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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
From September 25, 1990 to November 16, 1990
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Remarks:
it cannot be differentiated between possible toxic effects and effects due to stress during dosing due to the highly visous test substance preparation
Principles of method if other than guideline:
Female New-Zealand white rabbits (16/dose) were administered by gavage the following concentrations (dissolved in corn oil, at a volume of 3 mL/kg bw): 0, 100, 300 and 600 mg/kg bw/day from gestational day (GD) 6 to 18. Clinical observations were recorded, as well as maternal body weight and food consumption. At sacrifice on GD 30, the animals were subjected to gross necropsy and evaluated for body weight, liver and gravid uterine weight. Ovarian corpora lutea were counted and the status of uterine implantation sites (i.e., resorptions, dead fetuses, live fetuses, pre and post-implantations) was recorded. Fetuses were dissected from the uterus, counted, weighted, sexed and examined for external abnormalities as well as for visceral malformations and variations. Sections of the heads were examined for soft tissue craniofacial malformations and variations. Intact fetuses were examined for skeletal malformations and variations.
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
From: Charles River Laboraties
Number of females: 64 inseminated female rabbits (4 groups of 16 animals)
Age: ca. 6 months
Weight: 860 - 3850g
Food: no. 5322 Purina Certified Rabbit Chow and Water: deionized/filtered tap water ad libitum
Temperature: ca. 20°C
Humidity: 40 - 60%
Light: 12:12h light:dark cycle
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Pregnant females were exposed to the test substance, by gavage once daily from gestational days (GD) 6 through 18 at doses of 0, 100, 300 or 600 mg/kg bw/day in corn oil (based on a range-finding study). The dosing volume was 3 mL/kg bw and was adjusted based on each animal's most recent body weight.
Analytical verification of doses or concentrations:
yes
Remarks:
HPLC (Waters 840 HPLC and data system)
Details on analytical verification of doses or concentrations:
Prior to formulation of study dosing suspensions, aliquots of formulations of test substance in vehicle, bracketing the range of concentrations to be used in this used were assayed for homogeneity and stability. Suspension concentrations were also verified for all dose levels. Dosing formulations were homogeneous and stable for at least 28 days and the concentrations were within 93.2 - 98.0% of the nominal concentrations. The content of test substance in the vehicle was below the detection limit.
Triplicate 1.0 mL samples of the vehicle solution (corn oil) and of the dosing formulations, 33.3, 100.0 and 200.0 mg/mL were analysed.
Details on mating procedure:
Female rabbits were artificially inseminated (0.25 - 0.50 mL). To induce ovulation, the females received an intravenous injection of Pregnyl prior to insemination. Sperm was checked for mobility.
Duration of treatment / exposure:
From gestational days 6 to 18
Frequency of treatment:
Once daily
Duration of test:
Until GD 30
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
600 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
16 mated females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The doses were 0, 100, 300 and 600 mg/kg/day based on a range-finding study in pregnant rabbits. The highest dose level was chosen to induce overt maternal toxicity, but not to cause a weight loss greater than 20% when compared to concurrent controls, nor to cause greater than 10% maternal mortality. The low dose was selected to be a maternal No Observable Adverse Effect Level (NOAEL). The mid dose was onehalf of the high dose and three times the low dose.
Maternal examinations:
- Clinical observations: daily and twice daily during the dosing period (1-2h after dosing period)
- Maternal body weight: on gestational days 0, 6, 9, 12, 15, 18, 21, 24 and 30
- Food consumption: gestational days 0-6, 6-9, 9-12, 12-15, 15-18, 18-21, 21-24 and 24-30
Ovaries and uterine content:
- At scheduled sacrifice on gestational day 30, the dams were subjected to a gross necropsy and evaluated for body weight, liver and gravid uterine weight
- Ovarian corpora lutea were counted and the status of uterine implantation sites (i.e., resorptions, dead fetuses, live fetuses, pre and post-implantations) was recorded.
Fetal examinations:
- Fetuses were dissected from the uterus, counted, weighted, sexed and examined for external abnormalities as well as for visceral malformations and variations.
- Sections of the heads were examined for soft tissue craniofacial malformations and variations.
