Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
9 February 2009 to 19 March 2009
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study data over 12 years old provided by ECHA, on a previously notified substance considered comparable and suitable for read-across use for the substance being registered (see attachments for justification of read-across). Study was performed according to OECD and EU guidelines and according to GLP principles.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
other: OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Principles of method if other than guideline:
On Day 11 post-coitum animal 71 (Group 3) delivered. Evaluation: This animal’s data were excluded from calculation, because her first mating date was missed and thus was not dosed according to the appropriate schedule. Sufficient data were available from other animals.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Crl:WI(Han)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: 10-13 weeks
- Weight at study initiation: 187-250 grams (day 0 post-coitum)
- Fasting period before study: no
- Housing:
Pre-mating During acclimatization, females were housed in groups of 5 animals/cage in Macrolon cages (MIV type, height 18 cm).
Mating Females were caged together with males on a one-to-one-basis in Macrolon cages (MIII type, height 18 cm). During the weekend, mating procedures were suspended and the animals were housed in groups of maximum 5 animals/sex/cage in Macrolon cages (MIV type, height 18 cm).
Post-coitum Females were individually housed in Macrolon cages (MIII type, height 18 cm).
General Sterilized sawdust as bedding material and paper as cage-enrichment was supplied.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: At least 5 days prior to pairing under laboratory conditions.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.1 - 21.8
- Humidity (%): 29 - 79
- Air changes (per hr): approx. 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenized to a visually acceptable level. Adjustment was made for specific gravity of the vehicle (1.036) and not for the test substance.


VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on trial formulations performed at NOTOX
- Concentration in vehicle: 10, 40 and 200 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg bw
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: not specified in terms of days, but until successful pairing
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: not applicable.
- Further matings after two unsuccessful attempts: not applicable
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug / sperm in vaginal smear, referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
No analytical method based on gas chromatography (GC), liquid chromatography (HPLC), UV spectrophotometry or total organic carbon analysis (TOC) could be developed for the determination of the test substance in formulations with propylene glycol (determined during NOTOX Project 482838 - 90 day study).
Duration of treatment / exposure:
From Day 6 to Day 19 post-coitum, inclusive
Frequency of treatment:
daily.
Remarks:
Doses / Concentrations:
0, 50, 200, 1000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
24 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on results of a dose range finding study
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes (mortality/viability check)
- Time schedule: twice daily (early morning/late afternoon)


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily from Day 0 post-coitum onwards


BODY WEIGHT: Yes
- Time schedule for examinations:Days 0, 3 and 6-20 (daily) post-coitum


FOOD CONSUMPTION: Yes
- Food consumption for each animal determined: Days 0-3, 3-6, 6-9, 9-12, 12-15, 15-17 and 17-20 post-coitum


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day: Day 20 post-coitum
- Organs examined: External, thoracic and abdominal organs.

OTHER:
Organ weights: Spleen weights (and terminal body weight) were recorded from 10 pregnant animals of all dose groups on the scheduled day of necropsy. Previous results from a 28 day study indicated spleen parameters should be examined due to macroscopic and histological findings.

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





Litter observations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: Yes: [aproximately half per litter]

Other:
- The number and distribution of live and dead fetuses
- The number and distribution of embryo-fetal deaths
- The weight of each fetus
- The sex of each fetus from the ano-genital distance (during necropsy)
and also from gonadal inspections (during further fetal examination)
Statistics:
The following statistical methods were used to analyze the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (Dunnett, 1955) (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (Miller, 1981) (many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
- The Fisher Exact-test (Fisher 1950) was applied to frequency data.

Mean litter proportions (percent per litter) of total fetal malformations and developmental variations (external, visceral, skeletal and combined), and each particular external, visceral and skeletal malformation or variation was subjected to the Kruskal-Wallis nonparametric ANOVA test (Kruskal and Wallis 1952) to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunn’s test (Dunn 1964) was used to compare the compound-treated groups to the control group.

All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance.
Reproductive indices:
For each dose group reproduction parameters were expressed in two ways:
-As a mean (with standard deviation) of the number observed for each litter
-As a mean litter proportion calculated on a total group basis
Offspring viability indices:
For each litter the following calculations were performed:

Pre-implantation loss (Number of corpora lutea - number of implantation sites) / Number of corpora lutea x 100

Post-implantation loss (Number of implantation sites - number of live fetuses) / Number of implantation sites x 100


The fetal developmental findings were summarized by: 1) presenting the incidence of a given finding both as the number of fetuses and the number of litters available for examination in the group; and 2) considering the litter as the basic unit for comparison, calculating the number of affected fetuses as a mean litter proportion on a total group basis.

