Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study

Based on the data available from different studies, NOAEL for test material was considered to be of 30 mg/kg bw/day for F0, F1 generation. When male and female rats were treated with test material orally. Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.

Link to relevant study records
Reference
Endpoint:
one-generation reproductive 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 peer reviewed journal
Qualifier:
equivalent or similar to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Teratology and percutaneous toxicity study of test material was performed on rats
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: No data available
- Age at study initiation: No data available
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: Mated females were housed individually in temperature- and humidity-controlled rooms.
- Diet (e.g. ad libitum): Ralston Purina Laboratory chow, ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimatization period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%): No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: No data available
Route of administration:
dermal
Vehicle:
other: 6% hydrogen peroxide
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data available
- Concentration in vehicle: No data available
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
-Time-pregnant female rats were used.
-Presence of sperm in vagina considered day 0 of gestation
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
7 days
Frequency of treatment:
Every third day, i.e. on days 1, 4, 7, 10, 13, 16 and 19 of gestation
Details on study schedule:
No data available
Remarks:
0.1 % (0.001316 mg/kg)
No. of animals per sex per dose:
Total: 100
Control 1: 20 female
Control 1: 20 female
Control 1: 20 female
0.001316 mg/kg : 20 female

Positive Control : 20 female
Control animals:
yes
Details on study design:
Further details on study design
- Dose selection rationale: No data available
- Rationale for animal assignment (if not random): No data available
- Other: No data available
Positive control:
acetylsalicylic acid
Parental animals: Observations and examinations:
-Animals were weighed on the day the dyes were administered.
-The uteri were examined, corpora lutea of pregnancy counted, and the number, distribution and location of live, dead, and resorbed fetuses were recorded
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
Live fetuses and weight of fetuses were examined
Postmortem examinations (parental animals):
Number of Corpora lutea and number, distribution, and location of live, dead, and resorbed fetuses were examined.
Postmortem examinations (offspring):
-All fetuses were examined for gross anomalies, sexed, and weighed.
-One-third the fetuses from each litter were fixed in Bouin's solution and subsequently examined for visceral anomalies by razor blade sectioning.
-The remaining fetuses in each litter were fixed in 95% ethyl alcohol, eviscerated, cleared, stained with KOH-alizarin red S and examined for skeletal anomalies
Statistics:
All statistical analyses compared the treatment groups with the control groups. The number of females exhibiting resorption sites, number of females exhibiting two or more resorptions, number of dead or resorbed fetuses, and the number of fetuses with soft-tissue or skeletal anomalies and accessory ribs was compared using chi-square test criterion with Yates' correction on 2 X 2 contingency tables as described by Steel and Torrie (1960) or Fisher's exact probability test (Siegel, 1956) as appropriate to judge the significance of difference. The mean number of corpora lutea, implantation sites, live fetuses, and resorption sites was compared by analysis of variance (one-way classification) as described by Steel and Torrie (1960) using Dunnett's (1964) multiple comparison tables to judge the significance of differences. The live fetal weights were compared by analysis of variance (hierarchal classification) as described by Steel and Torrie (1960) using Dunnett's (1964) multiple comparison tables to judge the significance of differences. Statistically significant differences between groups were judged valid only when there were significant differences between any one of the dye treated groups and each of the three untreated control groups.
Reproductive indices:
No data available
Offspring viability indices:
No data available
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Changes in the color of the skin and hair at the site of dye application were observed in treated rats.
Dermal irritation (if dermal study):
no effects observed
Description (incidence and severity):
No irritation or other changes were observed in treated rats.
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effect on body weight of treated rats was observed as compared to control.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No effect on food consumption of treated rats was observed 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:
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:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not examined
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
No significant effect on number of corpora lutea and implantation sites oftreated rats was observed as compared to control.No significant effect on live fetuses, sex ratio, resorption sites or mean resorptions per pregnancy oftreated rats was observed as compared to control.
Dose descriptor:
NOAEL
Effect level:
0.001 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
dermal irritation
body weight and weight gain
food consumption and compound intake
reproductive performance
Remarks on result:
other: No effects on reproductive performance was 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:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
No effect on Live fetuses was observed in treated female rats as compared to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effect on body weight of fetuseswas observed in treated female rats 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
Histopathological findings:
no effects observed
Description (incidence and severity):
No significant soft-tissue anomalies were observed infetuses of treated female rats as compared to control.
Normally occurring accessory ribs variations were observed infetuses of treated female rats as compared to control.
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
0.001 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
viability
body weight and weight gain
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: No toxic effects were 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
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

