1'-acetonaphthone

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

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 393.6 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:

two-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 is from peer- reviewd journal

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Principles of method if other than guideline:

Two-generation reproductive toxicity study of α-methyl naphthyl ketone in rats

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

not specified

Details on species / strain selection:

No data available

Sex:

not specified

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: feed

Type of inhalation exposure (if applicable):

not specified

Vehicle:

other: Feed

Details on exposure:

No data available

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

8 months

Frequency of treatment:

Every other day

Details on study schedule:

No data available

Dose / conc.:

2 mg/kg diet

No. of animals per sex per dose:

No data available

Control animals:

not specified

Details on study design:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

No data available

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

No data available

Postmortem examinations (offspring):

No data available

Statistics:

No data available

Reproductive indices:

Reproduction were examined

Offspring viability indices:

No data available

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

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

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 specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Reproductive performance: No effects on reproduction of P generation were observed in treated rats at 2 mg.

Dose descriptor:

NOAEL

Effect level:

2 mg/kg diet

Based on:

test mat.

Sex:

not specified

Remarks on result:

other: No effect on reproduction

Critical effects observed:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

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

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

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

not specified

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:

not specified

Histopathological findings:

not specified

Other effects:

no effects observed

Reproductive performance: No effects on reproduction of F1 generation were observed in treated rats at 2 mg.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

2 mg/kg diet

Based on:

test mat.

Sex:

not specified

Remarks on result:

other: No effect on Reproduction

Critical effects observed:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

not specified

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:

not specified

Histopathological findings:

not specified

Other effects:

no effects observed

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Reproductive performance: No effects on reproduction of F2 generation were observed in treated rats at 2 mg.

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

2 mg/kg diet

Based on:

test mat.

Sex:

not specified

Remarks on result:

other: No effect on reproduction

Critical effects observed:

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

Conclusions:

NOAEL was considered to be 2 mg/kg in P0, F1 and F2 generation when rats were treated with test material orally in diet for 8 months.

Executive summary:

In a two generation reproductive toxicity study, rats were treated with test material in the concentration of 2 mg every other day in diet. No effects on reproduction of P, F1 and F2 generation were observed in treated rats at 2 mg. Therefore, NOAEL was considered to be 2 mg/kg in P0, F1 and F2 generation when rats were treated with test material orally in diet for 8 months.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

393.6 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from authoritative database

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity study

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

Study 1

In a two generation reproductive toxicity study, rats were treated with test material in the concentration of 2 mg every other day in diet. No effects on reproduction of P, F1 and F2 generation were observed in treated rats at 2 mg. Therefore, NOAEL was considered to be 2 mg/kg in P0, F1 and F2 generation when rats were treated with test material orally in diet for 8 months.

Study 2

In a 28 days repeated dose toxicity study, the effect of test material was evaluated in male and female Sprague Dawley rats. The test chemical was administered by oral gavage in the concentration of 0, 125, 250 or 500 mg/kg body weight/day. The results showed that methyl 2-naphthyl ether significantly increased the level of testosterone in the 500 mg/kg body weight/day group as well as it significantly increased the level of estrogen in the 250 mg/kg body weight/day group .The relative and absolute organ weight of ovaries decreased when treated with 125, 250 or 500 mg/kg body weight/day. In similarity, the relative and absolute organ weight of uterus decreased in the 125 or 500 mg/kg body weight/day groups.No significant changes in were detected in hematology,clinical biochemistry,mortality ororgan weight, and no effects were observed in water consumption,opthalmoscopic examination or locomotor activity. In male rats, the relative organ weights of the testes and epididymides increased when rats were treated with 500 mg/kg body weight/day. Histopathology performed on reproductive organs after treatment with 500 mg/kg body weight/day did not reveal any toxic lesions as compared to control. Hence, NOAEL was considered to be 250 mg/kg body weight/day when Sprague Dawley rats were exposed daily to test material by oral route for 28 days.

