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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to a current O.E.C.D. Testing Guideline under the GLP regulations including test substance concentration verification and stability.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report Date:
2005

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: O.E.C.D. 422 Combined Repeated dose Toxicity Test With the Reproduction/Developmental Toxicity Screening Test.
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
As per Vinyl Neodeconoate IUCLID4 Data Set 2007

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
Laboratory rats were acquired from Harlan Sprague Dawley, Indianapolis, In. Weitg range at study start was 262-310 gm males and 179-237 for the females. Animals were maintained insuspended wire bottom stainless steel cages. Pregnant females were housed in plastic shoebox-type cages. Enviroemental conditions were: Temperature 19-25 C; Humidity Range of 30-70%; 12-hour light/dark cycle and 10-12 air changes per hour. Rodent feed was Formulab No. 5008 from PMI Feeds, Inc ad libitum. Drinking water was municipal water available ad libitum.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Animal groups (ten males and ten females per group) were dosed daily with vinyl neodecanoate at 1000, 250, and 100 mg/kg, respectively. A syringe with stainless steel ball-tipped needle of appropriate size was used for dosing the animal by oral gavage. A concurrent vehicle control group was dosed with corn oil by the same way. All animals were dosed with a constant volume of 5 mL/kg. The daily dose was adjusted weekly based on the latest body weight. Males and females were dosed for 14 days prior to mating. While males were dosed for additional 14 days during mating for a total o 28, females were dosed daily until one day before termination (lactation day 4 for those that delivered and post-mating Day 23 or post-cohabitation Day 23 for those that did not deliver).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Test substance dosing mixtures were checked for homogeneity on the first week of dosing in order to assure mixing procedure. One sample was taken from the top, middle and bottom of mixing container and was analyzed for Vinyl Neodeconoate content. The homogeneity was found to be constant for all samples and thus no further evolution was conducted during the study. Only one sample was taken from the middle of weekly prepared dosing formulation during the in-life phase of the study for dose concentration and stabiliy verification. The analytical procedure was a company proprietary methodology.
Details on mating procedure:
After fourteen days of treatment, each female was cohabited with one male from the same treatment groug for a period of two weeks or untilsigns of pregnancy were observed. Pregnancy was determined during the morning when each female was examined for the presence of sperm or vaginal plug. Day 0 of pregnancy was the day the vaginal plug or sperm was found. A maximum of fourteen days was allowed for mating. After confirmation of mating, the male rats were returned to their home cages, and the females were placed in plastic shoebox cages with nesting material.
Duration of treatment / exposure:
Males and females rats were dosed for 14 days prior to mating. While males were dosed for additional 14 days during mating for a total of 28, females were dosed daily until one day before termination (lactation day 4 for those that delivered and post-mating Day 23 or post-cohabitation Day 23 for those that did not deliver).
Frequency of treatment:
Daily
Duration of test:
Approximately 38-39 days.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Female animals were observed twice daily for morbidity and mortality and once daily for signs of pharmacologic and/or toxicologic effects. Body weights of the females were recorded on Days 7, 14, 21 and 28, and/or gestation Days 0, 4, 7, 11, 14, 17 and 20, and on lactation Days 1 and 4. Body weights for pups were recorded on lactation Day 1 and 4. Food consumption was recorded weekly until the termination of the study with the exception of the cohabitation period.

On parturition day, pups were sexed, evaluated for abnormal malformation and stillbirth and abnormalities were recorded. Pups were marked for identification and any abnormalities in nesting or nursing behavior were recorded. On lactation Day 1 and 4, pups were weighed and re-sexed and were examined for general appearance; behavior and survival.

One-way analysis of variance (ANOVA) and Dunnett's t-test were used to identify differences from control when identified by ANOVA.

Examinations

Maternal examinations:
Necropsy examination was conducted on all females pups at the time of discovery of death or at the time of sacrifice. Necropsy was conducted on external surfaces and internal cavities and their viscera with special emphasis on the reproductive organs. Reproductive systems organs that showed macroscopic pathologic lesions were collected and preserved. Organs such as liver, kidneys, thymus, spleen, brain, and heart from five animals from each treatment group were removed, trimmed and weighed and then preserved for further evaluation. Histopathologic examination was conducted on all organs collected from all females from control and high dose groups.
Ovaries and uterine content:
The number of corpora lutea was recorded and ovaries with oviducts were carefully removed, trimmed and weighted for all dose groups.
Fetal examinations:
Not conducted.
Statistics:
One-way analysis of variance (ANOVA) and Dunnett's t-test were used to identify differences from control when identified by ANOVA.
Indices:
Mean litter size, Mean live pups/litter, Mean stillborn, Mean pup body weight
Historical control data:
No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No significant adverse findings up to the high dose level of 1000 mg/kg/day.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Remarks:
based on no significant adverse maternal findings.
Effect level:
>= 1 000 mg/kg bw/day
Basis for effect level:
other: effect type not specified

