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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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to OECD guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1974

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Test substance: Tine white granular material marked with FDA 71-87.

Test animals

Species:
rabbit
Strain:
Dutch

Administration / exposure

Route of administration:
oral: gavage
Duration of treatment / exposure:
6th to 18th day of pregnancy
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
1.69, 7.85, 35.6, 169 mg/kg/day
Basis:

Control animals:
other: sham-treated
Details on study design:
Sex: female
Duration of test: up to the last day of pregnancy

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
> 169 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
> 169 mg/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

 Table 1: Fate Summary
-------------------------------------------------------
Group Material Dose*** Total Surviving at Term
---------------- ---------------
mg/kg Mated Pregnant Total Pregnant*
-------------------------------------------------------
341 Sham 0.0 18 13 18 13
342 6-AN** 2.5 20 10 19 10
347 CaCl2 1.69 22 13 18 12
348 CaCl2 7.85 22 14 16 11
349 CaCl2 35.6 17 14 14 12
350 CaCl2 169.0 16 16 14 14
--------------------------------------------------------
* Includes all dams examined at term
** Positive Control: 2.5 mg/kg of 6-aminonicotinamide
dosed on Day 9
*** Administered as a water solution

- Table 2: Reproduction Data
--------------------------------------------------------
Group 341 342 347 348 349 350
Dose (mg/kg) Sham 6-AN* 1.69 7.85 35.6 169.0
--------------------------------------------------------

-----Pregnancies-----
Total No. 13 10 13 14 14 16
Died or Aborted (before Day 29)
0 1 1 3 2 2
To term (on Day 29)13 10 12 11 12 14
-----Corpora Lutea-----
Total No. 174 122 148 129 138 146
Average/dam mated 9.67 6.42 7.40 7.17 8.63 10.4
-----Live Litters-----
Total No.** 12 10 12 9 11 12
-----Implant Sites-----
Total No. 69 56 86 63 69 72
Average/dam** 5.31 5.60 7.17 7.73 5.75 5.14
-----Resorptions-----
Total No.** 4 2 12 8 8 4
Dams with 1 or more sites resorbed
3 1 4 4 6 3
Dams with all sites resorbed
1 - - 2 1 -
Per cent partial resorptions
23.1 10.0 33.3 36.4 50.0 21.4
Per cent complete resorptions
7.69 - - 18.2 8.33 -
-----Live Fetuses-----
Total No. 65 54 74 55 61 58
Average/dam** 5.00 5.40 6.17 5.00 5.55 4.83
Sex ratio (M/F) 0.86 0.74 1.47 1.04 1.16 1.24
-----Dead Fetuses-----
Total** - - - - - 10
Dams with 1 or more dead
- - - - - 2
Dams with all dead
- - - - - 1
Per cent partial dead
- - - - - 14.3
Per cent all dead - - - - - 7.14
-----Average Fetus Weight (g)-----
38.2 33.8 37.3 38.0 36.8 39.2
---------------------------------------------------------

* Positive Control: 2.5 mg/kg of 6-aminonicotinamide dosed
on Day 9
** Includes only those dams examined at term.

- Table 3: Summary of Skeletal Findings***
---------------------------------------------------------
Group No. 341 342 347 348 349 350
Dose (mg/kg) Sham 6-AN** 1.69 7.85 35.6 169.0
---------------------------------------------------------
Live Fetuses Examined
(at term) 65/12 53/10* 74/12 54/9* 61/11 58/12
-----Sternebrae-----
Incomplete oss. - - 2/1 - 1/1 -
Scrambled
Bipartite - - 1/1 - - -
Fused - 1/1 - - - -
Extra
Missing
Other
-----Rids-----
Incomplete oss.
Fused/split - 2/1 - - - -
Wavy
Less than 12
More than 13
Other
-----Vertebrae-----
Incomplete oss.
Scrambled - 5/1 - - - -
Fused
Extra ctrs. oss.
Scoliosis - 1/1 - - - -
Tail defects - 10/3 - - - -
Other; spina bifida
-----Skull-----
Incomplete closure
1/1 - - - - -
Missing
Craniostosis - - 2/1 - - -
Other
-----Extremities-----
Incomplete oss.
Missing
Extra
-----Miscellaneous-----
---------------------------------------------------------
* One pup lost in processing
** Positive Control: 2.5 mg/kg of 6-aminonicotinamide
dosed on Day 9
*** Numerator = Number of fetuses affected

- Table 4: Summary of Soft Tissue Abnormalities
---------------------------------------------------------
Group Material Dose Level Dam Number Description
(mg/kg) of Pups
---------------------------------------------------------
342 6-AN* 2.5 Z7640 2 Medial rotation
of hind limbs
----------------------------------------------------------
* Positive Control: 2.5 mg/kg of 6-aminonicotinamide dosed
on Day 9

- Table 5: Average body Weights*** (g)
---------------------------------------------------------
Group Material Dose Day0 Day6 Day12 Day18 Day29**
Level
(mg/kg)
---------------------------------------------------------
341 Sham 0.0 2.23 2.32 2.40 2.48 2.59
(13)
342 6-AN* 2.5 1.86 1.94 2.03 2.08 2.18
(10)
347 CaCl2 1.69 2.20 2.31 2.43 2.51 2.64
(12)
348 CaCl2 7.85 2.12 2.16 2.16 2.25 2.33
(11)
349 CaCl2 35.6 2.22 2.31 2.34 2.40 2.50
(12)
350 CaCl2 169.0 2.27 2.39 2.41 2.46 2.50
(14)
---------------------------------------------------------
* Positive Control: 2.5 mg/kg of 6-aninonicotinamide dosed
on Day 9
** Number of surviving dams in parentheses (c.f. Table 1)
*** Of pregnant dams

Applicant's summary and conclusion

Conclusions:
The administration of up to 169 mg/kg (body weight) of the
test material to pregnant rats for 13 consecutive days had
no clearly discernible effect on nidation or on maternal or
fetal survival. The number of abnormalities seen in either
soft or skeletal tissues of the test groups did not differ
from the number occurring spontaneously in the sham-treated
controls.