Summary of Teratology Study in Rats Receiving P-21

Observations

Control I

Untreated

Control II

Untreated

Control III

Untreated

Acetylsalicylic

acid (250 mg/kg-day)

P-21

(2 ml/kg)

Maternal parameters

 

 

 

 

 

Total no. females gravid

20

20

20

20

20

Mean no. corpora lutea

15.35

13.55

15.25

16.15°

13.45

Mean no. implantation sites

12.40

12.10c

13.90

13.25

11.65°

No. females exhibiting resorption

Sites

13

14

12

15

8

No. females exhibiting 2 ormore resorption sites

9

7

6

15d

4

No. females aborting

0

0

0

0

0

Fetal parameters

 

 

 

 

 

Mean no. live fetuses/group

10.65

10.85

12.50

8.70c

11.00

Mean live fetal weight (g)

3.38

3.58

3.62

2.89e

3.79f

No. dead or resorbed fetuses (%)

35(14.11)

25(10.33)

28 (10.07)

91 (34.34)e

13(5.58)f

Mean no. resorptions/pregnancy

1.75

1.25

1.40

4.5 5h,i

0.65g

Sex ratio, M:F

106:107

102:115

119:131

100:75

116:104

No. fetuses with soft-tissueanomalies (%)

4(6.35)

4(6.06)

6(7.79)

21 (36.84)e

7(10.29)

No. fetuses with skeletal

anomalies (%)

0(0.00)

1 (0.67)

2(1.16)

40(34.19)e

1 (0.65)

No. fetuses with accessory ribs

only (%)

75 (50.00)

56(37.09)

72 (41.62)

32 (27.35)

83 (54.60)b,h

aSignificantly different from control II atp < 0.05.

bSignificantly different from control III at p < 0.05.

cSignificantly different from control III at p < 0.01.

dSignificantly different from controls II, III atp < 0.05.

eSignificantly different from controls I, I I , III atp < 0.01.

fSignificantly different from control I at p < 0.01.

gSignificantly different from control I atp < 0.05.

^Significantly different from control II atp <0.01.

'Significantly different from controls I, III atp < 0.05.

Conclusions:
NOAEL was considered to be 0.001316 mg/kg for F0 and F1 geneartion when pregnent female CD rats were treatre wtih test material
Executive summary:

In a Teratology study, pregnent female  CD rats were treatre wtih test material in the concentration of 0 and 0.001316 mg/kg dermally in6% hydrogen peroxide on days 1, 4, 7, 10, 13, 16, and 19 of gestation. Acetylsalicylic acid were used as positive control. Changes in the color of the skin and hair at the site of dye application were observed in treated rats. No irritation or other changes were observed in treated rats.No effect on body weight and food consumption of treated rats was observed as compared to control. Similarly,No significant effects on number of corpora lutea, implantation sites, live fetuses, sex ratio, resorption sites or mean resorptions per pregnancy of treated female rats wereobserved as compared to control. In addition, No effect on body weight offetuseswas observedas compared to control. No significant soft-tissue anomalies were observed infetuses of treated female rats as compared to control.Normally occurring accessory ribs variations were observed infetuses of treated female rats as compared to control. Therefore, NOAEL was considered to be 0.001316 mg/kg for F0 and F1 geneartion when pregnent female  CD rats were treatre wtih test material dermally on days 1, 4, 7, 10, 13, 16, and 19 of gestation.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
subacute
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 adverse effect observed
Dose descriptor:
NOAEL
0.001 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from authoritative database

Additional information

Reproductive toxicity study

Data available from different studies were reviewed to determine the reproductive toxicity of test chemical.The studies are as mentioned below:

Study 1

In a Teratology study, pregnent female  CD rats were treatre wtih test materialin the concentration of 0 and 0.001316 mg/kg dermally in6% hydrogen peroxide on days 1, 4, 7, 10, 13, 16, and 19 of gestation. Acetylsalicylic acid were used as positive control. Changes in the color of the skin and hair at the site of dye application were observed in treated rats. No irritation or other changes were observed in treated rats.No effect on body weight and food consumption of treated rats was observed as compared to control. Similarly,No significant effects on number of corpora lutea, implantation sites, live fetuses, sex ratio, resorption sites or mean resorptions per pregnancy of treated female rats wereobserved as compared to control. In addition, No effect on body weight offetuseswas observedas compared to control. No significant soft-tissue anomalies were observed infetuses of treated female rats as compared to control.Normally occurring accessory ribs variations were observed infetuses of treated female rats as compared to control. Therefore, NOAEL was considered to be 0.001316 mg/kg for F0 and F1 geneartion when pregnent female  CD rats were treatre wtih test materialdermallyon days 1, 4, 7, 10, 13, 16, and 19 of gestation.