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Females of treated groups showed an insignificant increased incidence of stillborn pups than control although there was no dose relationship. Meanpup body weights were not significantly different among groups on Day 1. However, they were significantly lower in high dose group and 100 mg/kg group, but not the mid-dose group versus control on Day 4. There were no significance differences in corpora lutea counts among groups at the time of necropsy. The average body weight gains of pups in the treated groups were similar to the control value. But the mean weight gain was higher inpups of controls. However, pups in two of the control litters gained much more weight than other control litters and this may have biased the inter-group comparison of litter weights. Mean total litter body weight of the high dose 1000 mg/kg/day group was significantly lower than control on Day 4 being approximately 20% lower. The loss of four pups in this group may have contributed, at least in part, to this difference. Daily observation of litters did not reveal any abnormalities.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No specific effects identified

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables


Litter weights summary (Total of the litter on Days 1 and 4, and Mean on Days 1 and 4).

Dam
                       Litter Total                                           Mean
No.
                         D1          D4          Change D1          D4          Change
Control
  
49
                           75.9        117.3      41.4                        6.3          9.8          3.5
67
                           85.7        123.1      37.4                        6.6          10.3        3.7
68
                           98.0        145.1      47.1                        7.5          11.2        3.7
78
                           107.0      233.0      126.0                      7.1          15.5        8.4
77
                           107.4      198.5      91.1                        7.2          13.2        6.0
65
                           93.0        152.5      59.5                        6.2          10.2        4.0
47
                           89.6        150.8      61.2                        6.9          11.6        4.7
Mean
                     93.8        160.0      66.2                        6.8          11.7        4.9
StDev
                    11.4        41.6        31.8                        0.5          2.0          1.8

1000 mg/kg
63
                           90.0        123.2      33.2                        5.3          7.2          1.9
69
                           70.8        105.3      34.5                        5.9          8.8          2.9
66
                           89.4        130.3      40.9                        7.5          10.9        3.4
64
                           64.4        98.0        33.6                        6.4          9.8          3.4
61
                          58.1        82.0        23.9                        6.5          9.1          2.6
56
                           79.6        123.0      43.4                        6.6          10.3        3.7
Mean
                     75.4        110.3      34.9                        6.4          9.4          3.0
StDev
                    13.2        18.5        6.8                          0.7          1.3          0.7

250 mg/kg
71
                           86.5        116.5      30.0                        7.9          10.6        2.7
79
                           117.1      136.4      19.3                        8.4          11.4        3.0
74
                           113.6      136.1      22.5                        8.7          10.5        1.8
42
                           90.2        130.3      40.1                        6.9          10.0        3.1
50
                           103.9      154.6      50.7                        6.9          10.3        3.4
70
                           84.0        125.2      41.2                        6.5          9.6          3.1
43
                           104.9      151.4      46.5                        7.0          10.1        3.1
51
                           89.0        126.4      37.4                        7.4          10.5        3.1
Mean
                     98.7        134.6      36.0                        7.5          10.4        2.9
StDev
                    12.9        13.0        11.1                        0.8          0.5          0.5

100 mg/kg
There were no observed abnormal pups in any of the control and treated groups. The mean weights of individual pups at Day 1 after parturition in the control and treatment groups were not significantly different and there was no dose trend in pup weights. All pups in all litters in control and the three treatment groups survived from day 1 through day 4. 
75
                           84.1        109.8      25.7                        6.0          7.8          1.8
44
                           86.8        142.0      55.2                        6.7          10.9        4.2
46
                           98.8        126.1      27.3                        7.1          9.0          1.9
76
                           95.7        135.1      39.4                        6.0          8.4          2.4
72
                           124.1      171.9      47.8                        8.3          11.5        3.2
60
                           85.3        128.3      43.0                        7.1          10.7        3.6
48
                           91.1        116.1      25.0                        7.0          8.9          1.9
62
                           98.7        129.6      30.9                        7.1          10.0        2.9
Mean
                     95.6        132.4      36.8                        6.9          9.7          2.7
StDev
                    12.9        18.9        11.3                        0.7          1.3          0.9

Applicant's summary and conclusion

Conclusions:
Vinyl Neodecanoate induced no adverse maternal findings and is not a developmental toxicant in this study conducted up to a high limit dose of 1000 mg/kg/day. The developmental and maternal NOAELs are 1000 mg/kg/day.
Executive summary:

Oral gavage treatment of pregnant rats with Vinyl Neodeconoate up to a high limit dose of 1000 mg/kg/day in an O.E.C.D. 422 combined repeated-dose, reproductive/developmental screening study did not induce any significant maternal or developmental adverse effects. Therefore, the NOAEL for adverse maternal and developmental effects under the conditions of this study was 1000 mg/kg/day.