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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10th July 1989 to 11th August 1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report date:
1989

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Propargite
EC Number:
219-006-1
EC Name:
Propargite
Cas Number:
2312-35-8
Molecular formula:
C19H26O4S
IUPAC Name:
propargite
Test material form:
liquid

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Denver, Pennsylvania, USA
- Age at study initiation: approximately 5-6 months
- Weight at study initiation: 3049-4528 g on gestation day 0
- Housing: individually in suspended stainless steel cages
- Diet: Certified Rabbit Chow® #5322 ad libitum
- Water: tap water ad libitum
- Acclimation period: 25-67 days

ENVIRONMENTAL CONDITIONS
- Temperature: 67-76 ºF (mean 71 ± 2.3 ºF)
- Humidity: 54-70 % (mean 62 ± 4.4 %)
- Photoperiod: 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- The appropriate amount of test material was weighed into a beaker and the appropriate amount of corn oil added. The test material was stored at room temperature with fresh material prepared weekly.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Prior to test material administration, the 10 day stability of the test material stored at room temperature was established.

To ensure correct concentrations of the test material, analyses of the prepared dosing suspension was conducted prior to dosing on days 7 and 12.
Details on mating procedure:
- Impregnation procedure: artificial insemination
Duration of treatment / exposure:
Days 7 to 19 of gestation
Frequency of treatment:
Daily
Duration of test:
Up to gestation day 29.
Doses / concentrationsopen allclose all
Dose / conc.:
2 mg/kg bw/day (nominal)
Dose / conc.:
4 mg/kg bw/day (nominal)
Dose / conc.:
6 mg/kg bw/day (nominal)
Dose / conc.:
8 mg/kg bw/day (nominal)
Dose / conc.:
10 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Twenty-five
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked: mortality and overt changes in appearance and behaviour.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily on days 7 to 29 of gestation.

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 7, 13, 20, 24 and 29 of gestation.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29. The abdominal and thoracic cavities and organs of the females were examined for grossly evident morphological changes and the carcasses discarded.
- Females not surviving to scheduled sacrifice were necropsied in an attempt to determine the cause of death.

OTHER:
- Any female showing signs of abortion or premature delivery was sacrificed on the day such evidence was seen and the aborted tissue examined and preserved.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: location of viable and non-viable foetuses
Fetal examinations:
- External examinations: Yes [all per litter]
- Soft tissue examinations: Yes [all per litter]
- Skeletal examinations: Yes [all per litter]
- Head examinations: No
Statistics:
Sex ratios of offspring compared using chi-squared test and/or Fisher's exact probability test. Proportion of resorbed/dead foetuses and post-implantation losses compared using Mann-Whitney test. Mean maternal body weight, corpora lutea, total implantations, number of live foetuses and pups compared with one-way analysis of variance using Bartlett's test for homogeneity of variance and the appropriate t-test to determine significance of differences.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Antemortem signs observed prior to abortion included hair loss, aborted material, anogenital staining, decreased defecation and emaciation
Mortality:
mortality observed, non-treatment-related
Description (incidence):
There were no treatment-related effects on survival. One animal in each of the 6 and 8 mg/kg bw/d groups died although the cause of death was not established.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was a significant reduction in body weight and in body weight gain of the 8 and 10 mg/kg animals but only during gestation days 7-20 (see Tables 1 and 2).
Food consumption and compound intake (if feeding study):
not examined
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:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
effects observed, treatment-related
Description (incidence and severity):
Abortions occurred in three, one and four females in the 4, 8 and 10 mg/kg bw/d groups, respectively. The abortions at 4 and 8 mg/kg bw/d were not considered to be treatment-related due to a lack of dose-response (no abortions at 6 mg/kg bw/d). The abortions at 10 mg/kg bw/d, however, were deemed to be treatment-related by virtue of the other signs of toxicity observed at this dose level.
Pre- and post-implantation loss:
not specified
Description (incidence and severity):
Following caesarean section, pre- and post-implantation losses and total implantations in treated animals were all comparable to the control group.
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Description (incidence and severity):
Following caesarean section, foetal viability in treated animals was comparable to the control group.
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:
no effects observed
Description (incidence and severity):
Following caesarean section, corpora lutea in treated animals were comparable to the control group.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
4 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Following caesarean section, foetal body weight in treated animals was comparable to the control group.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): Following caesarean section, foetal body weight in treated animals was comparable to the control group.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Following caesarean section, foetal viability in treated animals was comparable to the control group.
Changes in sex ratio:
not examined
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
not specified
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
Fused sternebrae was observed in kits from females treated at dose levels of 8 and 10 mg/kg bw/d (in 2/125 and 9/116 foetuses, respectively; 8 % of foetuses, 56 % of litters at 10 mg/kg/day). Fused skull bones were also noted in kits from these dose groups but there was no dose-response (2.4 % of foetuses, 17 % of litters at 8 mg/kg/day). There were no other treatment related malformations or developmental variations.
Visceral malformations:
not specified