Study2

In a reproductive and developmental toxicity study oftest material was assessed in femaleWistar derived SPF-Albino Crl:Wi/Br rats when they were exposed at concentration0, 10, 30 and 60 mg/kg bw/dayduring gestation period of 5-15 days.During the study the mortality, signs of intoxication, body weight and food consumption were recorded. All mated females were sacrified on day 20 of gestation. In the pregnant female, a complete autopsy and a macroscopic examination of the organs were carried out. Uterus were weighed and examined. For each ovary, corpora lutea were counted and foetuses were individually weighed and sexed. A gross examination of all foetuses was performed and one-third of the foetuses were examined for visceral anomalies. The other foetuses were evaluated for skeletal defects. No rats died during the treatment period. No toxic effects were reported during the study. Females of all dose groups had orange-brown discoloured urine throughout the application period at dose related intensity. Mean maternal bodyweight gains and mean food consumptions over the gestation period were normal when compared to the control group. Gross necropsy did not reveal any organ alterations related to treatment. No significant differences in the number of viable foetuses, the male to female sex ratio, birth- position, number of runts, post-implantation losses, implantations, resorptions and corpora lutea between dosage groups and the control group were observed. At 60mg/kg bw dose group showed an increase in foetal body weight and uteri weights with a tendency towards dose-relation. Examination of the foetuses yielded minor variations (wavy ribs) at comparable inter-group frequencies and incidences within the historical control animals of this strain. There were no biologically significant differences in the number of litters with malformations or developmental variations between any of the dose groups and the control group.HenceNOAEL was considered to be 30 mg/kg/day for test material in femaleWistar derived SPF-Albino Crl:Wi/Br rats when they were exposed at concentration0, 10, 30 and 60 mg/kg bw/dayduring gestation period of 5-15 days by oral gavage.

Study 3

In a Teratology study,New Zealand White female rabbits were treated with test materialin the concentration of0, 19.5 and 97.5 mg/kg/day orally by gavage fromday 6 to day 18 of gestation. Bluebrown colored urine were observed in all treated rabbits.

No adverse effect onbody weight gain, Number of pregnancies, numbers of corpora lutea, implantations, resorptions, and live and stillborn fetuses were observed in treated female rabbits. No effect on fetusesweight were observed in treated female rabbits. In addition, No gross abnormalities, visceral and skeletal abnormalities were observed in fetusesof treated female rabbits. Therefore, NOAEL was considered to be 97.5 mg/kg/day for F0 and F1 geneartion when New Zealand White female rabbits were treated with test materialorally by gavage for 13 days.

Study 4

Reproductive and developmental toxicity study of test materialwas performed on male and female CFE-Srats .20 male and 20 female rats /dose group were used.One male was mated with one female until copulation was confirmed by the presence of sperm during daily vaginal inspections (day 0 of pregnancy).The females then were weighed, transferred into individual cages.The test materialmixed with feed were administers in dose concentration 0, 97.5,616 mg/kg bw/day (0, 1950,7800 ppm)from day from day 6 through day 15. Pregnancy was further confirmed by biweekly weighing of the females. All females were killed by chloroform inhalation on the 19th day of pregnancy and the fetuses delivered by Caesarian section. The number and distribution of fetuses, and the number of corpora lutea, live and stillboin fetuses, and early and late resorptions were recorded. Each fetus was weighed, measured, and examined for gross abnormalities. One-third of each litter was examined for visceral abnormalities by employing the slicing method of Wilson (1965). The remaining two-thirds were cleared and the bone structure stained with alizarin red S in order to define any skeletal abnormalities (Murphy, 1965)

 

No dose-related significant differences were observed in the parameters examined. The 616mg/kg /day (7800 ppm) dose group excreted blue-brown colour urine.No grossly abnormal pups were noted in the 97.5 mg/kg /day dose group (244 pups); there was one in control group (244 pups). One grossly abnormal pup was noted out of the 262 examined in the 616 mg/kg /day dose group.however, the average numbers of implantation sites, live pups, and early or late resorptions were not significantly different among the groups. HenceNo Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 616 mg/kg/day (7800ppm.When male and femaleCFE-Srats were treated with test material orally.

