N,N-diethyl-3-oxobutyramide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity study

 The data available for N,N-diethyl-3-oxobutanamide (2235-46-3)and structurally similar read across chemicals was reviewed to determine the reproductive toxicity.The NOAEL for reproductive toxicity was considered to be above 50-250mg/kg bw/day as No effects on reproductive parameters were observed .When male and female rats were treated with N,N-diethyl-3-oxobutanamide (2235-46-3).Thus, comparing this value with the criteria of CLP regulation N,N-diethyl-3-oxobutanamide (2235-46-3)not likely to classify as reproductive toxicant.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Remarks:

Experimental data of read across substances

Justification for type of information:

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:

other: As mentioned below

Principles of method if other than guideline:

WoE report is based on two reproductive toxicity studies on rats Study 1&2.Reproductive and Developmental toxicity study of test material was performed on Sprague Dawley rats.

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

No data available

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: feed

Vehicle:

not specified

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:

Study 1F0: 80 days before mating during mating, gestation, and lactation.F1: 93 days before mating during mating, gestation, and lactation.Study 214 days (from day 6 to day 20 p.c.)

Frequency of treatment:

daily

Details on study schedule:

No data available

Remarks:

Study 10, 500, 2,000, or 5,000 ppm ( 0, 25, 100, or 250 mg /kg/day)Study 20, 50,250,750 mg/kg bw/day

No. of animals per sex per dose:

Study 1Total:1120 mg/kg bw/day:28 male and 28 female 25 mg/kg bw/day:28 male and 28 female100 mg/kg bw/day:28 male and 28 female250mg/kg bw/day:28 male and 28 female

Control animals:

yes

Details on study design:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

Study 1&2Parental animals observation and examinationsCAGE SIDE OBSERVATIONS: yes DETAILED CLINICAL OBSERVATIONS: Yes Time schedule: twice daily BODY WEIGHT: YesTime schedule for examinations: twice dailyFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): twice dailyFood consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: no Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data availableWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data Time schedule for examinations:

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

Study 1The F1 and F2 litters were observed for number of live and stillborn pups, external anomalies, sex and body weight grouped by sex on lactation days 0, 4, 7, and 14, sex and individual body weights (only group weights reported) on lactation day 21, viability, and behavioral abnormalities at least twice daily during lactation.Study 2Pups were examined for external abnormalities.The number of viable and nonviable pups was recorded for each female. All pups were sexed and weighed individually

Postmortem examinations (parental animals):

Study 1&2Postmortem examinations (Parent Animal)SACRIFICE :yes GROSS NECROPSY: yes gross necropsy and histological examination of the ovaries, prostate, seminal vesicles, testes with epididymides, uterus, vagina, and all gross lesions were conducted in all parental rats HISTOPATHOLOGY / ORGAN WEIGHTSThe tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.: macroscopic examination was performed

Postmortem examinations (offspring):

Study 1&2SACRIFICE - The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at ) on lactation day 21 days of age. - These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows: GROSS NECROPSY - Gross necropsy consisted of external and internal examinations ,sex and body weight HISTOPATHOLOGY / ORGAN WEIGTHS The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.

Statistics:

No data available

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Study 1.Hair loss appeared to be more prominent in 250mg/kg dose group F0 females than in other groupsStudy 2.

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

Study 1.There were no chemical-related deaths during the studyStudy 2.1/24 females given 750 mg/kg/day found dead

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Study 1.Body weights of parental rats were lower in some of the 100mg/kg and 250 mg/kg dose groups at some points in the study, but the difference with controls was generally <10%.Study 2.Slight to markedly lower body weight gain at 250 and 750 mg/kg/day (statistically significant at 750 mg/kg/day, p<0.001) between Days 6 and 21 p.c. ; lower final body weight at 750 mg/kg/day (statistically significant, p<0.001).

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Study 1.Changes in food consumption tended to parallel the changes in body weight and were generally <10% different than controls.Study 2.Reduced food consumption at 250 and 750 mg/kg/day at initiation of the treatment period, persisting until Day 18 p.c. at 750 mg/kg/day.

