Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 2013-10-16 to 2014-05-02
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014
Report date:
2014

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
2001
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:
1998
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
A mixture of isomers of: 1,1'-[(3,5(or 2,4 or 4,6 or 2,6)-dihydroxy-o(or m or p)-phenylene)bis(azo-meta-phenyleneazo{1-[3-(dimethylamino)propyl]-1,2-dihydro-6-hydroxy-4-methyl-2-oxopyridine-5,3-diyl})]dipyridinium-dichloride-dihydrochloride; 1-(1-[3-(dimethylamino)propyl]-5-{3-[x-(4-{1-[3-(dimethylamino)propyl]-1,6-dihydro-2-hydroxy-4-methyl-6-oxo-5-pyridinio-3-pyridylazo}phenylazo)-2,4(or 2,6 or 3,5 or 4,6)-dihydroxyphenylazo]phenylazo}-1,2-dihydro-6-hydroxy-4-methyl-2-oxo-3-pyridyl)pyridinium-dichloride-dihydrochloride (where x is variable)
EC Number:
404-540-1
EC Name:
A mixture of isomers of: 1,1'-[(3,5(or 2,4 or 4,6 or 2,6)-dihydroxy-o(or m or p)-phenylene)bis(azo-meta-phenyleneazo{1-[3-(dimethylamino)propyl]-1,2-dihydro-6-hydroxy-4-methyl-2-oxopyridine-5,3-diyl})]dipyridinium-dichloride-dihydrochloride; 1-(1-[3-(dimethylamino)propyl]-5-{3-[x-(4-{1-[3-(dimethylamino)propyl]-1,6-dihydro-2-hydroxy-4-methyl-6-oxo-5-pyridinio-3-pyridylazo}phenylazo)-2,4(or 2,6 or 3,5 or 4,6)-dihydroxyphenylazo]phenylazo}-1,2-dihydro-6-hydroxy-4-methyl-2-oxo-3-pyridyl)pyridinium-dichloride-dihydrochloride (where x is variable)
Cas Number:
159405-95-5
Molecular formula:
C50H56Cl4N14O6
IUPAC Name:
1'-[3-(dimethylamino)propyl]-5'-(2-{3-[2-(4-{2-[3-(2-{1'-[3-(dimethylamino)propyl]-6'-hydroxy-4'-methyl-2'-oxo-1',2'-dihydro-1λ⁵-[1,3'-bipyridin]-1-ylium-5'-yl}diazen-1-yl)phenyl]diazen-1-yl}-2,6-dihydroxyphenyl)diazen-1-yl]phenyl}diazen-1-yl)-6'-hydroxy-4'-methyl-2'-oxo-1',2'-dihydro-1λ⁵-[1,3'-bipyridin]-1-ylium 1'-[3-(dimethylamino)propyl]-5'-(2-{4-[2-(4-{2-[4-(2-{1'-[3-(dimethylamino)propyl]-6'-hydroxy-4'-methyl-2'-oxo-1',2'-dihydro-1λ⁵-[1,3'-bipyridin]-1-ylium-5'-yl}diazen-1-yl)phenyl]diazen-1-yl}-2,6-dihydroxyphenyl)diazen-1-yl]phenyl}diazen-1-yl)-6'-hydroxy-4'-methyl-2'-oxo-1',2'-dihydro-1λ⁵-[1,3'-bipyridin]-1-ylium tetrahydrochloride tetrachloride

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: at least 10 weeks
- Weight at study initiation: females at day 0 post coitum: 222 - 315 g
- Housing: cages with standard, granulated, sotwood Lignocel S8/15 bedding (supplied by Harlan Laboratories Models, S.L.), females: maximally five animals per cage (58×38.5×20 cm) during acclimatization and individually (42.5×26.6×18 cm) during pregnancy; males: individually (42.5×26.6×18 cm)
- Diet (e.g. ad libitum): pelleted standard Harlan Teklad 2014C rat maintenance diet ad libitum
- Water (e.g. ad libitum): tap water ad libitum in bottles
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
distilled
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: a stock solution was prepared by gradually adding the test item to 60 % of the vehicle while stirring. Once a homogeneous mixture was obtained, the formulation was placed gradually in a volumetric flask and the remainder of the vehicle was used to rinse the recipient and then added to the flask. The stock solution was stored at 2-8 °C. The necessary volume was taken from the stock solution into appropriate containers for each administration day.