- All fetuses were eviscerated, fixed in alcohol, and stained with alizarin red S/alcian blue.
- Intact fetuses were examined for skeletal malformations and variations.
Statistics:
Appropriate General Linear Models procedures were used for the analysis of variances ANOVA + Bartlett's test for homogeneity of variance
Dunnett's Multiple Comparison Test
One-tailed or two-tailed tests were used depending on the endpoints
Chi-Square Test for Independance and Test for linear Trend on proportions
Fisher's Exact Probability Test
Indices:
Gestational parameters (ovarian corpora lutea, uterine implantation sites, resorptions, dead fetuses, live fetuses, pre and post-implantation losses)
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
- Clinical signs associated with the large volume of corn oil administered: gastro-intestinal stress (diarrhea and soft feces)
- Discolored urine and purple feet
- Stress and difficulties during dosing; the dosing solution is very thick
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Maternal gestational weight change (corrected for gravid uterine weight) was clearly reduced at 300 and 600 mg/kg bw/day
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Significant increase at 600 mg/kg bw/day for GD 6-9
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
In liver and gravid uterine weight
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Evidence of gastrointestinal stress from the large volume of corn oil, diarrhea and soft feces, was observed in all groups. Difficulties in dosing (nasal efflux, oral efflux, charging and biting, difficult to dose, aggressive, throat tight, struggling during dosing, charging/snorting, charges) were also observed in all groups, with the more extreme animal responses observed at 300 and 600 mg/kg bw/day, leading to mis-dosing and removal of animals from study due to dosing errors (one each at 100 and 300 mg/kg bw/day and two at 600 mg/kg bw/day). Respiratory signs were also observed sporadically in one doe each during the dosing period, on gd 7, 9, 14, 15 and 18 (apnea, rapid respiration, audible breathing) in all chemical-dosed groups.
Number of abortions:
effects observed, non-treatment-related
Description (incidence and severity):
One female in the group 300 and 600 mg/kg bw/day aborted
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
effects observed, non-treatment-related
Description (incidence and severity):
One litter was totally resorbed at 600 mg/kg bw/day
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
effects observed, non-treatment-related
Description (incidence and severity):
One female at 100 mg/kg bw/day delivered early
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): effects observed, non-treatment-related
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): One female at 100 mg/kg bw/day delivered early
Changes in number of pregnant:
no effects observed
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Pregnancy rate was apparently lower at 300 and 600 mg/kg bw/day
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Remarks on result:
not determinable because of methodological limitations
Remarks:
this might be stress related effects rather than toxic effects due to the highly viscous test substance preparation, which made dosing very difficult and led to struggling of animals during dosing
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Slight reduction at 600 mg/kg bw/day in males with no obvious dose-related trend
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Some effects were observed but they were not treatment- or dose-related and the fetuses did not exhibit any other consistent characteristics.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Some effects were observed but they were not treatment- or dose-related and the fetuses did not exhibit any other consistent characteristics.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Some effects were observed but they were not treatment- or dose-related and the fetuses did not exhibit any other consistent characteristics.
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
fetal/pup body weight changes
Remarks on result:
not determinable because of methodological limitations
Remarks:
this might be a secondary effect based on stress during dosing of dams due to the highly viscous test substance preparation, which made dosing very difficult and led to struggling of dams during dosing
Key result
Dose descriptor:
NOEL
Effect level:
>= 600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Administration of C.I. Disperse Blue 79:1 to New Zealand White rabbits during major organogenesis resulted in reduced body weight gain during gestation at 300 and 600 mg/kg bw/day and in a slight reduction in fetal body weight at 600 mg/kg bw/day. The no observable adverse effect level (NOAEL) for maternal toxicity was therefore 100 mg/kg bw/day and the NOAEL for developmental toxicity was 300 mg/kg bw/day in rabbits under the conditions of this study although it is highly questionable whether the effects were truly related to substance toxicity rather than secondary effects due to the test substance administration of a large amount of a highly viscous oily preparation. There was no indication of teratogenesis at any dose level employed.
