.8 ±2.7

Number of live pups on day 0

15.8± 1.2

15.4 ±1.6

14.7±2.3

14.8±2.7

Number of live pups on day 4

15.7 ±1.2

15.3  ±1.7

14.7 ±2.3

14.6 ±2.6

Live birth index (%) d)

98.97±2.41

100.00± 0.00

100.00±0.00

99.51 ±1.70

Viability index on day 4 (%) e)

98.97±2.41

99.35 ±2.14

100.00±0.00

98.92 ±2.54

Sex ratio of total number

of offspring at birth (M/Total)

0.50(96/192)

0.49 (83/169)

0.55(89/162)

0.53(94/178)

Sex ratio of total number of live

offspring at birth (M/Total)

0.51(96/190)

0.49(83/169)

0.55(89/162)

0.53(93/177)

Sex ratio of total number of live

offspring on day 4 (M/Total)

0.51(96/188)

0.49(82/168)

0.55(89/162)

0.53(93/175)

Sex ratio of total number of offspring

at birth (M/Total, litter)

0.499± 0.158

0.485  ±0.152

0.549 ±0.078

0.548±0.166

Sex ratio of total number of live

offspring at birth (M/Total, litter )

0.504±0.158

0.485±0.152

0.549 ±0.078

0.546 ±0.167

Sex ratio of total number of live

offspring on day 4 (M/Total, litter )

0.509±0.158

0.483 ±0.150

0.549 ±0.078

0.553  ±0.168

Body weight of pups (g)

on day 0  male               

       female

on day 4 male

              female

 

 

6.4±0.6

6.1 ±0.6

10.1± 0.9

9.6 ±0.7

 

 

6.9±0.7

6.5 ±0.8

10.4±1.3

9.9 ±1.5

 

 

6.9 ±0.7

6.5 ±0.7

10.5 ±1.3

9.8 ±1.2

 

 

6.8 ±0.8

6.4 ±0.7

10.6±1.8

10.2 ±1.8

 

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 areexpressed as Mean ±S.D. 

Applicant's summary and conclusion

Conclusions:
NOAEL was considered to be 1000 mg/kg bw/day for P and F1 generation when Crl:CD (SD) male and female rats were treated with test chemical orally by gavage for 42 days.
Executive summary:

In combined repeated dose toxicity study with reproduction and developmental screening, Crj:CD(SD)IGS male and female rats were treated with test chemical in the concentration of 0, 40, 200 and 1000 mg/kg bw/day 1 w/v% Tween 80 solution orally by gavage for male 42 days and femalesfrom 14 days before mating to day 4 of lactation (Females (satellite), 42 days).All animals were observed for clinical sign , body weights, food consumption.Males were sacrificed on day 43 of treatment and day 15 of recovery while Females were sacrificed on day 5 of lactation Females (satellite), day 15 of recovery and Offspring on day 4 after birth.

No effect on clinical sign , body weights, food consumption, hematology, clinical chemistry, urinalysis, organ weights, gross pathology and histopathological of treated rats as compared to control. Similarly no effect on estrous cycle, copulation index, fertility index, delivery index, gestation length, numbers of corpora lutea or implantations, implantation index, gestation index, number of offspring or live offspring at birth, sex ratio, live birth index, or viability index on day 4 of offspring were observed as compared to control. In addition, no effect on clinical signs, body weights, gross pathology and histopathology of treated offspings were observed as compared to control. Therfore, NOAEL was considered to be 1000 mg/kg bw/day for P and F1 generation when  Crl:CD (SD) male and female rats were treated with test chemical orally by gavage for 42 days.