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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:
November 07, 2007 to January 07, 2008
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report date:
2008

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
2001
Deviations:
yes
Remarks:
no determination of food consumption and fetal sex, reporting deficiencies
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
473-160-6
EC Name:
-
Molecular formula:
Hill formula: C24 H15 Cu F2 N7 Na3 O9 S2
IUPAC Name:
dicopper(2+) hexasodium 2-[(E)-{[(Z)-(2-{3-[(2,6-difluoropyrimidin-4-yl)amino]-2-oxido-5-sulfonatophenyl}hydrazin-2-id-1-ylidene)(phenyl)methyl]imino}amino]-4-sulfonatobenzoate 2-[(E)-{[(Z)-(2-{3-[(4,6-difluoropyrimidin-2-yl)amino]-2-oxido-5-sulfonatophenyl}hydrazin-2-id-1-ylidene)(phenyl)methyl]imino}amino]-4-sulfonatobenzoate

Test animals

Species:
mouse
Strain:
ICR
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Shanghai Slaccs Animal Experimental Co., Ltd., Shanghai, China
- Age at study initiation: Not reported
- Weight at study initiation: Females 23-26g, males 28-35 g
- Fasting period before study: Not reported
- Housing: Single after mating
- Diet: SuZhou Shuangshi Laboratory Animal Feed Science Co., Ltd.
- Water: Drinking water complying China national standard, ad libitum
- Acclimation period: Approx. 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 20-25 °C
- Humidity: 40-70%
- Air changes: Not reported
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: November 28, 2007 To: December 10, 2007

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
VEHICLE
- Concentration in vehicle: 1.825 mg/mL, 3.65 mg/mL, 7.3 mg/mL
- Amount of vehicle: 20 mL/kg bw
Analytical verification of doses or concentrations:
no
Details on mating procedure:
One male mouse was housed with two female mice in the same cage from afternoon of the first day to the morning of the following day. Female mice were then examined for successful mating by observation of vaginal plug or sperm in female vaginal smear. The day on which a vaginal plug or sperm was observed was considered as mating success and day 0 of gestation.
Duration of treatment / exposure:
Gestation day 6-14
Frequency of treatment:
Daily
Duration of test:
18 days
Doses / concentrationsopen allclose all
Dose / conc.:
36.5 mg/kg bw/day (nominal)
Dose / conc.:
73 mg/kg bw/day (nominal)
Dose / conc.:
146 mg/kg bw/day (nominal)
No. of animals per sex per dose:
30 pregnant animals
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses were selected based on acute oral toxicity data.
Doses were adjusted according to weight gain.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
Observations for clinical signs and mortality were made at least once daily, including changes in skin, fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behaviour pattern.

BODY WEIGHT AND BODY WEIGHT GAIN: Yes
Animals were weighed on days 0, 6, 9, 12, 14, 17 and 18.

FOOD CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 18
- Organs examined: Uterus

OTHER:
Necropsy was performed on all dead animals and animals with signs of abortion or premature delivery.
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 resorptions: Yes
- Other: number of dead (early and late stillbirth) litters, number of live litters, body/tail length of live litters
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [1/3 of live fetuses]
- Skeletal examinations: Yes: [2/3 of live fetuses ]
- Head examinations: Yes: [all per litter]
- Fetal body weight
Statistics:
Analysis of variance (one-way ANOVA, Dunnett's)
Chi-square and binomial distribution
Indices:
Teratogenic rate (%) = (total amount of live litters with teratogenic effects/total amount of litters) x 100
(One live litter with more than one teratogenic effect was counted as one)

Teratogenic index = LD50 of females/minimum teratogenic dose

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Description (incidence and severity):
In the high dose group 6/30 animals showed a skinny appearance whereas this was not apparent in the mid and low dose groups and the vehicle control group.
Mortality:
no mortality observed
Description (incidence):
There were no dead animals observed during the course of the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was no significant change in body weight in all dose groups. The body weight gain was significantly decreased in the high dose group when compared to the vehicle control.
Food consumption and compound intake (if feeding study):
not examined

