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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: 90-day toxicity study
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted under GLP and it was done according to valid methods for repeated dose toxicity. The study is reliable and relevant, however it is not fully adequate for classification.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report Date:
1985

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
other: EU Method B.27 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
other: OECD 408
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): Chloracetamid, Chloressigsäureamid
- Physical state: White powder
- Analytical purity: 99.7%
- Impurities (identity and concentrations):See confidential details
- Composition of test material, percentage of components: See confidential details
- Purity test date: 1983-11-29
- Lot/batch No.: 791
- Stability under test conditions: 7 days stable in feed
- Storage condition of test material: In the dark at ca. 22 °C
- Other: Technical substance , manufactured 1983-07-19 , content of active ingredient in test substance 997 g/kg (according to report Dr. Their dd 1984-07-12)

Test animals

Species:
rat
Strain:
other: Wistar; Hoe: WISKf(SPF71)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hoechst AG, Hattersheim-Kastengrund (Germany), SPF-Zucht,
- Age at study initiation: Males ca. 4 weeks; females ca. 5 weeks
- Weight at study initiation: Average males 79.8 g; average females 85.4 g
- Housing: Draft mesh cages (Type 3), in groups until 2 animals
- Diet: Rattendiät Altromin 1321 by Altromin GmbH Lage/Lippe (Germany) ad libitum
- Water: Tap water in plastic bottles, ad libitum
- Acclimation period: At least 5 days before study

ENVIRONMENTAL CONDITIONS
Fully airconditioned rooms

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Extraction of the active ingredient from the spiked diet using methanol (Chromasolv R). Concentration and dilution in methanol
(Chromasolv R). Determination of the active ingredient using gaschromatography with a nitrogen selective detector (PND).
(cf report Dr. Thier dd 1984-07-12 / encluded in the study report)
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 2, 10, 50 mg/kg bw/day
Basis:
nominal in diet
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: In an earlier 90 days oral repeated dose study doses of 12.5 and 50 mg/kg bw/day were administered. These doses were too high to determine a no effect level. Purpose of this experiment was to determine a no effect level.
- Rationale for selecting satellite groups: first 5 animals of each group were killed at the end of testing; the other 5 were killed after 29 days recovery period.
- Post-exposure recovery period in satellite groups:29 days

Examinations

Parental animals: Observations and examinations:
Monday - Friday 2x daily, on weekends 1x daily: behaviour /health state
1x weekly: neurological disorders, opacities of eyes, injuries of the mouth's mucous membrane, disturbed toothgrowth
2x weekly, during acclimation, study and recovery: body weight
2x weekly during study: feed used; 1x weekly water used
end of study or end of recovery period: haematological parameters in the blood
after sacrifice: clinical-chemical parameters in the serum
night between 88./89. study day, 16 h urine: urinanalysis (animals unfeed, unwatered)
Postmortem examinations (parental animals):
GROSS PATHOLOGY: Yes
- Sacrifice by i.p. injection of 50 mg Nembutal / kg bw / de-bleeding by opening the vena cava cranialis
- gross assessment according to Hoechst Sektionsordnung I, Prof. K/G dd 1982-02-04
- relative organ weights (% of bw)
HISTOPATHOLOGY: Yes
- histological assessment of fixated organ or preparations according to Hoechst Sektionsordnung I, Prof. K/G dd 1982-02-04: heart, lungs, liver, kidneys, spleen, stomach, jejunum, colon, bladder, testes, epidiymis, prostate, seminal vesicle, ovaries, uterus,thyroid, pancreas, adrenals, thymus, pituitary gland, brain, eyes with N. opticus, bone marrow (femur marrow)
Statistics:
Statistical evaluation of following measured values, using probability level 0.05:
- body weight at observation times
- body weight gain during intervals
- haematological parameters (except differential blood count)
- clinical chemical parameters
- urinanalysis (pH, density)
- absolute/ relative organ weights
Hoechst evaluation software used according to SOP Dr. Passing, Department of Practical Mathematics.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, treatment-related

Details on results (P0)

CLINICAL SIGNS AND MORTALITY: no effects, no mortalities during dosing & recovery period.
BODY WEIGHT AND WEIGHT GAIN: decreased in males & femaels in highest dose from week 2/3 onwards, respectively; reversible in recovery period.
FOOD CONSUMPTION AND COMPOUND INTAKE: decreased in males & females during first 30 dyas. No effects in recovery period.
FOOD EFFICIENCY: no data
WATER CONSUMPTION: no effects during dosing & recovery period.
OPHTHALMOSCOPIC EXAMINATION: no effects during dosing & recovery period.
HAEMATOLOGY: increased white blood cells at highest dose; reversible in recovery period.
CLINICAL CHEMISTRY: no effects during dosing & recovery period.
URINALYSIS: no effects during dosing & recovery period.
NEUROBEHAVIOUR: no effects during dosing & recovery period.
ORGAN WEIGHTS: male rats, highest dose: reduced testicular weights; still observed in the recovery group - decreased liver weight in females, highest dose; reversible in recovery period however decreased liver weight in males after recovery period.
GROSS PATHOLOGY: male rats, highest dose: smaller testes, reversible in the recovery group
HISTOPATHOLOGY: male rats, highest dose: depression - standstill of spermiogenesis and proliferation of Leydig cells and other interstitial cells in testes; absence of mature & immature sperms instead only loose connective tissue visible in epidydimides; in the recovery group starting to complete regeneration was observed.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
100 mg/kg diet
Based on:
act. ingr.
Sex:
male/female
Remarks on result:
other: Generation not specified (migrated information)
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Remarks on result:
other: Generation not specified (migrated information)

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
After the highest dose, male rats had smaller testes, disturbed spermiogenesis and proliferation of the Leydig cells.
After a 29 recovery period beginning or complete regeneration of testes tubuli were observed.

Chloroacetamide in this 90 day oral repeated dose study in rats caused a decreased body weight gain and increased leucocyte count in the high dose male and female rats. The high dose males had smaller testes, depression- standstill of the spermiogenesis and proliferation of Leydig cells. After a 29 day recovery period, there were signs of beginning or ended regeneration of the testicular tubuli.
The NOAEL for Chloroacetamide in this study was determined to be 10 mg/kg bw/day.
Executive summary:

In a 90 day oral repeated dose study in Wistar rats were given doses of 0, 20, 100 and 500 mg Chloroacetamide test substance/kg feed /day. Each group consisted of 10 male and 10 female animals, of which the first 5 animals of each group, were killed at the end of the 90 day, whereas the other 5 were killed after a 29 day recovery period. In the high dose (500 mg/kg feed) male and female animals showed reduced body weight gain and food consumption and increased leucocytes in both sexes, decreased liver weights in females, and smaller testes, reduced testicular weights, proliferation of Leydig/other interstitial cells and depression - standstill of spermiogenesis in males.Re-onset in the recovery group with partial to complete regeneration of testes was observed in males, therefore this was to be designated as reversible. Further liver weights were reversed in females and slightly decreased in males in the hightest dose recovery groups. The NOAEL was determined to be 100 mg/kg feed, which was reported to correspond with 10 mg/kg bw/day.