VEHICLE
- Concentration in vehicle: 20/60/200 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg
- Stability of test material in vehicle: 24 hours at room temperature and 7 days in the refrigerator (2-8 °C)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration of dose formulation was determined twice during the study. Duplicate samples of the dose formulations were taken into labelled vials. One aliquot was analyzed and the remaining aliquot retained at Harlan Laboratories S.A. for possible subsequent needs until finalization of the report. The vials were shipped refrigerated in the dark to the person responsible for concentration analysis at Harlan Laboratories S.A. The test item was used as analytical standard.

Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/2
- Length of cohabitation: approximately 16 hours
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear or copulation plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
14 days, from day 6 to day 19 post coitum
Frequency of treatment:
once daily
Duration of test:
until day 20 post coitum
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Total number of mated females per group
- group 1: 22
- group 2: 22
- group 3: 24
- group 4: 22
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: dose levels were selected based on a dose range finding study for prenatal developmental toxicty in Sprague Dawley rats.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: during days 6 to 19 of pregnacy

BODY WEIGHT: Yes
- Time schedule for examinations: on day 0 and daily from days 6 to 20

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations:

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: gross macroscopic examination of all internal organs with emphasis on uterus, uterine content, position of fetuses in the uterus and the number of corpora lutea

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: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
Statistical analysis on food consumption, body weight, reproductive and necropsy data, skeletal and soft tissue examination data.
Dunnett-test based on pooled variance estimate was applied when the variables can be assumed to follow normal distribution for the comparison of the treated groups and the control groups for each sex.
The Steel-test was applied when the data could not be assumed to follow a normal distribution.
The Fisher's exact-test for 2×2 tables was applied when the variables could be dichotomized without loss of information.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No relevant clinical signs were recorded.
Dark feces were observed in all the test-item-treated groups from the start of treatment onwards. This clinical sign was attributed to the color of the test item.
Other isolated clinical signs (crust in scapular area, hypotrichosis, alopecia and hair loss) were recorded as occasional observations or observations in single animals; their distribution among the groups suggests they were not test-item-related.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Lower body-weight gain (%) was observed in animals from Groups 3 and 4 (300 and 1000 mg/kg) compared to the Control group from day 7 of pregnancy onwards. These differences were statistically significant. No effects were recorded among the females from Group 2 (100 mg/kg).
The corrected body-weight gain (weight on day of cesarean section – weight on day 6 post coitum – weight of gravid uterus) was significantly lower in Groups 3 and 4 than in the Control group.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
No relevant differences were observed in the food consumption of the test-item-treated groups with respect to the Control group.
Statistically lower absolute and relative food consumption during days 6-9 of pregnancy was recorded in Groups 3 and 4 compared to the Control group.
Some slight differences were recorded in the absolute mean values from days 12 to 18 of pregnancy. There were no differences in the relative values.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Dark-brownish content in stomach and in small and large intestine recorded in the test-item treated groups is associated with the color of the test item.
Group 1: Control group
Female no. 5 showed unilateral slight pelvic dilation of kidney.
Female no. 8 showed unilateral slight pelvic dilation of kidney.

Group 2: 100 mg/kg
Dark-brownish content in stomach and/or in small and large intestine was recorded in females nos. 23, 24, 25, 27, 30, 31, 32, 34, 35, 37, 38, 39, 42 and 43.
Furthermore, these findings were accompanied in female no. 38 by pelvic dilation of kidneys (severe on the left side and slight on the right).

Group 3: 300 mg/kg
Dark-brownish content in stomach and/or in small and large intestine was recorded in females nos. 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 65, 66, 89 and 90.
Furthermore, these findings were accompanied in female no. 64 by hemorrhagic fluid content in the right uterine horn.
Female no. 89 showed unilateral slight pelvic dilation of kidney.