Maternal developmental toxicity

Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
No significant differences in implantations were observed when compared to the vehicle control.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
No significant difference in the number of pregnant rats with resorptions was observed when compared to the vehicle control.
Early or late resorptions:
no effects observed
Description (incidence and severity):
The number of resorptions was not significantly increased when compared to the vehicle control.
Dead fetuses:
no effects observed
Description (incidence and severity):
No significant difference in the number of pregnant rats with dead litters was observed when compared to the vehicle control.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
The number of pregnant rats in the treatment groups was comparable to the vehicle control group.
Other effects:
no effects observed
Description (incidence and severity):
There was no significant effect in the number of corpora lutea and the number of dead litters between the treated groups and the vehicle control.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
73 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs

Maternal abnormalities

Key result
Abnormalities:
no effects observed
Localisation:
other: no adverse effects observed up to maximum dose level

Results (fetuses)

Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
No significant differences were observed between the treatment groups and the vehicle control group.
Changes in sex ratio:
not examined
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
No significant differences were observed in the number of live fetuses and fetal body weight between the treatment groups and the vehicle control group.
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The incidence (%) of fetuses with external malformations/variations was 0 (vehicle control), 0.5 (36.5 mg/kg bw/d), 0.7 (73 mg/kg bw/d) and 0.7 (146 mg/kg bw/d). No significant differences were observed between the treatment groups and the vehicle control group.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The incidence (%) of fetuses with skeletal malformations/variations was 2.5 (vehicle control), 4.1 (36.5 mg/kg bw/d), 3.9 (73 mg/kg bw/d) and 6.5 (146 mg/kg bw/d). No significant differences were observed between the treatment groups and the vehicle control group.
Visceral malformations:
no effects observed
Description (incidence and severity):
No visceral malformations/variations were observed in the treatment groups and the vehicle control group.
Other effects:
no effects observed
Description (incidence and severity):
Placental weight, fetus body and tail length: No significant differences were observed between the treatment groups and the vehicle control group.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
> 146 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: no adverse effects observed up to maximum dose

Fetal abnormalities

Key result
Abnormalities:
effects observed, non-treatment-related
Localisation:
other: external/skeletal: not specified

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
The NOAEL for maternal toxicity was determined to be 73 mg/kg bw/d based on reduced body weight gain. The developmental NOEAL was determined to be > 146 mg/kg bw/d.
Executive summary:

The teratogenicity test of Blue MGI 1037-Na on mice was performed according to the Guidelines for the Testing of Chemicals (2004)414 which is referred to OECD 414.

Three different dose-level test groups of low, middle and high dosage, a negative control group and a Vitamin A positive control group were set up in this test. The dosage of each test group was 36.5mg/kg, 73mg/kg and 146mg/kg respectively. 30 pregnant female mice were assigned to each group. The day on which a vaginal plug or sperm were observed was counted as day 0 of gestation.
From day 6 to day 14 of gestation. 0.2 mL/10g bw of test substance was administered daily by garage to mice in 3 different dose-level test groups as well as control groups. Clinical observations
were recorded every day. From day 6 of gestation, mice were weighed every other 3 days dining the dosing period. All of female mice were sacrificed one day prior to the day of delivery (the 18th day since the gestation). Immediately after caesarean the uteri were removed and gravid uteri were weighed. Implantation status were record: the number of implantations, of dead litters (early stillbirth, late stillbirth), of resorptions, of live litters, of corpora luteas. The development of fetuses was recorded one by one: body weight, body length, tail length. And the examination of teratogenicity of fetuses: appearance, skeletal and organ alternatives. SPSS13.0 statistical software was applied to analyze all data and results. The maximum no observed adverse effect level (NOAEL) of teratogenicity test was obtained through statistical analysis.

This teratogenicity test in mice indicated that Blue MGI 1037-Na had maternal toxicity to a certain extent: however, no embryonic toxicity and teratogenicity were observed. The maximum teratogenic NOAEL was 146 mg/kg in this test.