Where:

Viable Fetuses Affected/Litter (%) = (No. Viable Fetuses Affected/Litter) / No. Viable Fetuses/Litter x 100
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
Maternal pregnancy data:
There were 23, 20, 16 and 22 females pregnant and used for calculation in Groups 1, 2, 3 and 4 respecitvely. Once control female had resorptions only.
Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no toxicologically signficant effects
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Litter size:
There were no treatment related effects on litter size for any group.

Sex ratio:
The male:female sex ratios of each treatment group were unaffected by treatment.

Fetal body weight:
The was no effecty on fetal body weights.

External malformations and variations:
No test substance related effects on fetal external morphology, visceral morphology, skeletal morpholgy.
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no toxicologically signficant effects
Reproductive effects observed:
not specified
Conclusions:
Maternal findings
No maternal toxicity was observed in the 50, 200 and 1000 mg/kg/day groups.
 
Developmental findings
No developmental toxicity was observed in the 50, 200 and 1000 mg/kg/day groups.

Based on the results in this prenatal developmental toxicity study the maternal, reproductive and developmental No Observed Adverse Effect Level (NOAEL) for AMIDE #71 was established as being at least 1000 mg/kg body weight/day.
Executive summary:

Summary

A prenatal developmental toxicity study of AMIDE#71 in rats by oral gavage.

Ninety-six mated female Wistar Han rats were assigned to four dose groups. The test item was administered once daily by gavage from Day 6 to 19 post-coitum inclusive, at doses of 50, 200 and 1000mg/kg/day(Groups 2, 3 and 4 respectively). The rats of the control group received the vehicle, propylene glycol, alone. Females were checked daily for the presence of clinical signs. Food consumption of females was determined at periodic intervals; body weight was determined daily during treatment and at periodic intervals in the other periods.

All animals surviving to Day 20 post-coitum were subjected to an examination post-mortem and external, thoracic and abdominal macroscopic findings were recorded. A laparohysterectomy was performed on each surviving female of the groups. The uteri, placentae and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. The fetuses were weighed, sexed and examined for external, visceral and skeletal malformations and developmental variations. All live fetuses were euthanised. One half of the fetuses were decapitated and the heads were fixed in Bouin's fixative, all fetuses were dissected and examined for visceral anomalies and subsequently fixed in 96% aqueous alcohol and stained with Alizarin Red S for skeletal examinations.

Results

Accuracy, homogeneity and stability of formulations were not demonstrated by analyses as no analytical method could be developed for gas chromatography (GC), liquid chromatography (HPLC), UV spectrophotometry or total organic carbon analysis (TOC).

Maternal findings

No maternal toxicity was observed in the 50, 200 and 1000 mg/kg/day groups.

Development findings

No developmental toxicity was observed in the 50, 200 and 1000 mg/kg/day groups.

Conclusion

Based on the results in the prenatal developmental toxicity study the maternal, reproductive and developmental No Observed Adverse Effect Level (NOAEL) for AMIDE#71 was established as being at least 1000 mg/kg body weight/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Study was performed according to OECD and EU guidelines and according to GLP principles.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The OECD 414 pre-natal developmental toxicity study was considered appropriate to assess toxicity to reproduction. Refer to discussion of developmental toxicity for further details of study.

The results of this study showed no effects for maternal toxicity or maternal pregnancy data. Subsequent litter size and sex ratios were unaffected by treatment at any dose level.

Based on the results in the prenatal developmental toxicity study the reproductive No Observed Adverse Effect Level (NOAEL) was established as being at least 1000 mg/kg body weight/day.

In addition, a 90 -day study found no toxicologically relevant alterations in any reproductive organs examined.


Short description of key information:
The test substance was assessed for developmental toxicity according to OECD Guideline 414 and EU Method B31. The maternal, reproductive and developmental No Observed Adverse Effect Level (NOAEL) was established as being at least 1000 mg/kg body weight/day.

Justification for selection of Effect on fertility via oral route:
Testing conducted on a previously notified substance considered comparable and suitable for read-across use for the substance being registered.