Executive summary:

A study was conducted to determine the developmental toxicity of the test substance (99.61% purity) in rabbit. Female New-Zealand white rabbits (16/dose) were administered by gavage the following concentrations (dissolved corn oil, at a volume of 3 mL/kg bw): 0, 100, 300 and 600 mg/kg bw/day from gestational day (GD) 6 to 18. The homogeneity, stability and concentrations of dosing suspensions were analysed and were within acceptable values. Clinical observations were recorded daily and twice daily during the dosing period (1-2 h after dosing period). Maternal body weight was measured on GD 0, 6, 9, 12, 15, 18, 21, 24 and 30 and food consumption on gestational days 0-6, 6-9, 9-12, 12-15, 15-18, 18-21, 21-24 and 24-30. At scheduled sacrifice on GD 30, the animals were subjected to gross necropsy and evaluated for body weight, liver and gravid uterine weight. Ovarian corpora lutea were counted and the status of uterine implantation sites (i.e., resorptions, dead fetuses, live fetuses, pre and post-implantations) was recorded. Fetuses were dissected from the uterus, counted, weighted, sexed and examined for external abnormalities as well as for visceral malformations and variations. Sections of the heads were examined for soft tissue craniofacial malformations and variations. All fetuses were eviscerated, fixed in alcohol, and stained with alizarin red S/alcian blue. Intact fetuses were examined for skeletal malformations and variations. Clinical signs associated with the large volume of corn oil administered were observed: gastro-intestinal stress (diarrhea and soft feces). Discolored urine and purple feet were also recorded in all groups. Finally, stress and difficulties during dosing (the dosing solution is very thick) were present. Maternal gestational weight change (corrected for gravid uterine weight) was clearly reduced at 300 and 600 mg/kg bw/day, which might be more likely related to the loss in nutrients and stress due to the administration of the highly viscous test substance rather than toxicity of the test substance. Significant increase in food consumption was measured at 600 mg/kg bw/day for GD 6-9. One female in the group 300 and 600 mg/kg bw/day aborted and one litter was totally resorbed at 600 mg/kg bw/day. A slight but not statistically significant reduction in fetal body weights per litter (all fetuses and males, but not females) was observed at 600 mg/kg/day, unaccompanied by any other indications of developmental toxicity. There were also no treatment-related increased incidences of individual or pooled external, visceral, skeletal or total fetal malformations or variations.

In conclusion, administration of C.I. Disperse Blue 79:1 to New Zealand White rabbits during major organogenesis resulted in reduced body weight gain during gestation at 300 and 600 mg/kg bw/day and in a slight reduction in fetal body weight at 600 mg/kg bw/day. The no observable adverse effect level (NOAEL) for maternal toxicity was therefore 100 mg/kg bw/day and the NOAEL for developmental toxicity was 300 mg/kg bw/day in rabbits under the conditions of this study although it is highly questionable whether the effects were truly related to substance toxicity rather than secondary effects due to the test substance administration of a large amount of a highly viscous oily preparation. There was no indication of teratogenesis at any dose level employed. (Rochelle, 1991).

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From July 04, 1990 to September 17, 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods
Principles of method if other than guideline:
Time pregnant CD (Sprague-Dawley) rats, 25 sperm-positive females per group, were exposed to the test substance by gavage once daily on Gestation Day (GD) 6 to 15 at 0, 500, 1000 or 2000 mg/kg bw/day in corn oil. Clinical observations were recorded, as well as maternal bodyweight and food consumption. At sacrifice on GD 20, the dams were evaluated for bodyweight, liver and gravid uterine weight. Ovarian corpora lutea were counted and the status of uterine implantation sites (i.e. resorptions, dead fetuses, live fetuses) was recorded. All fetuses were dissected from the uterus, counted, weighed, sexed and examined for external abnormalities. Approximately one half of the live fetuses in each litter were examined for visceral malformations and variations. The heads were fixed and examined for soft tissue craniofacial malformations and variations. Intact fetuses were examined for skeletal malformations and variations.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Remarks:
CD
Details on test animals or test system and environmental conditions:
From: Charles River Laboraties
Number of females: 100 sperm-positive female rats (4 groups of 25 animals)
Age: ca. 10 weeks
Weight: 223 - 268g
Food: no. 5002 Purina Certified Rodent Chow and Water: deionized/filtered tap water ad libitum
Temperature: ca. 23°C
Humidity: 40 - 70%
Light: 12:12h light:dark cycle
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Pregnant females were exposed to the test substance, by gavage once daily from gestational days 6 through 15 at doses of 0, 500, 1000 or 2000 mg/kg bw/day in corn oil (based on a range-finding study). The dosing volume was 10 mL/kg bw and was adjusted based on each animal's most recent body weight.