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:

effects observed, treatment-related

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

Description (incidence and severity):

Study 1.No treatment-related effects on reproduction or fertility were observed at any of the dose levels evaluated in this study.Study 2.Post implantation loss: slight to markedly higher at 250 and 750 mg/kg/day

Dose descriptor:

NOAEL

Effect level:

> 50 - < 250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

reproductive performance

Remarks on result:

other: No treatment-related effects on reproduction or fertility were observed at any of the dose levels

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:

effects observed, treatment-related

Description (incidence and severity):

Study 1.Hair loss appeared to be more prominent in 250mg/kg dose group F1 females than in other groups

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Description (incidence and severity):

Study 2.24/24, 21/24, 23/24 and 18/23 females with live fetuses at 0, 50, 250 and 750 mg/kg/day, respectively

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Study 1.reduced male and female F1 pup weights in the 250mg/kg dose group on lactation days 14 and 21Study 2.Fetal body weight/litter: statistically significantly lower at 750 mg/kg/day

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:

effects observed, treatment-related

Description (incidence and severity):

Study 1.F1 males showed mottled kidneys with incidences of 0/23, 2/23 (9%), 6/23 (26%), and 8/23 (35%) of the males (control and increasing dose groups). Microscopy revealed inflammation, hyaline droplet and granular cast formation, and regeneration of tubules.

Gross pathological findings:

not specified

Description (incidence and severity):

Study 2.malformations (anasarca, cleft palate, short trunk, anal atresia, short tail and/or acaudate) in 2 fetuses from 2/18 litters at 750 mg/kg/day

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

> 50 - <= 100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

clinical signs

body weight and weight gain

organ weights and organ / body weight ratios

Remarks on result:

other: overall no developmental toxic effects 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:

mortality observed, treatment-related

Description (incidence and severity):

Decreased F2 pup viability in the 50mg/kg and 250mg/kg dose groups on postnatal day 4

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Reduced male and female F2 pup weights in the 250mg/kg bw dose group on lactation days 14 and 21

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:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

mortality

body weight and weight gain

Remarks on result:

other: overall no developmental toxic effects 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

Body Weight (g) of Rats on Lactation Day 21 in a 2-Generation Reproductive Study

Doses (mg/kg/day)	0	25	100	250
F1 male	46.2±6.50^a	46.8 ±5.06	45.7 ±4.53	40.1 ±4.22^b
F1 female	44.1 ±4.64	44.6 ±4.44	44.2 ±4.51	39 1± 4.60^b
F2 males	50.4 ±4.31	49.4 ±6.07	47.9 ±4.02	44.5± 3.93^b
F2 Female	47.3± 4.52	47.6 ± 5.35	44.1 ±7.50	42.3± 3.23^b

 

 

^aMean±standard deviation.^bp<0.01.

Conclusions:

No Observed Effect Level (NOEL) for reproductive toxicity was considered to be 250mg/kg/day, and NOAEL dose-level of 100 mg/kg/day was considered to be for developmental toxicity. When male and female Sprague Dawley rats were treated with N,N-diethyl-3-oxobutanamide (2235-46-3)orally.

Executive summary:

Data available from different studies were reviewed to determine the reproductive toxicity of  N,N-diethyl-3-oxobutanamide (2235-46-3).The studies are as mentioned below:

Study 1

A two-generation reproductive study of test material was performed in male and female Sprague-Dawley rats. Test material in dose concentration 0, 500, 2,000, or 5,000 ppm ( 0, 25, 100, or 250 mg /kg/day) were fed diets. The F0 parental generation consisted of 28 males and 28 females per group which were administered treated or control diet for at least 80 days prior to mating. Twenty-eight male and 28female offspring per group from the F1 generation were selected randomly to become the parents of the F2generation. These animals were treated for at least 93 days prior to mating. For both parental groups, treatment was continued through gestation and lactation. After weaning, 10 pups/sex/groups were subjected to gross necropsy. F0 females were killed after the selection of F1 parents. F1 females were sacrificed after weaning of their litters. The parameters were used to assess toxicity were twice daily observations for deaths and clinical signs, body weight, and food consumption (not measured during the mating periods). Additionally, gross necropsy and histological examination of the ovaries, prostate, seminal vesicles, testes with epididymides, uterus, vagina, and all gross lesions were conducted in all parental rats and 10 weanlings/sex/group in the control and 250mg/kg/daydose groups. Parameters used to assess developmental toxicity in the F1 and F2 litters included number of live and stillborn pups, external anomalies, sex and body weight grouped by sex on lactation days 0, 4, 7, and 14, sex and individual body weights (only group weights reported) on lactation day 21, viability, and behavioral abnormalities at least twice daily during lactation.

