Sodium 2-amino-4,6-dinitrophenoxide

Endpoint summary

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

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 or test system 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	12.10^c	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	15^d	4
No. females aborting	0	0	0	0	0
Fetal parameters
Mean no. live fetuses/group	10.65	10.85	12.50	8.70^c	11.00
Mean live fetal weight (g)	3.38	3.58	3.62	2.89^e	3.79^f
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 5^h,i	0.65^g
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

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 or test system 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:

body weight and weight gain

clinical signs

early or late resorptions

food consumption and compound intake

pre and post implantation loss

total litter losses by resorption

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	12.10^c	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	15^d	4
No. females aborting	0	0	0	0	0
Fetal parameters
Mean no. live fetuses/group	10.65	10.85	12.50	8.70^c	11.00
Mean live fetal weight (g)	3.38	3.58	3.62	2.89^e	3.79^f
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 5^h,i	0.65^g
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.