Study 3

One generation reproductive toxicity study of test material was performed according to OECD Guideline 415. The test material mixed with diet in dose concentration 0, 100, 500 and 2500 ppm and adminstered to groups of 25 rats per sex per group. Males were treated for 10 weeks and during the mated period and females for at least two weeks before mating until sacrifice. Body weights were recorded weekly during gestation period and at days 1, 4, 7, 14 and 21 during lactation period. Food consumption was measured weekly during experimental period. Food intake was recorded on presumed gestation days 7, 14 and 20 and on lactation days 4, 7, 14, 18 and 21. At birth, the number of pups born, sex and body weight of individual pups on days 1 and 4 were recorded. After standardization of litter size to 8 pups, pups were weighed individually on days 7, 14 and 21 of lactation. On day of weaning sacrifice (day 21), only one randomly selected pup per sex per litter was submitted to macroscopic examination. Fertility index for dams, sires and pup survival index were calculated. On completion of the gross pathology examination, the following tissues and organs were preserved in 10% neutral buffered formalin and submitted to microscopic examination: grossly abnormal tissues, ovaries, uterus, vagina, testes, epididymides, seminal vesicles, prostate, coagulating glands, pituitary gland and target organs of all P animals. The number of corpora lutea and implantation sites were recorded for all the dams. Histopathological examination of the parents was initially restricted to preserved organs from control and high dose group animals.

There were significant lower body weights from control at high dose in males from weeks 2 to 6 and at week 8 associated with a significant lower food intake at weeks 2 and 8 at high dose in males. There was also a significant decrease in bodyweights at day 20 of the gestation period in females of the high dose group, also observed at days 4, 7 and 14 of lactation period. A statistically significant increase in relative kidney weights at mid dose in males and at high dose for males and females was observed. The increased kidney weights observed in males and females were minimal in nature (<12%) and were not associated with microscopic changes, hence considered as toxicologically insignificant changes. A statistically significant increase in relative epididymides was also recorded at high dose in males but with no related microscopic changes in left epididymides. Further, there were no corresponding change in the weight of right cauda epididymides and epididymal sperm count therefore the increased epididymal weights were considered as incidental changes.There were no test item related changes in sperm motility, cauda epididymal sperm counts and sperm morphology parameters. However, a statistically significant increase in percentage of abnormal sperms was observed in high dose males but this observed change was within the historical control data. Moreover, no fertility parameters were affected and there were no changes in the testes or epididymis grossly or histopathologically therefore, considered incidental and not related to the treatment. There were no test item related gross findings in males and females. Only single incidences of several gross findings observed in different groups were considered as incidental without any relation to test item administration. There were no test item related microscopic changes in males and females. All single or few incidences of microscopic findings observed in males and females were considered as incidental findings. The mean number and weight of male, female and total pups per litter at all the doses tested were unaffected by treatment. No treatment-related changes were observed in the data of pups up to lactation day 21 at all the doses tested. HenceNo Observed Adverse Effect Level (NOAEL) for maternal and developmental toxicity was considered to be2500 ppm which is equivalent to 153.8 mg/kg Bwt/day for males and 393.6 mg/kg Bwt/day for females,.When male and femalerats were treated with test material orally over one generation.

Based on the data available from different studies ,test material did not showedreproductive toxicityat dose concentration 393.6mg/kg body weight/day,when male and female rats were treated with test material orally,Thus, comparing this value with the criteria ofCLP regulationtest materialis 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 in range of 50-150mg/kg bw .When rats or rabbits 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:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Remarks:

Experimental data of read across substances

Justification for type of information:

Weight of evidence approach based on structurally similar chemicals

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

WoE report is based on two developmental toxicity studies on rats and rabbits
Developmental Toxicity study was performed on rabbits.

GLP compliance:

not specified

Limit test:

no

Species:

other: 1.rabbit 2.rat

Strain:

other: 1.New Zealand White 2.Crl:CD BR VAF/Plus

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

other: 0.5% Carboxymethyl cellulose

Details on exposure:

Study 1
Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test material dissolved in 0.5% Carboxymethyl cellulose

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): Test material dissolved in 0.5% Carboxymethyl cellulose
- Concentration in vehicle: 0, 3, 10,50mg/kg/day
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity:

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

No data available

Duration of treatment / exposure:

Study 1
23(gestation day 6 to 28)
Study 2
10 days (On gestation days 6-15.)

