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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
reproductive toxicity, other
Remarks:
90-day repeated dose toxicity study examining some fertility parameters
Type of information:
other: read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Study period:
27 December, 1978, to 26 March, 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Justification for type of information:
Justification for Read Across is provided in Section 13 of IUCLID

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1985

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD Guideline 408 90 day repeated dose toxicity study in rodents
Deviations:
no
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI, USA).
- Age at study initiation: 6-8 weeks old.
- Weight at study initiation: 23-25 g (male), 18-19 g (female).
- Housing: 5 animals per cage (polycarbonate).
- Diet (e.g. ad libitum): Purina Lab Chow meal (St. Louis, MO); available ad libitum.
- Water (e.g. ad libitum): Acidified with HCl (pH 2.5) tap water; available ad libitum.
- Acclimation period: 2 weeks.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24 (max 28).
- Humidity (%): 30-70
- Air changes (per hr): 12-15 room air changes/h.
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Appropriate amounts of test item were mixed with corn oil. Mixtures were resuspended before dosing.

VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil was chosen because of the potential for chemical hydrolysis in water.
- Concentration in vehicle: 0, 28.53, 57.06, 112.61, 225.22, 450.45 mg/mL
- Amount of vehicle: 3.33 mL/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical verification of doses or concentrations: Analyses of the test item in corn oil were performed on every eighth dose mixture to confirm that the correct concentrations were administered to the test animals. The method of analysis involved a methanolic extraction as a purification step and a gas chromatographic assay as a quantification step.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily, 5 days a week
Doses / concentrationsopen allclose all
Dose / conc.:
90 mg/kg bw/day (actual dose received)
Dose / conc.:
190 mg/kg bw/day (actual dose received)
Dose / conc.:
375 mg/kg bw/day (actual dose received)
Dose / conc.:
750 mg/kg bw/day (actual dose received)
Dose / conc.:
1 500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10 males and 10 females per dose
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
- Clinical signs:twice per day
- Mortality: twice per day
- Body weight: weekly
- Organ weight: no
- Food consumption: no
- Water consumption: no
- Haematology: no
- Biochemistry: no
- Urinalysis: no
Postmortem examinations (parental animals):
Necropsy performed on all animals; the following tissues from vehicle control and all but the 95 mg/kg bw dosed group of mice were microscopically examined: gross lesions, skin , parathyroids, colon, esophagus, brain, sternebrae (including marrow), liver, lung and mainstem bronchi, stomach, thymus, pancreas, kidney, urinary bladder, eyes, mandibular lymph node, saliva glands, thyroid gland, small intestine, ovaries/ uterus or prostate / testes, heart, trachea, spleen, adrenal glands, pituitary gland, gallbladder, mammary gland. Only heart, liver, and kidney examined for the 95 mg/kg group of mice.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
no effects observed
Description (incidence and severity):
final weights of surving dosed and vehicle control mice were comparable
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
final weights of surving dosed and vehicle control mice were comparable
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
effects observed, treatment-related
Reproductive performance:
not examined

Details on results (P0)

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:
All the mice of each sex that received the higher doses of 750 or 1500 mg/kg died during the first 4 weeks. 2 of the 10 males and 5 of 10 females that received 375 mg/kg also died. Mice that received 375 mg/kg or more had tremors and decreased activity. Final weights of surviving dosed and vehicle control mice were comparable. Lung congestion in males and females, cardiac mineralization in males, and hepatocellular vacuolization in females were probably compound related. Pulmonary congestion was observed in animals that died during the studies. Testicular atrophy, characterized by hypospermatogenesis with the formation of large giant spermatids and syncytial cells, was seen in male mice at 375, 750, and 1500 mg/kg.
These effects were probably secondary to the general toxicity.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
190 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Testicular atrophy, characterized by hypospermatogenesis with the formation of large giant spermatids and syncytial cells, was seen in male mice at 375, 750, and 1500 mg/kg. These effects were probably secondary to the general toxicity.
Dose descriptor:
LOAEL
Remarks:
reproductive toxicity
Effect level:
375 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Testicular atrophy, characterized by hypospermatogenesis with the formation of large giant spermatids and syncytial cells, was seen in male mice at 375, 750, and 1500 mg/kg. These effects were probably secondary to the general toxicity.

Target system / organ toxicity (P0)

Critical effects observed:
yes
Lowest effective dose / conc.:
375 mg/kg bw/day (actual dose received)
System:
male reproductive system
Organ:
testes
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL (reproductive, mouse, male) = 190 mg/kg bw/day
LOAEL (reproductive, mouse, male) = 375 mg/kg bw/day (testes)
Executive summary:

The toxicity to reproduction is able to be assessed using the data obtained from a 90-day repeated dose toxicity experimental study performed according to a method equivalent to the OECD Guideline 408. Groups of 10 male and 10 female B6C3F1 mice were administered the test item in corn oil at doses of 90, 190, 375, 750 or 1500 mg/kg bw/day alongside a vehicle control group five days a week for 90 days.

All the mice of each sex that received the higher doses of 750 or 1500 mg/kg bw/day died during the first 4 weeks. 20 % of males and 50 % of females that received 375 mg/kg bw/day also died. Mice that received 375 mg/kg bw/day or more had tremors and decreased activity. Final weights of surviving dosed and vehicle control mice were comparable. Lung congestion in males and females, cardiac mineralisation in males, and hepatocellular vacuolisation in females were probably compound related. Pulmonary congestion was observed in animals that died during the studies. Testicular atrophy, characterized by hypospermatogenesis with the formation of large giant spermatids and syncytial cells, was seen in male mice at 375, 750, and 1500 mg/kg. These effects were probably secondary to the general toxicity.

Based on the testicular atrophy, hypospermatogenesis and formation of large giant spermatids and sincytial cells in males at the three highest doses, the NOAEL for reproductive toxicity can be set at 190 mg/kg bw/day.