Analytical verification of doses or concentrations:
yes
Remarks:
HPLC (Waters 840 HPLC and data system)
Details on analytical verification of doses or concentrations:
Prior to formulation of study dosing suspensions, aliquots of formulations of test substance in vehicle, bracketing the range of concentrations to be used in this used were assayed for homogeneity and stability. Suspension concentrations were also verified for all dose levels. Dosing formulations were homogeneous and stable for at least 28 days and the concentrations were within 90-110% of the nominal concentrations. The content of test substance in the vehicle was below the detection limit.
Triplicate 1.0 mL samples of the vehicle solution (corn oil) and of the dosing formulations, 50.0, 100.0 and 200.0 mg/mL were analysed.
Details on mating procedure:
For breeding, individual females were placed in the home cage of singly-housed males. On the following morning and each morning thereafter, the females were examinated for the presence of vaginal sperm (considered as GD 0). Sperm-positive females were individually housed until scheduled sacrifice on GD 20.
Duration of treatment / exposure:
From GD 6 to 15
Frequency of treatment:
Once daily
Duration of test:
Until GD 20
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Dose / conc.:
2 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The doses were 0, 500, 1000 and 2000 mg/kg/day based on a rangefinding study in pregnant rats. The highest dose level was chosen to induce overt maternal toxicity, but not to cause a weight loss greater than 20% when compared to concurrent controls, nor to cause greater than 10% maternal mortality. The low dose was selected to be a maternal/developmental No Observable Adverse Effect Level (NOAEL). The mid dose was one-half the high dose and twice the low dose.
Maternal examinations:
- Clinical observations: daily and twice daily during the dosing period (1-2h after dosing period)
- Maternal body weight: on gestational days 0, 6, 9, 12, 15, 18 and 20
- Food consumption: gestational days 0-6, 6-9, 9-12, 12-15, 15-18 and 18-20
Ovaries and uterine content:
- At scheduled sacrifice on gestational day 20, the dams were evaluated for body weight, liver and gravid uterine weight
- Ovarian corpora lutea were counted and the status of uterine implantation sites (i.e., resorptions, dead fetuses, live fetuses, pre and post-implantations) was recorded.
Fetal examinations:
- Fetuses were dissected from the uterus, counted, weighted, sexed and examined for external abnormalities as well as for visceral malformations and variations.
- Sections of the heads were examined for soft tissue craniofacial malformations and variations.
- All fetuses were eviscerated, fixed in alcohol, and stained with alizarin red S/alcian blue.
- Intact fetuses were examined for skeletal malformations and variations.
Statistics:
Appropriate General Linear Models procedures were used for the analysis of variances ANOVA + Bartlett's test for homogeneity of variance
Dunnett's Multiple Comparison Test
One-tailed or two-tailed tests were used depending on the endpoints
Chi-Square Test for Independance and Test for linear Trend on proportions
Fisher's Exact Probability Test
Indices:
Gestational parameters (ovarian corpora lutea, uterine implantation sites, resorptions, dead fetuses, live fetuses, pre and post-implantation losses)
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
- Green, dark and/or green feces at 500 mg/kg bw/day and above
- Piloerection at all concentrations (GD 12-20)
- Vaginal bleeding at 2000 mg/kg bw/day in one dam on GD 15
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight loss in 5, 2 and 2 dams in the groups 500, 1000 and 2000 mg/kg bw/day (GD 7 - 10)
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
effects observed, non-treatment-related
Description (incidence and severity):
Two litters at 500 mg/kg bw/day were fully resorbed; all remaining pregnant animals had one or more live fetuses on GD 20
Early or late resorptions:
effects observed, non-treatment-related
Dead fetuses:
no effects observed
Description (incidence and severity):
The numbers of litters evaluated were 11-14 per groups
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Pregnancy rate was unexpectedly low (44-56%) and approximately equivalent across all groups
Key result
Dose descriptor:
NOAEL
Effect level:
> 2 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Just slightly reduced at 2000 mg/kg bw/day with no obvious dose-related trends
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
One fetus in each treatment group exhibited external malformations
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Some malformations were observed in 0-3 fetuses in each group with no treatment-related patterns of incidence or severity.