Frequency of treatment:

daily

Duration of test:

Study 1
30 days
Study 2
15 days

Remarks:

Study 1
0, 3, 10,50mg/kg/day.
Study 2
0, 150, 300, 600, or 1000 mg/kg/day

No. of animals per sex per dose:

Study 1
Total:100
0mg/kg/day: 25 female
3mg/kg/day:25 female
10mg/kg/day:25 female
50mg/kg/day:25 female

Control animals:

yes, concurrent vehicle

Details on study design:

Study 1
- Dose selection rationale: base on the preliminary range-finding study (0, 10, 60 and 300 mg/kg/day).
- Rationale for animal assignment (if not random):
- Other:

Maternal examinations:

Study 1&2
Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: twice daily

BODY WEIGHT: Yes
Time schedule for examinations: Individual body weights were recorded on gestation days 0, 3, 5, 8, 11, 14, 17, 20, 23, 26, 29 and 30.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes Food consumption per cage of animals were measured over the following periods during gestation: days 0-3, 3- 5, 5-8, 8-11, 11-14, 14-17, 17-20, 20-26, 26-29 and 29-30.
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
Time schedule for examinations:

OTHER:

Ovaries and uterine content:

Study 1&2
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:

Study 1&2
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes
- Skeletal examinations: Yes:
- Head examinations: Yes

Statistics:

Study 1
The test parameters body weight, percent body weight change, feed consumption, prenatal data and foetal data will be analysed using statistical techniques like Bartlett’s test, ANOVA and Dunett’s and Student’s t tests. Foetal examination will be analysed using Chi-square test.

Indices:

No data available

Historical control data:

No data available

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Study 2.tremors, uncoordinated movements, recumbent posture, languidness, cold body were observed

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Description (incidence):

Study 1.There were no maternal death.
Study 2.The increased mortality was observed in 1000mg/kg /day dose group.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Study 1.There was a significant reduction in the body weight gain during the treatment period in the high dose group (50 mg/kg).The reduction in body weight during the treatment period was considered treatment related.
Study 2.Decreased body weight gain.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Study 1.The food consumption was comparable to the vehicle control group.

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

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:

effects observed, treatment-related

Description (incidence and severity):

Study 1.One rabbit aborted in the 50mg/kg dose group

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

Study 1.The maternal data parameters comprising of pre and post-implantation loss in all the treatment groups were comparable to the vehicle control group

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Study 1.The maternal data parameters comprising of early and late resorptions in all the treatment groups were comparable to the vehicle control group

Early or late resorptions:

no effects observed

Description (incidence and severity):

Study 1.The maternal data parameters comprising of early and late resorptions in all the treatment groups were comparable to the vehicle control group

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:

effects observed, treatment-related

Description (incidence and severity):

Study 1.There were 2 non pregnant rabbits in control, 4 in low dose group, 3 in mid dose group and 4 in the high dose group. There was one complete resorption in mid dose group.

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

> 10 - <= 150 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

changes in number of pregnant

early or late resorptions

food consumption and compound intake

mortality

number of abortions

pre and post implantation loss

total litter losses by resorption

Remarks on result:

other: No toxic effects observed

Abnormalities:

not specified

Localisation:

not specified

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Study1.no effects observed
Study2.Fetal body weights were decreased at 600 and 1000 mg/kg/day.
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:

not specified

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

not specified

Skeletal malformations:

effects observed, treatment-related

Description (incidence and severity):

Study 2.Skeletal variations were seen at dose group 300 mg/kg/day and at higher doses. The skeletal variations manifested as increased unossified sternebrae, seventh cervical ribs, and misaligned sternebrae

Visceral malformations:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

> 50 - <= 150 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

changes in sex ratio

fetal/pup body weight changes

Remarks on result:

other: No developmental toxic effects 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

Main parameters of pregnant rabbits treated with test material during organogenesis period

Group		1	2		3	4
dose (mg/kg/d)		0	3		10	50
Maternal observations
Mortality		0/25	0/25	0/25		0/25
	Day 0-6	6.80	8.06	8.85		6.44
Body weight gain (%)
	Day 6-30	15.67	10.62		18.99	9.28*
	Day 0-30	20.55	17.54		25.32	14.74
No. of rabbits aborted		0	0		0	1
No. of non pregnant rabbits		2	4		3	4
No of pregnant rabbits		23	21		22	20
Dams with complete resorptions		0	1		0	0
Number of litter examined		23	20		22	20

* : Significantly different from vehicle control at p≤0.05

 

Main parameters of pregnant rabbits treated with test material during organogenesis period

Group		1	2	3	4
dose (mg/kg/d)		0	3	10	50
Litter observations
Number of Corpora lutea		8.43	8.24	8.77	6.70*
Pre-implantation loss (%)		9.00	11.33	6.37	19.43*
Post-implantation loss (%)		3.60	7.82	5.65	5.26
Early resorptions		0.35	0.24	0.36	0.25
Late resorptions		0.00	0.14	0.09	0.05
Mean litter size		7.70	7.52	8.27	5.50**
Fetus weight (g)	Male	44.03	43.15	41.83	43.27
	Female	42.28	40.82	42.10	42.85
Sex ratio- Male: Female		1:1.85	1:1.30	1:1.15	1:1.00

 

* : Significantly different from vehicle control at p≤0.05

**: Significantly different from vehicle control at p≤0.01

Conclusions:

No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be in range of 50-150 mg/kg/day, When rabbits or rats were treated with test material orally.