There were no chemical-related deaths during the study. Hair loss appeared to be more prominent in 250mg/kg /day dose group F0 and F1 females than in other groups. Body weights of parental rats were lower in some of the 100 mg/kg /day and 250mg/kg /day dose groups at some points in the study, but the difference with controls was generally <10%. Changes in food consumption tended to parallel the changes in body weight and were generally <10% different than controls. F1 males showed mottled kidneys with incidences of 0/23, 2/23 (9%), 6/23 (26%), and 8/23 (35%) of the males (control and increasing dose groups). Microscopy revealed inflammation, hyaline droplet and granular cast formation, and regeneration of tubules. No explicit information was provided in the review regarding the other organs examined. Neonatal toxicity as evidences by reduced pup sizes in both generations was noted for males and females250mg/kg /day groups on postnatal day 4 and reduced male and female F1 and F2 pup weights in the 250mg/kg /day dose group on lactation days 14 and 21.No treatment-related effects on reproduction or fertility were observed at any of the dose levels evaluated in this study. Hence No Observed Effect Level (NOEL) for reproductive toxicity was considered to be 250mg/kg/day, and NOAEL dose-level of 100 mg/kg/day was considered to be for developmental toxicity. When male and female Sprague Dawley rats were treated with test material orally.

Study 2

 

Reproductive and developmental toxicity study of test material was performed on female rats according OECD Guidelines for Testing of Chemicals; Methods No. 414. The test material in dose concentration0, 50,250,750 mg/kg bw/dayvia oral administration from day 6 to day 20 p.c. Clinical signs, Body weight and food consumption were noted. Pups were examined for external abnormalities. The number of viable and nonviable pups was recorded for each female. All pups were sexed and weighed individually. Clinical signs round back, emaciated appearance, piloerection , loud breathing, dyspnea, sneezing, reddish vaginal discharge, chromorhinorrhea and/or dacryhorrhea) in 1/24, 4/24 and 14/24 females given 50, 250 or 750 mg/kg/day, respectively. Ptyalism in 1/24 and 16/24 females given 250 or 750 mg/kg/day. 1/24 females given 750 mg/kg/day found dead. slight to markedly lower body weight gain at 250 and 750 mg/kg/day (statistically significant at 750 mg/kg/day, p<0.001) between Days 6 and 21 p.c. ; lower final body weight at 750 mg/kg/day (statistically significant, p<0.001). Reduced food consumption at 250 and 750 mg/kg/day at initiation of the treatment period, persisting until Day 18 p.c. at 750 mg/kg/day. Post implantation loss: slight to markedly higher at 250 and 750 mg/kg/day. Gravid uterus weight slight to markedly lower at 250 and 750 mg/kg/day. 24/24, 21/24, 23/24 and 18/23 females with live fetuses at 0, 50, 250 and 750 mg/kg/day, respectively. Fetal body weight/litter statistically significantly lower at 750 mg/kg/day. Malformations (anasarca, cleft palate, short trunk, anal atresia, short tail and/or acaudate) in 2 fetuses from 2/18 litters at 750 mg/kg/day were observed. HenceNo Observed Effect Level (NOEL) was considered to be 50mg/kg/day, and LOAEL dose-level of 250 mg/kg/day was considered to be for reproductive toxicity.When femalerats were treated withtest material orally.

Based on the data available from different studies, N,N-diethyl-3-oxobutanamide (2235-46-3)did not showed reproductive toxicity at dose concentration below 250mg/kg bw/day . Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subchronic

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  N,N-diethyl-3-oxobutanamide (2235-46-3).The studies are as mentioned below:

Study 1

A two-generation reproductive study of test material was performed in male and female Sprague-Dawley rats. Test material in dose concentration 0, 500, 2,000, or 5,000 ppm ( 0, 25, 100, or 250 mg /kg/day) were fed diets. The F0 parental generation consisted of 28 males and 28 females per group which were administered treated or control diet for at least 80 days prior to mating. Twenty-eight male and 28female offspring per group from the F1 generation were selected randomly to become the parents of the F2generation. These animals were treated for at least 93 days prior to mating. For both parental groups, treatment was continued through gestation and lactation. After weaning, 10 pups/sex/groups were subjected to gross necropsy. F0 females were killed after the selection of F1 parents. F1 females were sacrificed after weaning of their litters. The parameters were used to assess toxicity were twice daily observations for deaths and clinical signs, body weight, and food consumption (not measured during the mating periods). Additionally, gross necropsy and histological examination of the ovaries, prostate, seminal vesicles, testes with epididymides, uterus, vagina, and all gross lesions were conducted in all parental rats and 10 weanlings/sex/group in the control and 250mg/kg/daydose groups. Parameters used to assess developmental toxicity in the F1 and F2 litters included number of live and stillborn pups, external anomalies, sex and body weight grouped by sex on lactation days 0, 4, 7, and 14, sex and individual body weights (only group weights reported) on lactation day 21, viability, and behavioral abnormalities at least twice daily during lactation.

