1,2-dichloro-4-nitrobenzene

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Studies dealing specifically with toxicity to reproduction were not identified.
During 28-day-treatment of male and female Wistar rats with 0, 4, 20 or 100 mg/kg bw/d 1,2 -dichloro-4 -nitrobenzene dissolved in sesame oil according to OECD TG 407 reproductive organs were not affected up to the maximum tolerated dose of 100 mg/kg bw/day despite clear systemic toxicity was apparent (Hoechst AG 1993 cited in UNEP 2005, see also toxicity to reproduction: other studies). Therefore there is no evidence of toxicity to the reproductive organs.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

As confirmed by literature (e.g. Mangelsdorf I. et al (2003) Regul. Toxicol. Pharmacol. 37, 356 -369) histopathologogical examinations in repeated dose toxicity studies are of high value and of high sensitivity for the evaluation of reproductive toxicity. Also, it is agreed that histopathological changes on the reproductive organs in repeated dose toxicity studies are indicative of effects on fertility. In the above cited study no effects were observed in the reproductive organs up to the highest used dose of 100 mg/kg bw/day although clear systemic toxicity is given.Therefore no further testing should be required.

 

Effects on developmental toxicity

Description of key information

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).

Link to relevant study records

Reference

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

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

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

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

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

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

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)

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Abnormalities:

not specified

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).

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

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).

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

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 iincrease 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)

Toxicity to reproduction: other studies

Description of key information

During 28-day-treatment of male and female Wistar rats with 0, 4, 20 or 100 mg/kg bw/d 1,2 -dichloro-4 -nitrobenzene dissolved in sesame oil according to OECD TG 407 reproductive organs were not affected (Hoechst AG 1993).

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction: other studies

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD TG 407 including examination of reproductive organs

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: OECD TG 407

Deviations:

not applicable

Principles of method if other than guideline:

examination of reproductive organs in a repeated dose toxicity study according to OECD TG 407

GLP compliance:

yes

Type of method:

in vivo

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: approximately 6 week
- Housing: in groups of 5 animals
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 50
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: Sesame oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
the test compound was suspended homogenousely in the vehicle by means of a magnetic stirrer

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0 - 2 % (w/v)
- Amount of vehicle (if gavage): 5 ml/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

the determination of the concentration was performed by photometrical detection after HPLC seperation on a reversed phase column

Duration of treatment / exposure:

28 d

Frequency of treatment:

daily

Duration of test:

28 days

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

4 mg/kg bw/day (nominal)

Dose / conc.:

20 mg/kg bw/day (nominal)

Dose / conc.:

100 mg/kg bw/day (nominal)

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on preliminary dose range finding study

Statistics:

---One way analyses of variance with sequentially rejective multiple comparison
---One way analyses of variance based on ranks with equentially rejective multiple comparison
---Trend Test analyses for non-neoplastic lesions (ARMITAGE)

see 'Any other information on results'

OBSERVATIONS:
No death occurred throughout the study
unspecific signs of intoxication: 100 mg-group, m/f: irregular respiration, stilted gain, >= 20 mg/kg bw/day, m/f: increased salivation;
all groups: body weight gain was not impaired, food consumption unaffected, >=20 mg/kg bw/day(m/f): slightly increased water intake (not significant, not dose dependent)
REPRODUCTIVE ORGAN EVALUATION:
no pathologic findings were reported.

Conclusions:

No pathologic findings on reproductive organs were reported.

Executive summary:

During 28-day-treatment of male and female Wistar rats with 0, 4, 20 or 100 mg/kg bw/d 1,2 -dichloro-4 -nitrobenzene dissolved in sesame oil according to OECD TG 407 reproductive organs were not affected (Hoechst AG 1993).

Additional information

During 28-day-treatment of male and female Wistar rats with 0, 4, 20 or 100 mg/kg bw/d 1,2 -dichloro-4 -nitrobenzene dissolved in sesame oil according to OECD TG 407 reproductive organs were not affected (Hoechst AG 1993).

Justification for classification or non-classification

Fertility

Due to the above discussion no classification with respect to fertility in accordance with Regulation (EC) No 1272/2008 is warranted.

Developmental toxicity

The available developmental toxicity study shows that developmental toxic effects occur only in the presence of maternal toxicity. Thus, there is no need for classification with respect to developmental toxicity in accordance with Regulation (EC) No 1272/2008.