Effects on developmental toxicity

Description of key information
The test substance was assessed for developmental toxicity according to OECD Guideline 414 and EU Method B31.  The maternal, reproductive and developmental No Observed Adverse Effect Level (NOAEL) was established as being at least 1000 mg/kg body weight/day.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
9 February 2009 to 19 March 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study data over 12 years old provided by ECHA, on a previously notified substance considered comparable and suitable for read-across use for the substance being registered (see attachments for justification of read-across). Study was performed according to OECD and EU guidelines and according to GLP principles.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
see remarks OECD 414
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
see remarks OECD 414
Principles of method if other than guideline:
On Day 11 post-coitum animal 71 (Group 3) delivered. Evaluation: This animal’s data were excluded from calculation, because her first mating date was missed and thus was not dosed according to the appropriate schedule. Sufficient data were available from other animals.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Crl:WI(Han)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: 10-13 weeks
- Weight at study initiation: 187-250 grams (day 0 post-coitum)
- Fasting period before study: no
- Housing:
Pre-mating During acclimatization, females were housed in groups of 5 animals/cage in Macrolon cages (MIV type, height 18 cm).
Mating Females were caged together with males on a one-to-one-basis in Macrolon cages (MIII type, height 18 cm). During the weekend, mating procedures were suspended and the animals were housed in groups of maximum 5 animals/sex/cage in Macrolon cages (MIV type, height 18 cm).
Post-coitum Females were individually housed in Macrolon cages (MIII type, height 18 cm).
General Sterilized sawdust as bedding material and paper as cage-enrichment was supplied.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: At least 5 days prior to pairing under laboratory conditions.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.1 - 21.8
- Humidity (%): 29 - 79
- Air changes (per hr): approx. 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 9 February 2009 (start pairing) To: 19 March 2009
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenized to a visually acceptable level. Adjustment was made for specific gravity of the vehicle (1.036) and not for the test substance.


VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on trial formulations performed at NOTOX
- Concentration in vehicle: 10, 40 and 200 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg bw
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
No analytical method based on gas chromatography (GC), liquid chromatography (HPLC), UV spectrophotometry or total organic carbon analysis (TOC) could be developed for the determination of the test substance in formulations with propylene glycol (determined during NOTOX Project 482838 - 90 day study).
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: not specified in terms of days, but until successful pairing
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: not applicable.
- Further matings after two unsuccessful attempts: not applicable
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug / sperm in vaginal smear, referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
From Day 6 to Day 19 post-coitum, inclusive
Frequency of treatment:
daily.
Duration of test:
9 February 2009 (start pairing) to 19 March 2009 (last necropsy).
Remarks:
Doses / Concentrations:
0, 50, 200, 1000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
24 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on results of a dose range finding study

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes (mortality/viability check)
- Time schedule: twice daily (early morning/late afternoon)


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: At least once daily from Day 0 post-coitum onwards


BODY WEIGHT: Yes
- Time schedule for examinations:Days 0, 3 and 6-20 (daily) post-coitum


FOOD CONSUMPTION: Yes
- Food consumption for each animal determined: Days 0-3, 3-6, 6-9, 9-12, 12-15, 15-17 and 17-20 post-coitum


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day: Day 20 post-coitum
- Organs examined: External, thoracic and abdominal organs.

OTHER:
Organ weights: Spleen weights (and terminal body weight) were recorded from 10 pregnant animals of all dose groups on the scheduled day of necropsy. Previous results from a 28 day study indicated spleen parameters should be examined due to macroscopic and histological findings.
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
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: Yes: [aproximately half per litter]

Other:
- The number and distribution of live and dead fetuses
- The number and distribution of embryo-fetal deaths
- The weight of each fetus
- The sex of each fetus from the ano-genital distance (during necropsy)
and also from gonadal inspections (during further fetal examination)


Statistics:
The following statistical methods were used to analyze the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (Dunnett, 1955) (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (Miller, 1981) (many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
- The Fisher Exact-test (Fisher 1950) was applied to frequency data.

Mean litter proportions (percent per litter) of total fetal malformations and developmental variations (external, visceral, skeletal and combined), and each particular external, visceral and skeletal malformation or variation was subjected to the Kruskal-Wallis nonparametric ANOVA test (Kruskal and Wallis 1952) to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunn’s test (Dunn 1964) was used to compare the compound-treated groups to the control group.

All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance.
Indices:
For each dose group reproduction parameters were expressed in two ways:
-As a mean (with standard deviation) of the number observed for each litter
-As a mean litter proportion calculated on a total group basis

For each litter the following calculations were performed:

Pre-implantation loss (Number of corpora lutea - number of implantation sites) / Number of corpora lutea x 100

Post-implantation loss (Number of implantation sites - number of live fetuses) / Number of implantation sites x 100


The fetal developmental findings were summarized by: 1) presenting the incidence of a given finding both as the number of fetuses and the number of litters available for examination in the group; and 2) considering the litter as the basic unit for comparison, calculating the number of affected fetuses as a mean litter proportion on a total group basis.

