2,4,6-trichloroaniline

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Remarks:

based on generations indicated in Effect levels (migrated information)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

Data is from secondary source .

Data source

Reference

Reference 1

Reference Type:

secondary source

Title:

Provisional Peer-Reviewed Toxicity Values for- 2,4,6-Trichloroaniline (CASRN 634-93-5) and 2,4,6-Trichloroaniline Hydrochloride (CASRN 33663-50-2)

Author:

SRC, Inc

Year:

2010

Bibliographic source:

Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268

Reference 2

Reference Type:

publication

Title:

Hygienic standardization of 2,4,6-trichloroaniline in water

Author:

Sapegin, DI; Fomochkin, IP; Pis’ko, GT; et al.

Year:

1985

Bibliographic source:

Gig Sanit 3:83–84,1985

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: As mention below

Principles of method if other than guideline:

A chronic reproductive toxicity study of 2, 4, 6-trichloroaniline iwas conducted in white male and female rats by oral gavage.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,4,6-trichloroaniline

EC Number:

211-219-8

EC Name:

2,4,6-trichloroaniline

Cas Number:

634-93-5

Molecular formula:

C6H4Cl3N

IUPAC Name:

2,4,6-trichloroaniline

Details on test material:

- Name of test material (as cited in study report): 2,4,6-Trichloroaniline
- Molecular formula (if other than submission substance): C6-H4-Cl3-N
- Molecular weight (if other than submission substance): 196.464
- Substance type: Organic
- Physical state: Solid

Specific details on test material used for the study:

- Name of test material (as cited in study report): 2,4,6-Trichloroaniline
- Molecular formula (if other than submission substance): C6-H4-Cl3-N
- Molecular weight (if other than submission substance): 196.464
- Substance type: Organic
- Physical state: Solid

Test animals

Species:

rat

Strain:

not specified

Details on species / strain selection:

White rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

Not specified

Administration / exposure

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

other: not applicable

Vehicle:

other: Oil solution

Remarks:

Not specified

Details on exposure:

Details on exposure
PREPARATION OF DOSING SOLUTIONS: 2,4,6-trichloroaniline were mix with oil solution in the concentration of at doses of 0.4, 4, or 40 mg/kg-day, 5 days/week (adjusted to 0.3, 3, or 29 mg/kg-day).

VEHICLE
- Justification for use and choice of vehicle (if other than water): Oil solution were used
- Concentration in vehicle: 0, 0.3, 3 and 29 mg/kg/day

Details on mating procedure:

The animals were mated at the end of the 6-month treatment period.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 months

Frequency of treatment:

5days /week

Details on study schedule:

No data available

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.3, 3.0, and 29 mg/kg/day
Basis:
no data

No. of animals per sex per dose:

120 males and 60 females

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Positive control:

No data available

Examinations

Parental animals: Observations and examinations:

Observations and examinations performed & frequency
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
- Cage side observations checked in table [No.?] were included: Mortality was observed.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: On every 30 days throughout the treatment period.

BODY WEIGHT: Yes
- Time schedule for examinations: On every 30 days throughout the treatment period.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: On every 30 days of treatment period.
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: All 180 animals were examined.
- Parameters checked in table [No.?] were examined: Methemoglobin, conditioned reflexes, Concentration of formed elements and serum hemoglobin, Polychromaphilic and hypochromic RBCs and WBC were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: On every 30 days of treatment period.
- Animals fasted: No data available
- How many animals: All 180 animals were examined.
- Parameters checked in table [No.?] were examined: : Residual nitrogen, pyruvic acid, catalase, alanine aminotransferase [ALT] and aspartate aminotransferase [AST] levels, nitrogen and pyruvic acid in serum and lactate dehydrogenase (LDH), succinic dehydrogenase (SDH) and Chromosomal aberrations activities in the liver and kidney were examined.

Oestrous cyclicity (parental animals):

Any irregularities in the estrous cycle ovogenesis were investigated.

Sperm parameters (parental animals):

Sperm parameters (parent animal)
Parameters examined in [all P] male parental generations : Spermatogenesis were observed

Litter observations:

Number of live embreyos, Number of dead embreyos and numbers of fetuses/dam were observed

Postmortem examinations (parental animals):

Postmortem examinations (Parent Animal)
SACRIFICE
- Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]: Yes

- Maternal animals: All surviving animals [describe when, e.g. after the last litter of each generation was weaned.]: Number of implantation sites was examined.

GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic and abdominal viscera.]: Yes, at the termination of study.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively: Yes

Organ weights were examined.

Organ weighted:
Brain, Liver, kidneys and reproductive organs were examined.

Postmortem examinations (offspring):

Postmortem examinations (offspring)
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#?] days of age: No data available

- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows: Yes

GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]: Embryotoxicity and teratogenicity were examined.

HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively. : Yes, morphofunctional indices were examined.

Statistics:

No data available

Reproductive indices:

Fertility index, gestation index and implantation index were examined.

Offspring viability indices:

No data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Description (incidence and severity):

Body weight gain: In 29 mg/kg/day treated rat decreased in weight gain were observed as compared to control.

Food consumption and compound intake (if feeding study):

not specified

Description (incidence and severity):

Body weight gain: In 29 mg/kg/day treated rat decreased in weight gain were observed as compared to control.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

effects observed, treatment-related

Description (incidence and severity):

Decreased numbers of fetuses/dam were observed in 3 mg/kg/day treated rat.

Reproductive function: sperm measures:

not specified

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

Pre- and postimplantation fetal mortality and decreased numbers of fetuses/dam were reported at the mid-dose

Details on results (P0)

Mortality:
No mortality was observed in treated rat as compared to control.

Effect levels (P0)

1

Dose descriptor:

LOAEL

Effect level:

3 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Effect on weight gain, hematology, clinical chemistry, oxygen consumption, organ weight, gross pathology, histopathology and reproductive performance

Remarks on result:

other: Significant effect were observed

2

Dose descriptor:

NOAEL

Effect level:

0.3 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No adverse effect on survival, body weight gain, hematology, clinical, chemistry, gross pathology, histopathology and reproductive performance

Remarks on result:

other: No significant effect were observed at this dose.

Target system / organ toxicity (P0)

Critical effects observed:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Mortality / viability:

not specified

Body weight and weight changes:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Details on results (F1)

Mortality:
Pre and postimplantation fetal mortality were observed in 3 mg/kg/day treated rat.

Effect levels (F1)

1

Dose descriptor:

LOAEL

Generation:

F1

Effect level:

3 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Effect on survival of fetus

Remarks on result:

other: Effect were observed

2

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

0.3 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: No significant effect were observed

Remarks on result:

other: No significant effect were observed at this dose

Target system / organ toxicity (F1)

Critical effects observed:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The NOAEL and LOAEL was considered to be 0.3 mg/kg/day and 3 mg/kg/day for F0 generation respectively and LOAEL was considered to be 3 mg/kg/day for F1 generation when rats were treated with 2, 4, 6 trichloroaniline orally for 6 months.

Executive summary:

In a chronic reproductive toxicity study, white male and female rats were exposed to 2, 4, 6 trichloroaniline in the concentrations of 0, 0.3, 3 and 29 mg/kg/day by oral gavage. The results showed that 2, 4, 6 trichloroaniline is toxic at higher doses. Toxic changes were observed as decreased in weight gain,increased numbers of hypochromic RBCs and doubled levels of methemoglobin, Anisocytosis, poikilocytosis, reticulocytosis, hypochromia and presence of Heinz bodies in the RBCs and decreased in SDH and LDH activities in liver and the kidney of 29 mg/kg/day treated rat. Increased relative weights of brain and decreased liver weight. In addition, Degenerative changes and evidence of hemorrhage in the myocardium, kidneys, liver, spleen and brain in 29 mg/kg/day treated rats. Decreased numbers of fetuses/dam and massive hematomas were observed in abdominal cavities of 3 mg/kg/day treated rat of F0 generation. In F1 generation, Pre and postimplantation fetal mortality were also observed in 3 mg/kg/day treated rat. Therefore, LOAEL was considered to be 3 mg/kg/day for F0 and F1 generation and NOAEL was considered to be 0.3 mg/kg/day for F0 generation when rats were treated with 2, 4, 6 trichloroaniline orally for 6 months. This study is limited by inadequate data reporting, including the strain, size, and sex distribution of the control and treatment groups, the methods utilized,and the endpoints evaluated.