Based on the data available from different studies ,test material did not showedreproductive toxicityat dose concentration 30 mg/kg body weight/day,when male and female rats were treated with test material orally,Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive toxicant.

 

 

 

Effects on developmental toxicity

Description of key information

Developmental toxicity study

Based on the various studies available for the test chemical were reviewed to determine the developmental toxicity, NOAELfor test chemical was considered to be 30 mg /kg bw/day .When rats were treated with test chemical orally. Thus, comparing this value with the criteria of CLP regulation test chemical is not likely to classify as reproductive and developmental toxicant.

 

Link to relevant study records
Reference
Endpoint:
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 peer reviewed journal
Qualifier:
according to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Teratology study of test material in rats
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: Charles River CD
Details on test animals and environmental conditions:
- Source: No data available
- Age at study initiation: No data available
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: Mated females were housed individually in temperature- and humidity-controlled rooms.
- Diet (e.g. ad libitum): Ralston Purina Laboratory chow, ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimatization period: No data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%): No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To: No data available
Route of administration:
dermal
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: 6% hydrogen peroxide
Details on exposure:
The hair-dye (2.0 mL/kg) was applied to the dorsocapsular area (shaved skin) of each animal on days 1, 4, 7, 10, 13, 16, and 19 of gestation
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Presence of sperm in vagina considered day 0 of gestation
Duration of treatment / exposure:
20 days
Frequency of treatment:
Every third day, i.e. on days 1, 4, 7, 10, 13, 16 and 19 of gestation
Remarks:
Doses / Concentrations:
2.0 mL/kg of 0.1% (0.001316 mg/kg)
Basis:
no data
No. of animals per sex per dose:
Total: 100
Control 1: 20 female
Control 1: 20 female
Control 1: 20 female
0.001316 mg/kg : 20 female

Positive Control : 20 female
Control animals:
other: acetylsalicylic acid
Maternal examinations:
Animals were weighed on the day the dyes were administered.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes:One-third of the fetuses from each litter were examined for visceral anomalies.
- Skeletal examinations: Yes:The remaining fetuses were examined for skeletal anomalies
- Head examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data
Statistics:
All statistical analyses compared the treatment groups with the control groups.

The number of females exhibiting resorption sites, number of females exhibiting two or more resorptions, number of dead or resorbed fetuses, and the number of fetuses with soft-tissue or skeletal anomalies and accessory ribs was compared using chi-square test or Fisher's exact probability test as appropriate to judge the significance of difference.

The mean number of corpora lutea, implantation sites, live fetuses, and resorption sites was compared by analysis of variance (one-way classification) using Dunnett's multiple comparison tables to judge the significance of differences.

The live fetal weights were compared by analysis of variance (hierarchal classification) using Dunnett's multiple comparison tables to
judge the significance of differences.

Statistically significant differences between groups were judged valid only when there were significant differences between any one of the dye treated groups and each of the three untreated control groups
Indices:
No data available
Historical control data:
No data available
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Changes in the color of the skin and hair at the site of dye application were observed in treated rats.
Dermal irritation (if dermal study):
no effects observed
Description (incidence and severity):
No irritation or other changes were observed in treated rats.
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effect on body weight of treated rats was observed as compared to control.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No effect on food consumption of treated rats was observed 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:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Other effects:
not specified
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No signs of toxicity were seen throughout the study. Except for the changes in the color of the skin and hair at the site of dye application, no irritation or other changes in appearance were seen.

Changes in female body weights were similar for rats in the untreated controls and all dye-treated groups.

A marked reduction in maternal weight gain through gestation was observed in the rats receiving acetylsalicylic acid as compared with either the untreated control rats or dye-treated rats.

Mean food consumption for all groups throughout gestation was similar except for rats in the acetylsalicylic acid group; these rats showed a moderate decrease in food consumption from days 7 to .13 of gestation.

The dye formulations produced no significant differences in the mean number of corpora lutea, implantation sites and live fetuses, and the sex ratio when compared with the untreated control groups.