There were no chemical-related deaths during the study. Hair loss appeared to be more prominent in 250mg/kg /day dose group F0 and F1 females than in other groups. Body weights of parental rats were lower in some of the 100 mg/kg /day and 250mg/kg /day dose groups at some points in the study, but the difference with controls was generally <10%. Changes in food consumption tended to parallel the changes in body weight and were generally <10% different than controls. F1 males showed mottled kidneys with incidences of 0/23, 2/23 (9%), 6/23 (26%), and 8/23 (35%) of the males (control and increasing dose groups). Microscopy revealed inflammation, hyaline droplet and granular cast formation, and regeneration of tubules. No explicit information was provided in the review regarding the other organs examined. Neonatal toxicity as evidences by reduced pup sizes in both generations was noted for males and females250mg/kg /day groups on postnatal day 4 and reduced male and female F1 and F2 pup weights in the 250mg/kg /day dose group on lactation days 14 and 21.No treatment-related effects on reproduction or fertility were observed at any of the dose levels evaluated in this study. Hence No Observed Effect Level (NOEL) for reproductive toxicity was considered to be 250mg/kg/day, and NOAEL dose-level of 100 mg/kg/day was considered to be for developmental toxicity. When male and female Sprague Dawley rats were treated with test material orally.

Study 2

 Reproductive and developmental toxicity study of test material was performed on female rats according OECD Guidelines for Testing of Chemicals; Methods No. 414. The test material in dose concentration0, 50,250,750 mg/kg bw/dayvia oral administration from day 6 to day 20 p.c. Clinical signs, Body weight and food consumption were noted. Pups were examined for external abnormalities. The number of viable and nonviable pups was recorded for each female. All pups were sexed and weighed individually. Clinical signs round back, emaciated appearance, piloerection , loud breathing, dyspnea, sneezing, reddish vaginal discharge, chromorhinorrhea and/or dacryhorrhea) in 1/24, 4/24 and 14/24 females given 50, 250 or 750 mg/kg/day, respectively. Ptyalism in 1/24 and 16/24 females given 250 or 750 mg/kg/day. 1/24 females given 750 mg/kg/day found dead. slight to markedly lower body weight gain at 250 and 750 mg/kg/day (statistically significant at 750 mg/kg/day, p<0.001) between Days 6 and 21 p.c. ; lower final body weight at 750 mg/kg/day (statistically significant, p<0.001). Reduced food consumption at 250 and 750 mg/kg/day at initiation of the treatment period, persisting until Day 18 p.c. at 750 mg/kg/day. Post implantation loss: slight to markedly higher at 250 and 750 mg/kg/day. Gravid uterus weight slight to markedly lower at 250 and 750 mg/kg/day. 24/24, 21/24, 23/24 and 18/23 females with live fetuses at 0, 50, 250 and 750 mg/kg/day, respectively. Fetal body weight/litter statistically significantly lower at 750 mg/kg/day. Malformations (anasarca, cleft palate, short trunk, anal atresia, short tail and/or acaudate) in 2 fetuses from 2/18 litters at 750 mg/kg/day were observed. HenceNo Observed Effect Level (NOEL) was considered to be 50mg/kg/day, and LOAEL dose-level of 250 mg/kg/day was considered to be for reproductive toxicity.When femalerats were treated withtest material orally.

Based on the data available from different studies, N,N-diethyl-3-oxobutanamide (2235-46-3)did not showed reproductive toxicity at dose concentration below 250mg/kg bw/day . Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.

Effects on developmental toxicity

Description of key information

Developmental toxicity study

 The data available for N,N-diethyl-3-oxobutanamide (2235-46-3)andstructurally similarread across chemicals was reviewed to determine the developmental toxicity.The NOAEL for reproductive toxicity was considered to be above 50-250mg/kg bw/day as No effects on reproductive parameters were observed .When male and female rats were treated with

N,N-diethyl-3-oxobutanamide (2235-46-3).