Visceral malformations:
no effects observed
Details on embryotoxic / teratogenic effects:
No effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
> 2 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Treatment related:
no
Conclusions:
Under the study conditions, the maternal and developmental NOAELs for the test substance administered by gavage from GD 6 to 15 were determined to be >2000 mg/kg bw/day (i.e. 1992 mg a.i./kg bw/day).
Executive summary:

A study was conducted to determine the developmental toxicity of the test substance (99.61% purity). in rat. Female Sprague Dawley rats (25/dose) were administered by gavage the following concentrations (dissolved corn oil, at a volume of 10 mL/kg bw): 0, 500, 1000 and 2000 mg/kg bw/day from gestational day (GD) 6 to 15. The homogeneity, stability and concentrations of dosing suspensions were analysed and were within acceptable values. Clinical signs were recorded daily and twice daily during the dosing period. Maternal body weight were measured on GD 0, 6, 9, 12, 15, 18 and 20 and food consumption on GD 0-6, 6-9, 9-12, 12-15, 15-18 and 18-20. At scheduled sacrifice on GD 20, the dams were evaluated for body weight, liver and gravid uterine weight. Ovarian corpora lutea were counted and the status of uterine implantation sites (i.e., resorptions, dead fetuses, live fetuses, pre and post-implantations) was recorded. Fetuses were dissected from the uterus, counted, weighted, sexed and examined for external abnormalities as well as for visceral malformations and variations. Sections of the heads were examined for soft tissue craniofacial malformations and variations. All fetuses were eviscerated, fixed in alcohol, and stained with alizarin red S/alcian blue. Intact fetuses were examined for skeletal malformations and variations. Except for green, dark and/or green feces at 500 mg/kg bw/day and above, piloerection at all concentrations (GD 12-20) and vaginal bleeding at 2000 mg/kg bw/day in one dam on GD 15, no other effects were observed. Gestational parameters (e.g. ovarian corpora lutea, uterine implantation sites, resorptions, dead fetuses, live fetuses, pre and post-implantation losses) were not modified by the treatment. Two litters at 500 mg/kg bw/day were fully resorbed; all remaining pregnant animals had one or more live fetuses on GD 20. Fetal body weight was slightly reduced at 2000 mg/kg bw/day with no obvious dose-related trends. Malformations (external and skeletal) were recorded but with no treatment-related patterns of incidence or severity. Under the study conditions, the maternal and developmental NOAELs were determined to be >2000 mg/kg bw/day (i.e. 1992 mg a.i./kg bw/day) (Rochelle, 1990).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
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 study was conducted to determine the developmental toxicity of the test substance (99.61% purity) in rat. Female Sprague Dawley rats (25/dose) were administered by gavage the following concentrations (dissolved corn oil, at a volume of 10 mL/kg bw): 0, 500, 1000 and 2000 mg/kg bw/day from gestational day (GD) 6 to 15. The homogeneity, stability and concentrations of dosing suspensions were analysed and were within acceptable values. Clinical signs were recorded daily and twice daily during the dosing period. Maternal body weight were measured on GD 0, 6, 9, 12, 15, 18 and 20 and food consumption on GD 0-6, 6-9, 9-12, 12-15, 15-18 and 18-20. At scheduled sacrifice on GD 20, the dams were evaluated for body weight, liver and gravid uterine weight. Ovarian corpora lutea were counted and the status of uterine implantation sites (i.e., resorptions, dead fetuses, live fetuses, pre and post-implantations) was recorded. Fetuses were dissected from the uterus, counted, weighted, sexed and examined for external abnormalities as well as for visceral malformations and variations. Sections of the heads were examined for soft tissue craniofacial malformations and variations. All fetuses were eviscerated, fixed in alcohol, and stained with alizarin red S/alcian blue. Intact fetuses were examined for skeletal malformations and variations. Except for green, dark and/or green feces at 500 mg/kg bw/day and above, piloerection at all concentrations (GD 12-20) and vaginal bleeding at 2000 mg/kg bw/day in one dam on GD 15, no other effects were observed. Gestational parameters (e.g. ovarian corpora lutea, uterine implantation sites, resorptions, dead fetuses, live fetuses, pre and post-implantation losses) were not modified by the treatment. Two litters at 500 mg/kg bw/day were fully resorbed; all remaining pregnant animals had one or more live fetuses on GD 20. Fetal body weight was slightly reduced at 2000 mg/kg bw/day with no obvious dose-related trends. Malformations (external and skeletal) were recorded but with no treatment-related patterns of incidence or severity. Under the study conditions, the maternal and developmental NOAELs were determined to be >2000 mg/kg bw/day (i.e. 1992 mg a.i./kg bw/day) (Rochelle, 1990).