No differences between groups were seen regarding the number of females exhibiting resorption sites or mean resorptions per pregnancy
Dose descriptor:
NOAEL
Effect level:
0.001 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
pre and post implantation loss
total litter losses by resorption
early or late resorptions
Remarks on result:
other: No effects on reproductive performance was observed
Abnormalities:
not specified
Localisation:
not specified
Fetal body weight changes:
no effects observed
Description (incidence and severity):
No effect on body weight of fetuseswas observed in treated female rats as compared to control.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Description (incidence and severity):
No significant soft-tissue anomalies were observed infetuses of treated female rats as compared to control.
Normally occurring accessory ribs variations were observed infetuses of treated female rats as compared to control.
Dose descriptor:
NOEL
Effect level:
0.001 mg/kg bw/day
Based on:
test mat.
Sex:
not specified
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
external malformations
skeletal malformations
visceral malformations
Remarks on result:
other: No developmental toxic effects were observed
Abnormalities:
not specified
Localisation:
other: not specified
Developmental effects observed:
not specified
Treatment related:
not specified
Relation to maternal toxicity:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Summary of Teratology Study in Rats Receiving P-21

Observations

Control I

Untreated

Control II

Untreated

Control III

Untreated

Acetylsalicylic

acid (250 mg/kg-day)

P-21

(2 ml/kg)

Maternal parameters

 

 

 

 

 

Total no. females gravid

20

20

20

20

20

Mean no. corpora lutea

15.35

13.55

15.25

16.15°

13.45

Mean no. implantation sites

12.40

12.10c

13.90

13.25

11.65°

No. females exhibiting resorption

Sites

13

14

12

15

8

No. females exhibiting 2 ormore resorption sites

9

7

6

15d

4

No. females aborting

0

0

0

0

0

Fetal parameters

 

 

 

 

 

Mean no. live fetuses/group

10.65

10.85

12.50

8.70c

11.00

Mean live fetal weight (g)

3.38

3.58

3.62

2.89e

3.79f

No. dead or resorbed fetuses (%)

35(14.11)

25(10.33)

28 (10.07)

91 (34.34)e

13(5.58)f

Mean no. resorptions/pregnancy

1.75

1.25

1.40

4.5 5h,i

0.65g

Sex ratio, M:F

106:107

102:115

119:131

100:75

116:104

No. fetuses with soft-tissueanomalies (%)

4(6.35)

4(6.06)

6(7.79)

21 (36.84)e

7(10.29)

No. fetuses with skeletal

anomalies (%)

0(0.00)

1 (0.67)

2(1.16)

40(34.19)e

1 (0.65)

No. fetuses with accessory ribs

only (%)

75 (50.00)

56(37.09)

72 (41.62)

32 (27.35)

83 (54.60)b,h

aSignificantly different from control II atp < 0.05.

bSignificantly different from control III at p < 0.05.

cSignificantly different from control III at p < 0.01.

dSignificantly different from controls II, III atp < 0.05.

eSignificantly different from controls I, I I , III atp < 0.01.

fSignificantly different from control I at p < 0.01.

gSignificantly different from control I atp < 0.05.

^Significantly different from control II atp <0.01.

'Significantly different from controls I, III atp < 0.05.

Conclusions:
NOAEL was considered to be 0.001316 mg/kg for F0 and F1 geneartion when pregnent female CD rats were treatre wtih test material
Executive summary:

In a Teratology study, pregnent female  CD rats were treatre wtih test material in the concentration of 0 and 0.001316 mg/kg dermally in6% hydrogen peroxide on days 1, 4, 7, 10, 13, 16, and 19 of gestation. Acetylsalicylic acid were used as positive control. Changes in the color of the skin and hair at the site of dye application were observed in treated rats. No irritation or other changes were observed in treated rats.No effect on body weight and food consumption of treated rats was observed as compared to control. Similarly,No significant effects on number of corpora lutea, implantation sites, live fetuses, sex ratio, resorption sites or mean resorptions per pregnancy of treated female rats wereobserved as compared to control. In addition, No effect on body weight offetuseswas observedas compared to control. No significant soft-tissue anomalies were observed infetuses of treated female rats as compared to control.Normally occurring accessory ribs variations werewere observed infetuses of treated female rats as compared to control. Therefore, NOAEL was considered to bhe 0.001316 mg/kg for F0 and F1 geneartion when pregnent female  CD rats were treatre wtih test material dermally on days 1, 4, 7, 10, 13, 16, and 19 of gestation.