Thus, comparing this value with the criteria of CLP regulation N,N-diethyl-3-oxobutanamide (2235-46-3) not likely to classify as reproductive 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:

other: As mentioned below

Principles of method if other than guideline:

WoE report is based on two developmental toxicity studies on rats Study 1&2 .Developmental toxicity study of test material was performed on female CD rats.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

other: CD

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on exposure:

No data available

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

mated female used

Duration of treatment / exposure:

Study 1.14 days (from days 6 to 15 of gestation)Study 2.14 days (from day 6 to day 20 p.c.)

Frequency of treatment:

daily

Duration of test:

No data available

Remarks:

Study 1.0, 125, 250or 750 mg/kg/dayStudy 20, 50,250,750 mg/kg bw/day

No. of animals per sex per dose:

Study 1.Total:1000 mg/kg bw/day:25 females 125 mg/kg bw/day:25 females 250mg/kg bw/day:25 females 750mg/kg bw/day: 25 females

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Maternal examinations:

Study 1& 2Parental animals observation and examinationsCAGE SIDE OBSERVATIONS: yes DETAILED CLINICAL OBSERVATIONS: Yes Time schedule: BODY WEIGHT: YesTime schedule for examinations: FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: no Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data availableWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data Time schedule for examinations: OTHER:

Ovaries and uterine content:

Study 1& 2The ovaries and uterine content was examined after termination: Yes Examinations included: - Gravid uterus weight: Yes - Number of corpora lutea: No data - Number of implantations: No data - Number of early resorptions: No data - Number of late resorptions: No data - Other:

Fetal examinations:

Study 1& 2- External examinations: Yes: all per litter - Soft tissue examinations: Yes: all per litter - Skeletal examinations: Yes: all per litter - Head examinations: No data

Statistics:

No data available

Indices:

No data available

Historical control data:

No data available

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Study 1.Clinical signs such as hypoactivity, ataxia, decreased muscle tone, foot splay, perinasal encrustation, and perioral wetness were observed; some of these signs were suggestive of neurotoxicity in this dose group because none of these signs were seen in the controls. Some of these clinical signs were seen only sporadically in the other treated groups. Study 2.Clinical signs round back, emaciated appearance, piloerection , loud breathing, dyspnea, sneezing, reddish vaginal discharge, chromorhinorrhea and/or dacryhorrhea) in 1/24, 4/24 and 14/24 females given 50, 250 or 750 mg/kg/day, respectively. Ptyalism in 1/24 and 16/24 females given 250 or 750 mg/kg/day.

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

Study 1.In the 750mg/kg /day dose group dams, there was an increase in mortality rateStudy 2.1/24 females given 750 mg/kg/day found dead

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Study 1.In the 750mg/kg /day dose group dams, there was an a reduction in body weight gain Study 2.Slight to markedly lower body weight gain at 250 and 750 mg/kg/day (statistically significant at 750 mg/kg/day, p<0.001) between Days 6 and 21 p.c. ; lower final body weight at 750 mg/kg/day (statistically significant, p<0.001).

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Study 1.In the 750mg/kg /day dose group dams, there was an a reduction in food consumptionStudy 2.Reduced food consumption at 250 and 750 mg/kg/day at initiation of the treatment period, persisting until Day 18 p.c. at 750 mg/kg/day.

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:

effects observed, treatment-related

Description (incidence and severity):

Study 1.an increase in mean liver weights.Study 2.Gravid uterus weight slight to markedly lower at 250 and 750 mg/kg/day.

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:

effects observed, treatment-related

Description (incidence and severity):

Study 1.A slight increase in percent post-implantation loss was seen in the 750mg/kg/day dose groupStudy 2.Post implantation loss: slight to markedly higher at 250 and 750 mg/kg/day

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

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

Dose descriptor:

NOAEL

Effect level:

> 50 - <= 250 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

mortality

organ weights and organ / body weight ratios

pre and post implantation loss

Remarks on result:

other: overall no toxic effects observed

Abnormalities:

not specified

Localisation:

not specified

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Study 1.a statistically-significant decrease in mean fetal body weight/litter was seen in the 750mg/kg /day dose group Study 2.Fetal body weight/litter: statistically significantly lower at 750 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:

effects observed, treatment-related

Description (incidence and severity):

Study 2.24/24, 21/24, 23/24 and 18/23 females with live fetuses at 0, 50, 250 and 750 mg/kg/day, respectively.