Group 4: 1000 mg/kg
Dark-brownish content in stomach and/or in small and large intestine was recorded in females nos. 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87 and 88.
Furthermore, female no. 72 showed reddish mucosa in the stomach.
No other test-item-related findings were recorded.

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
No relevant test-item-related differences were recorded.
GROUP 1 GROUP 2 GROUP 3 GROUP 4
CONTROL 100 mg/kg 300 mg/kg 1000 mg/kg

NUMBER OF DAMS 20 20 21 20
CORPORA LUTEA 349 343 334 340
MEAN (+) 17.5 17.2 15.9 17.0
ST.DEV. 3.0 2.2 2.5 2.1

PRE-IMPLANTATION LOSS 31 29 39 26
% OF CORP. LUTEA (#) 8.9 8.5 11.7 7.6
MEAN (+) 1.6 1.5 1.9 1.3
ST.DEV. 2.5 1.8 2.2 1.4
NUMBER OF DAMS AFFECTED 9 11 13 13

IMPLANTATION SITES 318 314 295 314
% OF CORP. LUTEA (#) 91.1 91.5 88.3 92.4
MEAN (+) 15.9 15.7 14.0 15.7
ST.DEV. 2.3 2.3 3.7 2.3

POST-IMPLANTATION LOSS 16 12 13 7
% OF IMPL. SITES (#) 5.0 3.8 4.4 2.2 #
MEAN (+) 0.8 0.6 0.6 0.4
ST.DEV. 1.0 0.8 1.1 0.6
NUMBER OF DAMS AFFECTED 11 9 7 6

IMPLANTATION SITE SCARS 0 0 0 0

EMBRYONIC/FETAL DEATHS TOTAL 16 12 13 7

EMBRYONIC RESORPTIONS 16 12 13 7

FETAL RESORPTIONS 0 0 0 0

TOTAL FETUSES 302 302 282 307
% OF IMPL. SITES (#) 95.0 96.2 95.6 97.8 #
MEAN (+) 15.1 15.1 13.4 15.4
ST.DEV. 2.5 2.1 4.0 2.1

LIVE FETUSES 302 302 282 307

DEAD FETUSES 0 0 0 0

# : Fisher's Exact Test significant at level 5% (#)

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
body weight and weight gain
changes in number of pregnant
clinical signs
dead fetuses
early or late resorptions
food consumption and compound intake
maternal abnormalities
mortality
necropsy findings
number of abortions
pre and post implantation loss
total litter losses by resorption
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day
Based on:
act. ingr.
Basis for effect level:
body weight and weight gain

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
No test-item-related differences were recorded in fetal body weights.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
No differences were recorded in sex ratio or distribution of males and females in the uterus content compared to the Control group.
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related findings were recorded.

Group 1: Control group
No findings were recorded.

Group 2: 100 mg/kg
Litter no. 28 had one fetus (no. 202) with exencephaly (abnormality).

Group 3: 300 mg/kg
No findings were recorded.

Group 4: 1000 mg/kg
Litter no. 85 had two fetuses (no. 1016 and 1017) with fused placenta (variation).
No further findings were recorded in the fetuses examined.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No toxicologically relevant alterations were observed in the skeletal examination.
There was a slightly higher percentage of litters with lower ossification of some digits in Group 4 compared to the Control group. Although some differences recorded were statistically significant, the findings observed were not considered of pathological relevance.
The skeletal examination revealed a range of variations in all groups. There was no indication of a test-item-related trend in the type or incidence of these findings.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No toxicologically relevant alterations were observed in the visceral examination.
The observation of the fetuses revealed findings (variations) in all the groups, including Control: dilated renal pelvis, absent renal papilla, malpositioned kidney, dilated and/or convoluted ureter, dilated stomach, left-side umbilical artery, long cranial thymus, malpositioned cranial testis, additional small lobe in the liver.
Although statistically significant differences were recorded in the percentage of fetuses with convoluted and/or dilated ureter and dilated renal pelvis in Group 4 with respect to the Control group, these findings were not considered of pathological relevance.