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

Developmental toxicity study

Data available from different studies for test chemicals were reviewed to determine the developmental toxicity of test chemical. The studies are as mentioned below:

Study 1

In a Teratology study, pregnent female  CD rats were treatre wtih test materialin the concentration of 0 and 0.001316 mg/kg dermally in6% hydrogen peroxide on days 1, 4, 7, 10, 13, 16, and 19 of gestation. Acetylsalicylic acid were used as positive control. Changes in the color of the skin and hair at the site of dye application were observed in treated rats. No irritation or other changes were observed in treated rats.No effect on body weight and food consumption of treated rats was observed as compared to control. Similarly,No significant effects on number of corpora lutea, implantation sites, live fetuses, sex ratio, resorption sites or mean resorptions per pregnancy of treated female rats wereobserved as compared to control. In addition, No effect on body weight offetuseswas observedas compared to control. No significant soft-tissue anomalies were observed infetuses of treated female rats as compared to control.Normally occurring accessory ribs variations werewere observed infetuses of treated female rats as compared to control. Therefore, NOAEL was considered to bhe 0.001316 mg/kg for F0 and F1 geneartion when pregnent female  CD rats were treatre wtih test materialdermallyon days 1, 4, 7, 10, 13, 16, and 19 of gestation.

Study 2

In a reproductive and developmental toxicity study oftest material was assessed in femaleWistar derived SPF-Albino Crl:Wi/Br rats when they were exposed at concentration0, 10, 30 and 60 mg/kg bw/dayduring gestation period of 5-15 days.During the study the mortality, signs of intoxication, body weight and food consumption were recorded. All mated females were sacrified on day 20 of gestation. In the pregnant female, a complete autopsy and a macroscopic examination of the organs were carried out. Uterus were weighed and examined. For each ovary, corpora lutea were counted and foetuses were individually weighed and sexed. A gross examination of all foetuses was performed and one-third of the foetuses were examined for visceral anomalies. The other foetuses were evaluated for skeletal defects. No rats died during the treatment period. No toxic effects were reported during the study. Females of all dose groups had orange-brown discoloured urine throughout the application period at dose related intensity. Mean maternal bodyweight gains and mean food consumptions over the gestation period were normal when compared to the control group. Gross necropsy did not reveal any organ alterations related to treatment. No significant differences in the number of viable foetuses, the male to female sex ratio, birth- position, number of runts, post-implantation losses, implantations, resorptions and corpora lutea between dosage groups and the control group were observed. At 60mg/kg bw dose group showed an increase in foetal body weight and uteri weights with a tendency towards dose-relation. Examination of the foetuses yielded minor variations (wavy ribs) at comparable inter-group frequencies and incidences within the historical control animals of this strain. There were no biologically significant differences in the number of litters with malformations or developmental variations between any of the dose groups and the control group.HenceNOAEL was considered to be 30 mg/kg/day for test material in femaleWistar derived SPF-Albino Crl:Wi/Br rats when they were exposed at concentration0, 10, 30 and 60 mg/kg bw/dayduring gestation period of 5-15 days by oral gavage.

Study3

In a Teratology study,CFE-S female rats were treated with test material in the concentration of 0, 195 and 616 mg/kg/day orally in diet fromday 6 to day 15 of gestation. No adverse effect onaverage number of implantation sites, live pups or in the number of females with one or more resorption sites were observed in treated female rats. No effect on fetuses weight were observed in treated female rats. In addition, No were gross abnormalities, visceral and skeletal abnormalities were observed in fetusesoftreated female rats. Therefore, NOAEL was considered to be 616mg/kg/day for F0 and F1 geneartion when CFE-S female rats were treated with test material orally in diet for 10 days.

Study 4

In a Teratology study,New Zealand White female rabbits were treated with test materialin the concentration of0, 19.5 and 97.5 mg/kg/day orally by gavage fromday 6 to day 18 of gestation. Bluebrown colored urine were observed in all treated rabbits.

No adverse effect onbody weight gain, Number of pregnancies, numbers of corpora lutea, implantations, resorptions, and live and stillborn fetuses were observed in treated female rabbits. No effect on fetusesweight were observed in treated female rabbits. In addition, No gross abnormalities, visceral and skeletal abnormalities were observed in fetusesoftreated female rabbits. Therefore, NOAEL was considered to be 97.5 mg/kg/day for F0 and F1 geneartion when New Zealand White female rabbits were treated with test material orally by gavage for 13 days.

Thus, based on the data available fortest chemical,No Observed Adverse Effect Level (NOAEL) was considered to be 30mg /kg bw .When rats were treated with test chemical orally. Thus, comparing this value with the criteria of CLP regulationtest chemicalis not likely to classify as reproductive and developmental toxicant.

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation test chemical is not likely to classify as reproductive and developmental toxicant.