1,2-dichloro-4-nitrobenzene

Developmental toxicity / teratogenicity

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

Test material information

Constituent 1

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

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).