Executive summary:

Data available from different studies for the target as well as the read across substances were reviewed to determine the developmental toxicity of test material.The studies are as mentioned below:

Study 1

The developmental toxicity study of test material was performed according to OECD guideline 414 on rabbits. Young adult nulliparous New-Zealand white strain female and male rabbits (Oryctolagus cuniculus) were used in study. The test material dissolved in 0.5% Carboxymethyl cellulose in dose concentration 0, 3, 10 and 50 mg/kg/day and administered by daily gavage through gestation day 6 to 28to mated females (25/dose group).The preliminary range-finding study (0, 10, 60 and 300 mg/kg/day) was performed, Based on preliminary range-finding study findings, 0, 3, 10 and 50 mg/kg/day were selected for the main study. Animals were observed twice daily for morbidity and mortality. Individual clinical signs were recorded at least once a day during the treatment period and once daily during the pre- and post-treatment periods. Individual body weights were recorded on gestation days 0, 3, 5, 8, 11, 14, 17, 20, 23, 26, 29 and 30. Food consumption per cage of animals were measured over the following periods during gestation: days 0-3, 3- 5, 5-8, 8-11, 11-14, 14-17, 17-20, 20-26, 26-29 and 29-30. On Day 29 of gestation, all the rabbits were sacrificed using intravenous injection of sodium thiopentone. Any gross pathological changes in all the visceral organs of dams were recorded. Organs with macroscopic findings and kidneys were preserved for possible histological evaluation. The ovaries, uteri and uterine contents were removed and examined to determine: the number of corpora lutea, the number of implantations, early and late resorptions, the weight of intact gravid uterus, the number and distribution of live foetuses, the number and distribution of intra-uterine dead foetuses, the individual foetal weight and sex, foetal abnormalities.

There were no maternal death or necropsy findings at any dose levels. There was a significant reduction in the body weight gain during the treatment period in the high dose group (50 mg/kg). The food consumption was comparable to the vehicle control grou. The reduction in body weight during the treatment period was considered treatment related. One rabbit aborted in the high dose group, there were 2 non pregnant rabbits in control, 4 in low dose group, 3 in mid dose group and 4 in the high dose group. There was one complete resorption in mid dose group. At the end, at least 20 litters were observed in each of the dose groups. The maternal data parameters comprising of implantations, early and late resorptions, pre and post-implantation loss in all the treatment groups were comparable to the vehicle control group. The mean number of corpora lutea, implantation and live foetus were significantly lower in high dose group (50 mg/kg body weight/day) when compared with the control group. Observed decrease in corpora lutea at 50 mg/kg body weight/day is considered as biological variation because the treatment was initiated after the implantation (gestation day 6). Therefore, the decrease observed in the absolute uterine weight, implantation and live foetus reported at this dose level are also considering as biological variation as these observations are directly correlated with the decrease in the number of the corpora lutea. Hence No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be 50 mg/kg/day,When female rabbits were treated with test material orally.

 Study2.

The developmental toxicity study of test material was performed on Crl:CD BR VAF/Plus rats. Test material in dose concentration0, 150, 300, 600, or 1000 mg/kg/day was administered orally on gestation days 6-15. The mortality observed on1000 mg/kg/day dose group. Clinical signs like Tremors, uncoordinated movements, recumbent posture, languidness, cold body and decreased body weight gain observed. Fetal body weights were decreased at 600 and 1000 mg/kg/day. Skeletal variations were seen at the 300 mg/kg/day and at higher doses. The skeletal variations manifested as increased unossified sternebrae, seventh cervical ribs, and misaligned sternebrae. Hence No Observed Effect Level (NOELs )for maternal and developmental toxicity were considered to be 150mg/kg/day. When rats were treated with test material orally on gestation days 6-15.

