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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test guideline (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1978
Report date:
1978

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPP 83-4 (Reproduction and Fertility Effects)
Deviations:
not specified
Principles of method if other than guideline:
Evaluation Criteria
Both pre and post implantation losses contribute to dominant lethality. The former is reflected in the total number of implantation sites per pregnant female and strictly measured by the difference between the number of corpora lutea gravidus and the number of implantation sites. Toxic or physiologic effects on sperm may also reduce the number of implantation sites Therefore unless subtle physiological effects on sperm can be discounted pre implantation loss is not as rigorous an indication of dominant lethality as post implantation loss. Corpora lutea can not be reliably counted in mice and therefore pre-implantation loss is not evaluated in studies using mice. Post-implantation losses are measured as early and late fetal deaths plus the number of resorption sites.
Dominant lethality is typically determined from a mutation index derived from the ratio of dead to total implants or the number of dead implants per pregnant female. In interpreting these values it must be remembered that the former measurement reflects both pre and post-implantation losses and that the ratio is affected by changes in either the numerator or the denominator. For this reason the second parameter is perhaps a better indicator of post-implantation loss. This becomes especially so if one concurrently examines the number of living embryos per pregnant female. The two sets of data should be inversely related In other words if true dominant lethality is being observed then a significant increase in the number of dead implants per pregnant female should be accompanied by a significant decrease in the number of living implants per pregnant female.
These ratios are compared with both concurrent and historical control data for significant statistical differences. Dose related trends are also looked for but may not always be found For example some compounds such as EMS tested in mice show a threshold value and then a very steep rise. Certain portions of the response might be missed depending on the spacing of the dose levels used. True, as opposed to spurious, dominant lethality also tends to cluster according to the stage of spermatogenesis affected and typically would not be expected to appear in widely spaced weeks or blocks of weeks.
All data which are indicated as being statistically significant must also be strongly evaluated for their biological significance. By bringing both statistical and biological selective pressures to bear on the data gathered an estimate of dominant lethality and of risk to the gene pool should be obtainable.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,4,5,6,7,7-hexachloro-8,9,10-trinorborn-5-ene-2,3-dicarboxylic anhydride
EC Number:
204-077-3
EC Name:
1,4,5,6,7,7-hexachloro-8,9,10-trinorborn-5-ene-2,3-dicarboxylic anhydride
Cas Number:
115-27-5
Molecular formula:
C9H2Cl6O3
IUPAC Name:
3-({3-carboxy-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene-2-carbonyloxy}carbonyl)-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene-2-carboxylic acid
Details on test material:
- Name of test material (as cited in study report): Chlorendic anhydride- Physical state: White powder- Analytical purity: 93.81%- Impurities (identity and concentrations): Chlorendic acid 4.31% Maleic anhydride 0.40%- Purity test date: 16 Aug 77- Lot/batch No.: 3-12-206

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles Rivers Breeding Laboratories, Inc.
- Age at study initiation: (P) 8 wks; (F1) x wks
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g
- Fasting period before study:
- Housing:
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet: ad libitum
- Water: ad libitum
- Acclimation period:


ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod: 12hrs dark / 12 hrs light


IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: feed
Vehicle:
DMSO
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:


DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:


VEHICLE
- Justification for use and choice of vehicle (if other than water): Chlorendic anhydride soluble in DMSO
- Concentration in vehicle:
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity:
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 7 weeks
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]
- After successful mating each pregnant female was caged (how):
- Any other deviations from standard protocol:
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
5 days
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:0.05 g / kgBasis:actual ingested
Remarks:
Doses / Concentrations:0.1 g / kgBasis:actual ingested
Remarks:
Doses / Concentrations:0.5 g / kgBasis:actual ingested
Remarks:
Doses / Concentrations:1 g / kgBasis:actual ingested
Remarks:
Doses / Concentrations:5 g / kgBasis:actual ingested
No. of animals per sex per dose:
6
Control animals:
yes, concurrent vehicle
Positive control:
The positive control was (TEM), Triethyleneamine, and was administered as a single intraperitoneal injection..

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
not examined
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Other effects:
effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined

Effect levels (P0)

Remarks on result:
other: Chlorendic Anhydride was considered to be inactive in this test and did not induce dominant lethality in mice under the test conditions employed in this evaluation.

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
not examined
Body weight and weight changes:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined

Effect levels (F1)

Dose descriptor:
other: Fetal mortality
Generation:
F1
Effect level:
> 223 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: Chlorendic Anhydride was considered to be inactive in this test and did not induce dominant lethality in mice under the test conditions employed in this evaluation.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Chlorendic Anhydride was considered to be inactive in this test and did not induce dominant lethality in mice under the test conditions employed in this evaluation.
Executive summary:

Chlorendic Anhydride was examined for its ability to induce dominant lethality in male mice. The test material was evaluated at 0.223 g/kg, 0.074 g/kg and 0.022 g/kg. The vehicle for this test was DMSO and the route of administration was oral (PO). Following dosing the males were mated sequentially for 7 weeks to virgin female mice. Pregnant females were scored for dominant lethal indexes at mid pregnancy. The results did not indicate any evidence of compound induced dominant lethality. Some reduction in fertility was observed at Week 5 but none of the other parameters produced significant trends during the same week. The positive control TEM was active over the first three mating weeks indicating induction of alterations in sperm and spermatids. Chlorendic Anhydride was considered to be inactive in this test and did not induce dominant lethality in mice under the test conditions employed in this evaluation.