Group 1: Control group
Litter no. 9 had one fetus (no. 512) with findings in thyroid gland, left (large) and right (was not recognizable) (variations). Furthermore, this fetus presented bilateral azygos vein (variation).
Litter no. 10 had one fetus (no. 431) with dark area in the liver (variation).
Litter no. 15 had one fetus (no. 741) with small hematoma in the liver (variation).
Litter no.17 had one fetus (no. 798) with a discrete space in the liver compatible with a cyst (variation).
Litter no. 21 had two fetuses (nos. 1031 and 1033) with bilateral azygos vein (variation).

Group 2: 100 mg/kg
Litters nos. 26, 38 and 40 had one, two and one fetuses (nos. 5, 878 and 872 and 986), respectively with a small hematoma in the liver (variation).
Litter no. 28 had one fetus (no. 202) with visible exencephaly, misshapen brain and misshapen pituitary gland (abnormalities).

Group 3: 300 mg/kg
Litter no. 46 had one fetus with unilateral misshapen lens (oval), considered a variation.
Litter no. 64 had one fetus (no. 948) with a small hematoma in the liver (variation) and one fetus (no. 954) with bilateral azygos vein (variation).
Litter no. 60 had one fetus (no. 714) with malrotated left hind paw. This finding was observed during the Bouin examination and was attributed to the fixation.

Group 4: 1000 mg/kg
Litters nos. 74 and 77 had two fetuses each (nos. 495 and 505 and nos. 465 and 467, respectively) with dilated esophagus parallel to trachea (variation).
Litter no. 78 had one fetus (no. 607) with abnormal liver lobation (variation).
Litter no. 86 had one fetus (no. 1094) had large eye and unilateral misshapen lens (oval), both considered variations.
Litters nos. 80 and 83 had one fetus each (nos. 860 and 969, respectively) with small hematoma in the liver (variation).
Description (incidence and severity):
GROUP 1 GROUP 2 GROUP 3 GROUP 4
CONTROL 100 mg/kg 300 mg/kg 1000 mg/kg
NUMBER OF DAMS 20 20 21 20
ABNORMAL FETUSES 0 1 0 0
% OF FETUSES (#) 0.3
MEAN (+) 0.1
ST.DEV. 0.2
NUMBER OF DAMS AFFECTED 1

ABNORMAL LIVE FETUSES
AT EXTERNAL EXAMINATION 0 1 0 0

ABNORMAL DEAD FETUSES
AT EXTERNAL EXAMINATION 0 0 0 0

#/## : Fisher's Exact Test significant at level 5% (#) or 1% (##)
+ : Steel Test significant at level 5%

SEX OF FETUSES
TOTAL MALES 152 158 156 134
% OF FETUSES (#) 50.3 52.3 55.3 43.6
MEAN (+) 7.6 7.9 7.4 6.7
ST.DEV. 2.1 1.8 2.7 2.4

TOTAL FEMALES 150 144 126 173
% OF FETUSES (#) 49.7 47.7 44.7 56.4
MEAN (+) 7.5 7.2 6.0 8.7
ST.DEV. 3.5 2.2 2.6 2.0

LIVE MALES 152 158 156 134

LIVE FEMALES 150 144 126 173

WEIGHTS OF LIVE FETUSES (g)
(LITTER BASIS)

TOTAL FETUSES
N (LITTERS) 20 20 21 20
MEAN (*) 4.0 4.1 4.0 3.9
ST.DEV. 0.3 0.3 0.3 0.3

MALES
N (LITTERS) 20 20 21 20
MEAN (*) 4.1 4.2 4.1 4.0
ST.DEV. 0.3 0.3 0.3 0.3

FEMALES
N (LITTERS) 20 20 20 20
MEAN (*) 3.8 4.0 3.8 3.7
ST.DEV. 0.3 0.3 0.3 0.3


WEIGHTS OF LIVE FETUSES (g)
(INDIVIDUAL BASIS)