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

no effects observed

Description (incidence and severity):

Study 1.The incidence of external variations and/or malformations were comparable in the control and treatment groups

Skeletal malformations:

no effects observed

Description (incidence and severity):

Study 1.The incidence of skeletal variations and/or malformations were comparable in the control and treatment groupsStudy 2..malformations (anasarca, cleft palate, short trunk, anal atresia, short tail and/or acaudate) in 2 fetuses from 2/18 litters at 750 mg/kg/day

Visceral malformations:

no effects observed

Description (incidence and severity):

Study 1.The incidence of visceral variations and/or malformations were comparable in the control and treatment groups

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

> 50 - <= 250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

reduction in number of live offspring

external malformations

skeletal malformations

visceral malformations

Remarks on result:

other: overall 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

Conclusions:

No Observed Effect Level (NOEL) for developmental toxicity was considered to be above 50-250mg/kg/day, When female rats were treated with N,N-diethyl-3-oxobutanamide (2235-46-3) orally.

Executive summary:

Data available from different studies were reviewed to determine thedevelopmental toxicityof  N,N-diethyl-3-oxobutanamide (2235-46-3).The studies are as mentioned below:

Study 1

Developmental toxicity study of test material was performed on mated female CD rats. Undiluted test material in dose concentration0, 125, 250, or 750 mg/kg/day were administered via oral gavage route from days 6 to 15 of gestation.Control animals received corn oil .Twenty-five mated female rats per group were used in study. Clinical signs, body weights, food consumption, maternal liver and gravid uterine weights, maternal ovarian and uterine examination were noted. fetal external examinations and internal soft-tissue and skeletal examinations were carried out.In the 750mg/kg/day dose dams clinical signs such as hypoactivity, ataxia, decreased muscle tone, foot splay, perinasal encrustation, and perioral wetness were observed; some of these signs were suggestive of neurotoxicity in this dose group because none of these signs were seen in the controls. Some of these clinical signs were seen only sporadically in the other treated groups. In the high-dose dams, there was an increase in mortality rate, a reduction in body weight gain and food consumption, and an increase in mean liver weights. A slight increase in percent post-implantation loss was seen in the 750mg/kg/day dose group and a statistically-significant decrease in mean fetal body weight/litter was seen in the 750mg/kg/day dose group. No additional compound-related effects were found.The incidence of external, visceral, and skeletalvariations and/or malformations were comparable in the control and treatment groups. HenceNo Observed Effect Level (NOEL) for developmental toxicity was considered to be 250mg/kg/day,When femaleCD rats were treated withtest material orally.

Study 2

Developmental toxicity study of test material was performed on female rats according OECDGuidelines for Testing of Chemicals; Methods No. 414. The test material in dose concentration0, 50,250,750 mg/kg bw/dayvia oral administration fromday 6 to day 20 p.c.Clinical signs,Body weight and food consumptionwere noted.Pups were examined for external abnormalities. The number of viable and nonviable pups was recorded for each female. All pups were sexed and weighed individually.Clinical signs round back, emaciated appearance, piloerection , loud breathing, dyspnea, sneezing, reddish vaginal discharge, chromorhinorrhea and/or dacryhorrhea) in 1/24, 4/24 and 14/24 females given 50, 250 or 750 mg/kg/day, respectively. Ptyalism in 1/24 and 16/24 females given 250 or 750 mg/kg/day. 1/24 females given 750 mg/kg/day found dead. slight to markedly lower body weight gain at 250 and 750 mg/kg/day (statistically significant at 750 mg/kg/day, p<0.001) between Days 6 and 21 p.c. ; lower final body weight at 750 mg/kg/day (statistically significant, p<0.001). Reduced food consumption at 250 and 750 mg/kg/day at initiation of the treatment period, persisting until Day 18 p.c. at 750 mg/kg/day. Post implantation loss: slight to markedly higher at 250 and 750 mg/kg/day. Gravid uterus weight slight to markedly lower at 250 and 750 mg/kg/day. 24/24, 21/24, 23/24 and 18/23 females with live fetuses at 0, 50, 250 and 750 mg/kg/day, respectively. Fetal body weight/litter statistically significantly lower at 750 mg/kg/day. Malformations (anasarca, cleft palate, short trunk, anal atresia, short tail and/or acaudate) in 2 fetuses from 2/18 litters at 750 mg/kg/day were observed. HenceNo Observed Effect Level (NOEL) was considered to be 50mg/kg/day for developmental toxicity.When femalerats were treated withtest materialorally.