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
6 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
skeletal malformations

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Table 1: Summary of body weight values (g)

 0 mg/kg/day  2 mg/kg/day  4 mg/kg/day  6 mg/kg/day  8 mg/kg/day  10 mg/kg/day
 Day of study  Mean  S.D.  Mean  S.D.  Mean  S.D.  Mean  S.D.  Mean  S.D.  Mean  S.D.
 0  3471  329.0  3570  360.7  3632  352.4  3664  358.2  3574  414.0  3530  329.0
 7  3674  350.9  3784  398.1  3824  373.6  3811  376.3  3752  435.0  3733  347.5
 13  3760  353.1  3872  374.4  3910  344.3  3824  343.3  3792  399.7  3679  248.8
 20  3787  276.7  3950  361.3  3943  331.0  3849  365.6  3760  401.4  3648  272.3
 24  3885  274.0  4001  419.6  4006  378.5  3904  371.4  3918  423.0  3781  227.2
 29  3958  250.2  4110  358.3  4093  337.4  3985  334.8  4014  406.0  3907  261.3

Table 2: Summary of body weight gain values (g)

 0 mg/kg/day  2 mg/kg/day  4 mg/kg/day  6 mg/kg/day  8 mg/kg/day  10 mg/kg/day
 Day of study  Mean  S.D.  Mean  S.D.  Mean  S.D.  Mean  S.D.  Mean  S.D.  Mean  S.D.
 0-7  203  107.6  214  84.8  193  91.0  147  60.5  177  73.0  203  73.5
 7-13  87  100.3  88  69.7  86  98.8  13  116.6  41  119.4  -55  171.8
 13-20  27  147.1  78  89.9  33  201.8  25  203.0  -32  198.2  -4  209.2
 7-20  114  188.3  165  133.2  119  253.4  38  290.7  9  267.5  -20  308.4
 20-24  98  77.6  52  92.7  55  158.6  54  101.3  139  118.4  101  89.3
 24-29  73  254.9  108  144.6  49  129.7  46  150.7  97  94.2  126  129.8
 0-29  487  254.9  540  135.0  493  205.8  318  369.9  447  201.6  464  188.9

Applicant's summary and conclusion

Conclusions:
Under the conditions of the test, dose levels of 8 and 10 mg/kg bw/day led to maternal toxicity as evidenced by abortions at the 10 mg/kg level and significantly reduced body weight/body weight gain at both dose levels. The only potential developmental toxicity was manifested by fused sternebrae in a small percentage of kits from the 8 and 10 mg/kg bw/d females (i.e. from groups treated with a maternally toxic dose). However, this is a spontaneously occurring variation that is commonly seen in kits delivered by control animals (as supported by a large historical control database). Moreover, there were no other signs of developmental toxicity as evidenced by an absence of adverse effects on foetal viability, foetal body weight, pre- and post implantation losses, total implantations and corpora lutea. Detailed analysis of the litters containing kits with fused sternebrae indicate that only two litters contained >1 kit with the condition (3 and 2 foetuses in each, respectively), the other litters each containing just one kit exhibiting fused sternebrae, an incidence which would not be considered treatment-related. Taken with the absence of any other indications of developmental toxicity in this study, this very slight increase in incidence of a normally spontaneously occurring variation in just two litters is not considered to indicate a teratogenic potential for the test material. In addition, this developmental variation was not observed at dose levels below the maternally toxic dose of 8 mg/kg bw/d. Based on these results, the NOEL for maternal toxicity was determined to be 6 mg/kg bw/d; this value also covers the increased incidence of fused sternebrae seen in the 8 mg/kg bw/d animals.
Executive summary:

New Zealand White rabbits were dosed with 0, 2, 4, 6, 8 and 10 mg/kg/day test material by oral gavage as a single daily dose on days 7 to 19 of gestation. Caesarean examinations were performed on all surviving females on gestation day 29 followed by teratologic examinations.

8 and 10 mg/kg/day does exhibited evidence of maternal toxicity with respect to abortions at the 10 mg/kg/day level and body weight inhibition/loss during the treatment period at both levels. There were malformed (fused) sternebrae in 2 and 9 kits respectively in the 8 and 10 mg/kg/day groups. This was the only evidence of developmental toxicity.

The NOEL was determined to be 6 mg/kg/day for both maternal and developmental toxicity.