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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:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP Study according to Guideline, well documented, meets generally accepted scientific principles, TS commercial grade

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report date:
1987

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
1,2-dichloro-4-nitrobenzene
EC Number:
202-764-2
EC Name:
1,2-dichloro-4-nitrobenzene
Cas Number:
99-54-7
Molecular formula:
C6H3Cl2NO2
IUPAC Name:
1,2-dichloro-4-nitrobenzene
Constituent 2
Chemical structure
Reference substance name:
1,2-dichloro-3-nitrobenzene
EC Number:
221-717-7
EC Name:
1,2-dichloro-3-nitrobenzene
Cas Number:
3209-22-1
Molecular formula:
C6H3Cl2NO2
IUPAC Name:
1,2-dichloro-3-nitrobenzene

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 10 weeks
- Weight at study initiation: 194-251 g
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
diluted in corn oil
ADMINISTRATION VOLUME:
10 ml/kg bw/day
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
gas chromatography
Details on mating procedure:
- Impregnation procedure: cohoused
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
gd 6 - 15
Frequency of treatment:
once daily
Duration of test:
sacrifice on gestation day 21
No. of animals per sex per dose:
25 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on dose range finding study

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Cage side observations were included. survival, clinical signs

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations:
gestation day 0, 6, 10, 13, 18, 21

FOOD CONSUMPTION yes
interval of gestastion days 0-6, 6-10, 10-13,13-18, 18-21

WATER CONSUMPTION No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: uterus

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: preimplantation loss and postimplantation loss
Fetal examinations:
All live fetuses from dams which survived to scheduled sacrifice were subjected to a gross external examination, sexed, weighed, and tagged for identification. One-half of each litter for visceral examination one-half of each litter for skeletal examination. Abnormal findings were classified as malformations or variations. control, low, mid, high dose:
Total number of litters examined (no. of fetuses): 23(323), 25(353), 23(340), 24(339)
no. of examined viscerally: 22(160), 25(176), 23(170), 24(169)
no. examined skeletally: 23(163), 25(177), 23(170), 24(170)
Statistics:
in general: one-side comparison (except sex distribution of fetuses: two-side comparison), Dunnett's test, Mann-Whitney U test, Fisher's exact test, cochran-armitrage test, Bonferroni's inequality

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Mortality:
no mortality observed
Description (incidence):
All dams survived to scheduled sacrifice.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
100 mg: significantly reduced mean body weights on gd 10 (267.8 g versus 284.5 g of controls), gd 13 (284.8 g versus 302.3 g of controls) and gd 16 (307.7g [approx. 5 %] versus 324.4 g of controls)

Mean body weight change on gd 6-10, dose-related:
control: 8.4 g/dam
10 mg: 6.2 g/dam
30 mg: 4.0 g/dam (significant, p<=0.05)
100 mg.: -4.4 g/dam (significant, p<=0.01), corresponding to a significant body weight loss of approximately 5 %
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
10 mg/kg bw:
significantly reduced food consumption on gd 6-10;
30 mg/kg bw:
significantly reduced food consumption for gd 6-10
100 mg/kg bw:
significantly reduced food consumption on gd 6-10 and gd 10-13
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
controls: hydronephrosis of the kidneys in 1/23 rat
10 mg-group: hydronephrosis of the kidneys in 1/25 rat
100 mg-groups: hydronephrosis of the kidneys in 3/25 rats

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:
effects observed, treatment-related
Description (incidence and severity):
100 mg: increased mean early resorptions (1.1/dam versus 0.5/dam in controls)
Dead fetuses:
no effects observed
Description (incidence and severity):
pregnancy rates (Total pregnant females: control, low, mid, high dose: 23/25, 25/25, 23/25, 24/25)

Effect levels (maternal animals)

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

Maternal abnormalities

Abnormalities:
not specified

Results (fetuses)

Fetal body weight changes:
no effects observed
Changes in sex ratio:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
No statistically significant differences for the incidence of total or individual malformations.
Findings observed in multiple foetuses in treated rats included: anophthalmia/microphthalmia (100 mg: 4 in 3 litters; 10 mg: 2 in 2 litters, control: 1 in 1 litter), small oral opening (100 mg: 2 in 2 litters), skull misshapen (100 mg: 2 in 2 litters), nasal passages misshapen (100 mg: 2 in 2 litters and gastroschesis (100 mg: 2 in 2 litters).
None of these findings were seen in mid-dosed rats
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Dilated ureters were elevated in mid- and high-dosed rats: control, low, mid, high dose (7 fetuses in 3 litters, 8 fetuses in 4 litters, 17 fetuses in 9 litters 15 fetuses in 10 litters).
Dilated ureters are regarded to be of low concern (ECETOC Monograph No. 31, 2003).

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
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:
The NOAEL for maternal toxicity and developmental toxicity is 10 mg/kg bw/d.
Executive summary:

Pregnant female Sprague-Dawley rats were orally applied with 0, 10, 30, or 100 mg/kg bw/day 1,2 -dichloro-4-nitrobenzene dissolved in corn oil by gavage resulting in developmental effects (significant increase in dilated ureters) in the presence of maternal toxicity (significantly reduced body weight gain on gd 6 -10). The NOAEL for maternal toxicity and developmental toxicity is 10 mg/kg bw/d (Monsanto 1987).