Thus, Based on the data available forthe target as well as the read across substances ,No Observed Adverse Effect Level (NOAEL) was considered to be in range of 50-150mg/kg bw . Thus, comparing this value with the criteria of CLP regulation test material is not likely to classify as reproductive and developmental toxicant.

 

 

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

50 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 study available

Additional information

Developmental toxicity study

Data available from different studies for the target as well as the read across substances were reviewed to determine the developmental toxicity of test material.The studies are as mentioned below:

Study 1

The developmental toxicity study of test material was performed according to OECD guideline 414 on rabbits. Young adult nulliparous New-Zealand white strain female and male rabbits (Oryctolagus cuniculus) were used in study. The test material dissolved in 0.5% Carboxymethyl cellulose in dose concentration 0, 3, 10 and 50 mg/kg/day and administered by daily gavage through gestation day 6 to 28to mated females (25/dose group).The preliminary range-finding study (0, 10, 60 and 300 mg/kg/day) was performed, Based on preliminary range-finding study findings, 0, 3, 10 and 50 mg/kg/day were selected for the main study. Animals were observed twice daily for morbidity and mortality. Individual clinical signs were recorded at least once a day during the treatment period and once daily during the pre- and post-treatment periods. Individual body weights were recorded on gestation days 0, 3, 5, 8, 11, 14, 17, 20, 23, 26, 29 and 30. Food consumption per cage of animals were measured over the following periods during gestation: days 0-3, 3- 5, 5-8, 8-11, 11-14, 14-17, 17-20, 20-26, 26-29 and 29-30. On Day 29 of gestation, all the rabbits were sacrificed using intravenous injection of sodium thiopentone. Any gross pathological changes in all the visceral organs of dams were recorded. Organs with macroscopic findings and kidneys were preserved for possible histological evaluation. The ovaries, uteri and uterine contents were removed and examined to determine: the number of corpora lutea, the number of implantations, early and late resorptions, the weight of intact gravid uterus, the number and distribution of live foetuses, the number and distribution of intra-uterine dead foetuses, the individual foetal weight and sex, foetal abnormalities.

There were no maternal death or necropsy findings at any dose levels. There was a significant reduction in the body weight gain during the treatment period in the high dose group (50 mg/kg). The food consumption was comparable to the vehicle control grou. The reduction in body weight during the treatment period was considered treatment related. One rabbit aborted in the high dose group, there were 2 non pregnant rabbits in control, 4 in low dose group, 3 in mid dose group and 4 in the high dose group. There was one complete resorption in mid dose group. At the end, at least 20 litters were observed in each of the dose groups. The maternal data parameters comprising of implantations, early and late resorptions, pre and post-implantation loss in all the treatment groups were comparable to the vehicle control group. The mean number of corpora lutea, implantation and live foetus were significantly lower in high dose group (50 mg/kg body weight/day) when compared with the control group. Observed decrease in corpora lutea at 50 mg/kg body weight/day is considered as biological variation because the treatment was initiated after the implantation (gestation day 6). Therefore, the decrease observed in the absolute uterine weight, implantation and live foetus reported at this dose level are also considering as biological variation as these observations are directly correlated with the decrease in the number of the corpora lutea. Hence No Observed Adverse Effect Level (NOAEL) for developmental toxicity was considered to be 50 mg/kg/day,When female rabbits were treated with test material orally.

 Study2.

The developmental toxicity study of test material was performed on Crl:CD BR VAF/Plus rats. Test material in dose concentration0, 150, 300, 600, or 1000 mg/kg/day was administered orally on gestation days 6-15. The mortality observed on1000 mg/kg/day dose group. Clinical signs like Tremors, uncoordinated movements, recumbent posture, languidness, cold body and decreased body weight gain observed. Fetal body weights were decreased at 600 and 1000 mg/kg/day. Skeletal variations were seen at the 300 mg/kg/day and at higher doses. The skeletal variations manifested as increased unossified sternebrae, seventh cervical ribs, and misaligned sternebrae. Hence No Observed Effect Level (NOELs )for maternal and developmental toxicity were considered to be 150mg/kg/day. When rats were treated with test material orally on gestation days 6-15.

Thus, Based on the data available forthe target as well as the read across substances ,No Observed Adverse Effect Level (NOAEL) was considered to be in range of 50-150mg/kg bw . Thus, comparing this value with the criteria of CLP regulation test material is 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.