TOTAL FETUSES
N (FETUSES) 302 302 282 307
MEAN (*) 3.9 4.1 ** 3.9 3.9 *
ST.DEV. 0.4 0.4 0.4 0.4

MALES
N (FETUSES) 152 158 156 134
MEAN (*) 4.1 4.2 ** 4.0 4.0
ST.DEV. 0.4 0.4 0.4 0.4

FEMALES
N (FETUSES) 150 144 126 173
MEAN (*) 3.8 4.0 ** 3.8 3.7
ST.DEV. 0.4 0.4 0.3 0.4
Details on embryotoxic / teratogenic effects:
In the observations derived from hysterectomy, no test-item-related embryofetal toxicity was observed at any of the administered doses.
No treatment-related abnormal findings were recorded in the external examination of the fetuses.
One fetus from Group 2 (no. 202) from litter no. 28 showed exencephaly (abnormality). This abnormality should be regarded as spontaneous and was not considered treatment-related.
The skeletal examination of the fetuses did not reveal any toxicologically relevant alterations.
A slight delay of ossification was recorded among some litters from Group 4 compared with the Control group. This finding should be considered a variation, which was considered devoid of pathological meaning.
The visceral examination of the fetuses confirmed the presence of exencephaly, already recorded in one fetus from Group 2 in the external examination.
The remaining visceral findings recorded in the Control and test-item-treated groups were simple variations mainly involving urogenital morphology (dilated renal pelvis, and dilated and or convoluted ureter, malpositioned kidney, absent renal papilla, malpositioned cranial testis) in addition to others findings (dilated stomach, left-sided umbilical artery, additional small lobe in the liver and bilateral azygos vein). These alterations should be regarded as spontaneous variations of limited pathological relevance.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
changes in sex ratio
fetal/pup body weight changes
external malformations
skeletal malformations
visceral malformations

Fetal abnormalities

Abnormalities:
effects observed, non-treatment-related

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Based on the study results:
NOAEL for maternal toxicity: 1000 mg/kg/day
NOEL for maternal toxicity: 100 mg/kg/day
NOEL for embryofetal development: 1000 mg/kg/day
NOAEL for teratogenic effects: 1000 mg/kg/day.
Executive summary:

The purpose of this study was to detect effects on the pregnant rat and development of embryo and fetus consequent to exposure of the female to the test item orally by gavage from day 6 post coitum until day 19 post coitum. Each group consisted of at least 22 mated females. The test substance was administered at 0, 100, 300, 1000 mg/kg/day to groups 1, 2, 3 and 4, respectively. The dose volume was 5 ml/kg and was adjusted based on the actual body weight. Control animals received the vehicle (distilled water) at the same dose volume as the test item groups.

 

Maternal data

All animals survived the scheduled treatment period. There were relevant no clinical signs. Dark feces were seen in all dose groups. This was considered to be due to the color of the test item. No relevant effects on food consumption were recorded. Lower body weight gain was seen in females treated at 300 and 1000 mg/kg/day from day 7 of pregnancy onwards. No effects on body weight gain were seen at 100 mg/kg/day. There were no test item related differences on reproduction data. Dark brown content was recorded in the stomach and intestine. This was considered to be due to the color of the test item.

 

Fetal data

There were no differences in body weight and sex ratio. No test item related abnormal findings were recorded in the external examination of fetuses. One fetus showed exencephaly which was considered to be spontaneous. There were no relevant alterations in sketetal and visceral serial examination. Slight increase in percentage of convoluted and/or dilated ureter and dilated renal pelvis was recorded at 1000 mg/kg/day which was considered of no pathological relevance.

 

Based on the findings of this study, 1000 mg/kg/day was considered to be the NOAEL and 100 mg/kg/day was considered to be the NOEL for pregnant females. The NOEL for embryofetal development was considered to be 1000 mg/kg/day. The NOAEL for teratogenic effect is 1000 mg/kg/day.