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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
repeated dose toxicity: oral
Remarks:
other: range-finding
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
14 March 1989 - 5 April 1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was designed to assess the toxicity of formal [bis (2-chloroethoxy) methane) when administered orally, via gastric intubation, to rats for at least two weeks to select dose levels for a 90-day study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1990

Materials and methods

Test guideline
Qualifier:
no guideline followed
GLP compliance:
no
Remarks:
inhouse QA was in place
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): FORMAL [BIS(2-Chloroethoxy)Methane]
- Physical state: Clear liquid
- Analytical purity: Approximately 85% active ingredient. The identity, strength, purity and composition; and synthesis, fabrication, and/or derivation of the test substance have been documented by the sponsor.
- Impurities (identity and concentrations): Documented by the sponsor.
- Composition of test material, percentage of components: Documented by the sponsor.
- Lot/batch No.: 237-81
- Expiration date of the lot/batch: not indicated
- Stability under test conditions: The stability of the test substance has been determined by the sponsor.
- Storage condition of test material: At room temperature in a temperature monitored room.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
three weeks
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
Main study week 1: 20, 40, 50, 60, 80, 100 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
Main study week 2: 150, 200, 50, 60, 80, 100 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
Satelite study I: 200 mg/kg bw/day at 100 mg/ml animals fasted and unfasted
Basis:
actual ingested
Remarks:
Doses / Concentrations:
Satelite study I: 160 mg/kg bw/day and 120 mg/kg bw/daya t 100 mg/ml animals unfasted
Basis:
actual ingested
No. of animals per sex per dose:
Main study: 5
Satelite study I: 3
satelite study II: 5
Control animals:
yes, concurrent vehicle

Results and discussion

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

This study was designed to assess the toxicity of formal [bis (2-chloroethoxy) methane) when administered orally, via gastric intubation, to rats for at least two weeks to select dose levels for a 90-day study. The test substance, administered as a 100 mg/ml solution in corn oil, was initially administered to 60 Sprague-Dawley CD rats (5/sex/group) at dose levels of 20, 40, 50, 60, 80 and 100 mg/kg bw/day. Control animals (5/sex) received the vehicle at the same dose volume as administered to group VII animals (1.0 ml/kg bw/day). Because no signs of toxicity were seen after the first week, the two lower doses were raised from 20 and 40 mg/kg bw/day to 150 and 200 mg/kg bw/day, respectively, for the second week of the study.

Physical observations and body weight and food consumption measurements were performed for all animals pretest and weekly thereafter. hematology and clinical chemistry parameters were evaluated for all survivors just prior to sacrifice. Opthalmology examinations were performed for all animals pretest. After at least two weeks of treatment, all survivors were sacrificed, selected organs were weighed and organ/bodyweight ratios were calculated. Complete gross-mortem examinations were conducted on all animals.

Two additional (satellite) studies were performed to 1) clarify the effect of fasting on mortality at the 100 mg/kg dose level and 2) provide information on mortality, clinical signs and clinical laboratory values in animals receiving doses of 120 and 160 mg/kg bw/day (5/sex/dose) for up to seven days.

In the first satelite group all females in group I (fasted) died and all males in group I were moribund. All animals in group II (unfasted) survived.

Oral administration produced partial mortality (one in five females) at doses as low as 60 and 80 mg/kg bw/day and complete mortality (ten of ten animals) at doses of 160 and 200 mg/kg bw/day. Intermediate doses produced no mortality at the 100 mg/kg bw/day level and mortality in 7 of 10 and 8 of 10 animals at the 120 and 150 mg/kg bw/day doses. Animals receiving doses of 20 and 40 mg/kg bw/day survived for the week these doses were administered. Time to death was generally dose related. Animals in the 60 and 80 mg/kg bw/day groups died after 16 doses, while animals which died at doses of 120 mg/kg bw/day and higher died after receiving one to nine doses.

Abnormal signs, body weight depressions and hematological abnormalities weer seen as antemortem findings in animals which died. Unusual signs in some of these animals included lethargy, dyspnea, tremors, irregular gait, yellow or brown staining of the ano-genital area, salivation, moist rales, hypothermia and general poor condition as well as antemortem weight losses or decreased weight gains, relative to control values, and marked decreases in food consumption.

Hematological alterations consited of elevated hemoglobin, hematocrit and total erythrocyte values, relative to control values, for the two males each in the 120 and 160 mg/kg bw/day groups which were bled in a moribund condition and one of the two males surviving after one week of dosing at 150 mg/kg bw/day. This may be a direct effect of the test substance administration or may represent hemoconcentration secondary to dehydration in these animals. Similar differences were not apparent in females. No clear effects on platelets or total and differential leukocyte counts were seen in animals of either sex.

Clinical chemistry studies in animals which were bled in a moribund condition at the120 and 160mg/kg bw/day dose levels revealed a variety of abnormalities. Altered values seen in several animals included elevated serum transaminase (SGOT and SGPT), alkaline phosphatase, BUN and glucose levels and decreased serum sodium levels. Similar differences were not evident in females. Evaluations performed on animals surviving after one week of FORMAL administration at the150 mg/kg bw/day dose level revealed elevated serum glutamic oxoalecetic (SGOT) values. SimiIar elevations in akaline phosphatase values were also seen in 3 of the 5 males which received 100 mg/kg bw/day for two weeks. A non dose-related trend toward elevated blood urea nitrogen values was evident in females which were treated with daily doses of 50, 60, 80 or 100 mg/kg bw/day of FORMAL for at least two weeks. Alterations in organ weight values were limited to elevations in liver weights and liver/body weight ratios for females which received 80 or 100 mg/kg bw/day of test substance for at least two weeks. Gross postmortem examinations revealed no abnormalities attributable to test substance administration

Based on the apparent effects on blood urea nitrogen levels in females receiving doses as low as 50 mg/kg bw/day and on the elevated alkaline phosphatase level in males receiving 100 mg/kg bw/day, the NOEL for FORMAL in rats under conditions of this study was40 mg/kg bw/day for females and 80 mg/kg bw/day for males.