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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: Study performed to GLP and guideline

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Monosodium cyanurate monohydrate
- Substance type: powder
- Analytical purity: 99% (equivalent to 77.4% cyanuric acid)
- Lot/batch No.: 1219649-1 (Monsanto)

Test animals

Species:
rat
Strain:
other: Charles River CD
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan, USA
- Age at study initiation: ~ 12 weeks
- Weight at study initiation: 219 – 288 g
- Housing: Wire mesh cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 15 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 69
- Humidity (%): 36-68
- Air changes (per hr): 12.2-12.5
- Photoperiod: 12 hour light/dark


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 4% carboxymethyl cellulose
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The appropraite amount of test article was weighed and suspended in the vehicle, 4% carboxymethyl cellulose, using a tissue homogenizer. The test article was prepared daily at concentrations of 1, 5 and 25% to permit administration at dosage levels of 200, 1000 and 5000 mg/kg/day at a constant volume of 20 ml/kg.

Details on mating procedure:
- Impregnation procedure:cohoused
- If cohoused:
- M/F ratio per cage: One male to one female
- Proof of pregnancy: vaginal smear referred to as day 0 of gestation
Duration of treatment / exposure:
days 6-15 post-mating
Frequency of treatment:
daily
Duration of test:
20 days
Doses / concentrations
Remarks:
Doses / Concentrations:
200, 1000, 5000 mg/kg bw
Basis:

No. of animals per sex per dose:
25
Control animals:
other: Vehicle control and Sodium control (sodium hippurate) at 1118 and 5590 mg/kg/day

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily for mortality and once daily for clinical signs of toxicity on days 6 through 20 of gestation.


BODY WEIGHT: Yes
- Time schedule for examinations: Gestation days 0, 6, 9, 12, 15, 18 and 20. Due to an error, two females in the 200 mg/kg group were weighed on gestation days 0, 5, 8, 11, 14, 17 and 20.



POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20


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: all per litter
Statistics:
All statistical analyses compared the treatment groups and the sodium control groups to both the vehicle control group and the untreated control group with the level of significance at p<0.01. In addition all statistical analyses compared the untreated control group with the vehicle control group at the same level of significance. The male to female fetal sex distribution and the number of litters with malformations were compared using the Chi-square test criterion with Yates' correction for 2 x 2 contingency tables and/or Fishers exact probability test as described by Siegal to judge significance of differences.
The number of early and late resorptions and postimplantation losses were compared by the Mann-Whitney U-test as described by Siegal and Weil to judge significance of differences.
The mean number of viable fetuses, total implantations, corpora lutea and mean fetal body weights were compared by analysis of variance (one-way classification), Bartlett's test for homogeneity of variances and the appropriate t-test (for equal or unequal variances) as described by Steel and Torrie using Dunnets multiple comparison tables to judge significance of differences.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
11 females in the high dose sodium control group (5590 mg/kg/day) died between days 8 and 16 of gestation. Survival was 100% in all other groups.The mean maternal body weight in the high dose sodium control group was slightly reduced when compared to the control group.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
5 000 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
A decrease was noted in the mean gravid uterus weights only in the high dose sodium control group. There were no treatment related differences in the number of viable foetuses, post implantation losses, total implantations and corpora lutea, the foetal sex distribution or in the mean foetal body weight or crown-rump length in the test groups when compared to the vehicle control groups. In the high dose sodium group mean foetal body weight and mean foetal crown-rump length were decreased compared to the vehicle control and untreated groups. An increased mean post implantation loss and a corresponding slight reduction in the mean number of foetuses were also noted in the high dose sodium group. These factors in the low dose sodium group were comparable to those in the vehicle control.
There was no dose dependent or statistically significant difference in the total number of litters with malformed foetuses in the monosodium cyanurate groups when compared to both the vehicle control and the untreated control group. In the high dose sodium control group an increased incidence of malformation in foetuses and litters were due primarily to an increased incidence of bent ribs in this group. In the high dose (5000 mg/kg) group the percentage of foetuses with variations in sternaebrae no. 1, 2, 3 and / or 4 unossified or vertebra reduced in ossification was increased when compared to the control. Additionally the high dose sodium control group also had sternebrae no. 5 and 6 unossified, entire sternum unossified or skull reduced in ossification. No such variations were observed in the low dose sodium group.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
5 000 mg/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Monosodium cyanurate did not produce a teratogenic response when administered orally by gavage to rats at a dose level of 5000 mg/kg/day or less. Various effects were found in the high dose sodium control group. In addition there was an increased incidence of malformed foetuses in litters from the high dose sodium control group, namely bent ribs.