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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: Study well documented, meets generally accepted scientific priciples, 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:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
IUCLID4 Test substance: other TS: technical grade: 85 % 3,4-dichloronitrobenzene, 15 % 2,3-dichloronitrobenzene

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
- 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
ADMINISTRATIO VOLUME:
10 ml
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
analysis of testmaterialsolutions:by 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
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 30 or 100 mg/kg bw in corn oil
Basis:

No. of animals per sex per dose:
25 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Sex: female
Duration of test: sacrifice on gd 21

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 sdacrifice were subjected to a gross external examination, sexed, weighed, and tagged for identtification. one-half of each litter for visceral examination one-half of each litter for skeletal examination
Abnormal findings were classified as malformations or variations
Indices:
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

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
see section "remarks on results including tables and figures"

Effect levels (maternal animals)

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

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
see section "remarks on results including tables and figures"

Effect levels (fetuses)

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

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

RS-Freetext:
Total mated females on study: 25/group
All dams survived to scheduled sacrifice.

CLINICAL OBSERVATIONS:
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:
urogenital staining increasing number of dams with duration of pregnancy (3/25 to 16/25) and wet/matted fur (5/25 gd6-13);
significantly reduced mean bodyweights on gd 10 (267.8g versus 284.5g of controls), gd 13(284.8g versus 302.3g of controls) and gd 16 (307.7g [approx.5 %] versus 324.4g of controls); significantly reduced food consumption on gd 6-10 and gd10-13

Mean body weight change: gd 6-10, dose-related:
control 8.4 g/dam, 10 mg-gr.: 6.2 g/dam, 30 mg-g.: 4.0 g/dam (significant,p<=o.05), 100 mg-gr.: -4.4 g/dam (significant,p<=0.01), corresponding to a significant body weight loss of approximately 5 %

POST MORTEM FINDINGS:
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 REPRODUCTIVE DATA
No adverse effects on:
pregnancy rates (Total pregnant females: control, low, mid, high dose: 23/25, 25/25, 23/25, 24/25), live or dead foetuses/dam, late resorptions/dam, total implants/dam, or corpora lutea/dam or preimplantation loss
100 mg: increased mean early resorptions (1.1/dam versus 0.5/dam in controls
FETAL DATA
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)

No adverse effects on foetal body weights or sex
distribution.
Total number with malformation: 2(4), 3(4), 4(6), 5(9)
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 (100mg: 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

For variations 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).

Applicant's summary and conclusion

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)