A study was conducted to determine the developmental toxicity of the test substance (99.61% purity) in rabbit. Female New-Zealand white rabbits (16/dose) were administered by gavage the following concentrations (dissolved corn oil, at a volume of 3 mL/kg bw): 0, 100, 300 and 600 mg/kg bw/day from gestational day (GD) 6 to 18. The homogeneity, stability and concentrations of dosing suspensions were analysed and were within acceptable values. Clinical observations were recorded daily and twice daily during the dosing period (1-2 h after dosing period). Maternal body weight was measured on GD 0, 6, 9, 12, 15, 18, 21, 24 and 30 and food consumption on gestational days 0-6, 6-9, 9-12, 12-15, 15-18, 18-21, 21-24 and 24-30. At scheduled sacrifice on GD 30, the animals were subjected to gross necropsy and evaluated for body weight, liver and gravid uterine weight. Ovarian corpora lutea were counted and the status of uterine implantation sites (i.e., resorptions, dead fetuses, live fetuses, pre and post-implantations) was recorded. Fetuses were dissected from the uterus, counted, weighted, sexed and examined for external abnormalities as well as for visceral malformations and variations. Sections of the heads were examined for soft tissue craniofacial malformations and variations. All fetuses were eviscerated, fixed in alcohol, and stained with alizarin red S/alcian blue. Intact fetuses were examined for skeletal malformations and variations. Clinical signs associated with the large volume of corn oil administered were observed: gastro-intestinal stress (diarrhea and soft feces). Discolored urine and purple feet were also recorded in all groups. Finally, stress and difficulties during dosing (the dosing solution is very thick) were present. Maternal gestational weight change (corrected for gravid uterine weight) was clearly reduced at 300 and 600 mg/kg bw/day, which might be more likely related to the loss in nutrients and stress due to the administration of the highly viscous test substance rather than toxicity of the test substance. Significant increase in food consumption was measured at 600 mg/kg bw/day for GD 6-9. One female in the group 300 and 600 mg/kg bw/day aborted and one litter was totally resorbed at 600 mg/kg bw/day. A slight but not statistically significant reduction in fetal body weights per litter (all fetuses and males, but not females) was observed at 600 mg/kg/day, unaccompanied by any other indications of developmental toxicity. There were also no treatment-related increased incidences of individual or pooled external, visceral, skeletal or total fetal malformations or variations.

In conclusion, administration of the test substance to New Zealand White rabbits during major organogenesis resulted in reduced body weight gain during gestation at 300 and 600 mg/kg bw/day and in a slight reduction in fetal body weight at 600 mg/kg bw/day. The no observable adverse effect level (NOAEL) for maternal toxicity was therefore 100 mg/kg bw/day and the NOAEL for developmental toxicity was 300 mg/kg bw/day in rabbits under the conditions of this study although it is highly questionable whether the effects were truly related to substance toxicity rather than secondary effects due to the test substance administration of a large amount of a highly viscous oily preparation. There was no indication of teratogenesis at any dose level employed. (Rochelle, 1991).

Justification for classification or non-classification

Based on the results of the pre-natal developmental toxicity studies in rats and rabbits, no classification for this endpoint is required according to CLP (EC 1272/2008) criteria.​

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