  Based on the data available from different studies, N,N-diethyl-3-oxobutanamide (2235-46-3)did not showeddevelopmental toxicity at dose concentration below 250mg/kg bw/day . Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.

 

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 toxicitystudy

Data available from different studies were reviewed to determine thedevelopmental toxicityof  N,N-diethyl-3-oxobutanamide (2235-46-3).The studies are as mentioned below:

Study 1

Developmental toxicity study of test material was performed on mated female CD rats. Undiluted test material in dose concentration0, 125, 250, or 750 mg/kg/day were administered via oral gavage route from days 6 to 15 of gestation.Control animals received corn oil .Twenty-five mated female rats per group were used in study. Clinical signs, body weights, food consumption, maternal liver and gravid uterine weights, maternal ovarian and uterine examination were noted. fetal external examinations and internal soft-tissue and skeletal examinations were carried out.In the 750mg/kg/day dose dams clinical signs such as hypoactivity, ataxia, decreased muscle tone, foot splay, perinasal encrustation, and perioral wetness were observed; some of these signs were suggestive of neurotoxicity in this dose group because none of these signs were seen in the controls. Some of these clinical signs were seen only sporadically in the other treated groups. In the high-dose dams, there was an increase in mortality rate, a reduction in body weight gain and food consumption, and an increase in mean liver weights. A slight increase in percent post-implantation loss was seen in the 750mg/kg/day dose group and a statistically-significant decrease in mean fetal body weight/litter was seen in the 750mg/kg/day dose group. No additional compound-related effects were found.The incidence of external, visceral, and skeletalvariations and/or malformations were comparable in the control and treatment groups. HenceNo Observed Effect Level (NOEL) for developmental toxicity was considered to be 250mg/kg/day,When femaleCD rats were treated withtest materialorally.

Study 2

Developmental toxicity study of test material was performed on female rats according OECDGuidelines for Testing of Chemicals; Methods No. 414. The test material in dose concentration0, 50,250,750 mg/kg bw/dayvia oral administration fromday 6 to day 20 p.c.Clinical signs,Body weight and food consumptionwere noted.Pups were examined for external abnormalities. The number of viable and nonviable pups was recorded for each female. All pups were sexed and weighed individually.Clinical signs round back, emaciated appearance, piloerection , loud breathing, dyspnea, sneezing, reddish vaginal discharge, chromorhinorrhea and/or dacryhorrhea) in 1/24, 4/24 and 14/24 females given 50, 250 or 750 mg/kg/day, respectively. Ptyalism in 1/24 and 16/24 females given 250 or 750 mg/kg/day. 1/24 females given 750 mg/kg/day found dead. slight to markedly lower body weight gain at 250 and 750 mg/kg/day (statistically significant at 750 mg/kg/day, p<0.001) between Days 6 and 21 p.c. ; lower final body weight at 750 mg/kg/day (statistically significant, p<0.001). Reduced food consumption at 250 and 750 mg/kg/day at initiation of the treatment period, persisting until Day 18 p.c. at 750 mg/kg/day. Post implantation loss: slight to markedly higher at 250 and 750 mg/kg/day. Gravid uterus weight slight to markedly lower at 250 and 750 mg/kg/day. 24/24, 21/24, 23/24 and 18/23 females with live fetuses at 0, 50, 250 and 750 mg/kg/day, respectively. Fetal body weight/litter statistically significantly lower at 750 mg/kg/day. Malformations (anasarca, cleft palate, short trunk, anal atresia, short tail and/or acaudate) in 2 fetuses from 2/18 litters at 750 mg/kg/day were observed. HenceNo Observed Effect Level (NOEL) was considered to be 50mg/kg/day for developmental toxicity.When femalerats were treated withtest material orally.

 Based on the data available from different studies, N,N-diethyl-3-oxobutanamide (2235-46-3)did not showeddevelopmental toxicity at dose concentration below 250mg/kg bw/day . Hence the test chemical is not likely to classify as a reproductive toxicant as per the criteria mentioned in CLP regulation.

 

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation N,N-diethyl-3-oxobutanamide (2235-46-3)not likely to classify as reproductive and developmental toxicant.