Where:

Viable Fetuses Affected/Litter (%) = (No. Viable Fetuses Affected/Litter) / No. Viable Fetuses/Litter x 100

Historical control data:
NOTOX Historical control data were used for external, visceral and skeletal malformations.
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No toxic effects observed.
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Based on:
other: no toxicologically signficant effects
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Based on:
other: no toxicologically signficant effects
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No toxic effects observed.
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
Maternal findings
No maternal toxicity was observed in the 50, 200 and 1000 mg/kg/day groups.
 
Developmental findings
No developmental toxicity was observed in the 50, 200 and 1000 mg/kg/day groups.

Based on the results in this prenatal developmental toxicity study the maternal, reproductive and developmental No Observed Adverse Effect Level (NOAEL) for AMIDE #71 was established as being at least 1000 mg/kg body weight/day.
Executive summary:

Summary

A prenatal developmental toxicity study of AMIDE#71 in rats by oral gavage.

Ninety-six mated female Wistar Han rats were assigned to four dose groups. The test item was administered once daily by gavage from Day 6 to 19 post-coitum inclusive, at doses of 50, 200 and 1000mg/kg/day(Groups 2, 3 and 4 respectively). The rats of the control group received the vehicle, propylene glycol, alone. Females were checked daily for the presence of clinical signs. Food consumption of females was determined at periodic intervals; body weight was determined daily during treatment and at periodic intervals in the other periods.

All animals surviving to Day 20 post-coitum were subjected to an examination post-mortem and external, thoracic and abdominal macroscopic findings were recorded. A laparohysterectomy was performed on each surviving female of the groups. The uteri, placentae and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. The fetuses were weighed, sexed and examined for external, visceral and skeletal malformations and developmental variations. All live fetuses were euthanised. One half of the fetuses were decapitated and the heads were fixed in Bouin's fixative, all fetuses were dissected and examined for visceral anomalies and subsequently fixed in 96% aqueous alcohol and stained with Alizarin Red S for skeletal examinations.

Results

Accuracy, homogeneity and stability of formulations were not demonstrated by analyses as no analytical method could be developed for gas chromatography (GC), liquid chromatography (HPLC), UV spectrophotometry or total organic carbon analysis (TOC).

Maternal findings

No maternal toxicity was observed in the 50, 200 and 1000 mg/kg/day groups.

Development findings

No developmental toxicity was observed in the 50, 200 and 1000 mg/kg/day groups.

Conclusion

Based on the results in the prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Level (NOAEL) for AMIDE#71 was established as being at least 1000 mg/kg body weight/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Study was performed according to OECD and EU guidelines and according to GLP principles.
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

A prenatal developmental toxicity study of AMIDE#71 in rats by oral gavage was conducted according to OECD Guideline 414 and EU Method B31

Ninety-six mated female Wistar Han rats were assigned to four dose groups. The test item was administered once daily by gavage from Day 6 to 19 post-coitum inclusive, at doses of 50, 200 and 1000mg/kg/day(Groups 2, 3 and 4 respectively). The rats of the control group received the vehicle, propylene glycol, alone. Females were checked daily for the presence of clinical signs. Food consumption of females was determined at periodic intervals; body weight was determined daily during treatment and at periodic intervals in the other periods.

All animals surviving to Day 20 post-coitum were subjected to an examination post-mortem and external, thoracic and abdominal macroscopic findings were recorded. A laparohysterectomy was performed on each surviving female of the groups. The uteri, placentae and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. The fetuses were weighed, sexed and examined for external, visceral and skeletal malformations and developmental variations.

Results

Maternal findings

No maternal toxicity was observed in the 50, 200 and 1000 mg/kg/day groups.

Development findings

No developmental toxicity was observed in the 50, 200 and 1000 mg/kg/day groups.

Conclusion

Based on the results in the prenatal developmental toxicity study the maternal, reproductive and developmental No Observed Adverse Effect Level (NOAEL) for AMIDE#71 was established as being at least 1000 mg/kg body weight/day.


Justification for selection of Effect on developmental toxicity: via oral route:
Testing conducted on a previously notified substance considered comparable and suitable for read-across use for the substance being registered.

Justification for classification or non-classification

The tested substance was assessed for developmental toxicity according to OECD Guideline 414 and EU Method B31. No maternal or developmental toxicity was observed at any of the doses tested. The maternal, reproductive and developmental No Observed Adverse Effect Level (NOAEL) was established as being at least 1000 mg/kg body weight/day.

Based on the OECD 414 study (and supported by the 90 -day study) there is no evidence that the tested substance has an adverse effect on reproduction or development at the highest dose level (1000 mg/kg bw/day). The substance is therefore not classified for reproductive toxicity.