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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and Well-conducted study performed by Southern Research Institute.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1994

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
Similar to OECD 453, however neither neurological nor ocular assessments were made during the study.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Source: Dow Chemical Company, Lot No.: 840429-162, Purity: approximately 78.6%, Identity of impurities: 2,2-bis (hydroxymethyl)-1-bromo-3-hydroxypropane (6.6%), 2,2-bis (bromomethyl)-1-bromo-3-hydroxypropane (6.9%), pentaerythritol (0.2%), dimers and structural isomers (7.7%).

Test animals

Species:
other: rat, mouse
Strain:
other: F344/N (rat), B6C3F1 (Mouse)
Sex:
male/female
Details on test animals and environmental conditions:
Age: Rats/mice-6 weeks old

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: feed
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The dose formulations were prepared weeklyby mixing the test substance with feed. Homogeneity and stability studies were performed by the analytical chemistry laboratory using Gas chromatography. Homogeneity was confirmed, and the stability of the dose formulations was confirmed for at least 3 weeks when stored in the dark at -20o.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Continuous, ad libitum
Doses / concentrations
Remarks:
Doses / Concentrations:
Rats – 0, 1250, 2500, 5000, 10000 ppm Rat, 20000 ppm, Mice – 0, 625, 1250, 2500, 5000 ppm.
Basis:
other: This dose levels corrresponded approx. to 95, 185, 400, 800, 1700 mg/bw/day for males and 100, 200, 400, 800, 1630 mg/kg (females) . Mice – 100,200,480, 1285, 2930 mg/kg (males) and 140, 300,640, 1180,2900mg/kg (females).
No. of animals per sex per dose:
Rats/mice -10male/10 female per dose.
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
Observed twice daily; body weights and clinical observations recorded initially, weekly for weeks 2 to 13th. Feed consumption was measured every 4 weeks by cage.
Sacrifice and pathology:
Complete histopathologic examinations were performed on all animals necropsied. In addition to gross lesions, tissue masses and associated lymph nodes, the tis sues examined included: adrenal gland, bone and marrow, brain, esophagus, gallbladder (mice), heart, kidney, large intestine (cecum, colon and rectum), liver, lung, lymph nodes (mandibular or mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial or clitoral gland, prostate gland, salivary
gland, skin, small intestine, (duodenum, jejunum and ileum), spleen, stomach (forestomach and glandular), testis with epididymis and seminal vesicle, thymus, thyroid gland, trachea, urinary bladder and uterus.
Statistics:
Kaplan & Meier product-limit procedure (probability of survival, estimate of neoplasm incidence). Cox’s method for testing 2 groups for equality and Tarone’s life table test (doserelated
trends). Dinse & Lagakos, Dinse & Haseman prevalence analysis ( time-specific neoplasm incidences). Fisher exact test, Cochran-Armitage trend test. Dunnett and Williams parametric multiple comparisons (organ & body weights). Shirley and Dun’s non-parametric multiple comparison methods
(clinical chemistry, urinalysis, spermatid and epididymal spermatozoa data). Jonckheere’s test
(significance of dose-related trends). Mann-Whitney U test (average severity values). Morrison
multivariate analysis of variance (treatment effects).

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
Body weight:
Rats: mean body weighs of exposed male and female rats receiving 10000 ppm and stop exposure males receiving 20000 were lower than those of controls throughout most of the study.
Mice: Mean body weight of exposed male and female mice were similar to controls throughout the study. Final mean bodyweights were also generally similar to those of controls.
Food/water consumption:
Rats: In continous study feed consumption generally similar to controls. In the 20000-ppm stop exposure males, the feed consumption was lower than the control.
Mice: Feed consumption was similar in exposed and control mice.
Clinical findings:
Rats: included skin and subcutaneous tissue masses on the face, tail and the ventral and dorsal surfaces of exposed rats.
Mice: included swelling, discarge and tissue masses involving the eye in exposed mice.
Ophthalmologic findings; Hematologic findings; Clinical biochemistry findings: No data.
Mortality and time to death:
Rats: Survival of 5000 and 1000 continous exposure males and females and 20000-ppm stop exposure males was significantly lower than control.
Mice: Survival of 1250-ppm males and females was significantly lower than control.
Gross pathology: No data, although it is likely that some or all the neoplasm found would be visible macroscopically.
Organ weight changes:
Rats: At the 3 month evaluation the right kidney and liver weights of 20000-ppm stop exposure males was significantly lower than controls. The right kidney and liver weights relative to bodyweight in this group were significantly higher than controls.
Mice: No significant differences.

Effect levels

open allclose all
Key result
Dose descriptor:
LOAEL
Remarks:
rats
Effect level:
ca. 2 500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
histopathology: non-neoplastic
Key result
Dose descriptor:
LOAEL
Remarks:
mice
Effect level:
312 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Rats: Groups of 10 male and 10 female rats were fed diets containing 0, 1250, 2500, 5000, 10000, 20000 ppm, of test substance for 13 weeks. No rats died during the study. The final mean body weights and weight gain of 5000, 10,000, and 20,000 ppm males and females were significantly lower than those of the controls. Feed consumption by exposed animals was lower than that by controls at week 1, but was generally similar to slightly higher than that by controls at week 13. No chemical related clinical findings were observed. Chemical related differences in clinical pathology parameters included increase in urine volumes accompanied by decreased urine specific gravity and minimally increased protein excretion in 10,000, and 20,000 ppm males. In females, urine parameters were less affected than males. Water deprivation tests demonstrated that male and female rats were able to adequately concentrate their urine in response to decreased water intake. Serum protein and albumin concentrations in female rats exposed to 2,500 ppm and higher were slightly lower than those of the controls. Renal papillary degeneration was present in 5000 and 10,000 ppm males, and in 20,000 ppm males and females. Hyperplasia of the urinary bladder was present in 20,000 ppm males.
Mice: Groups of 10 male and 10 female mice were fed diets containing 0, 625, 1250, 2500, 5000 ppm., of test substance for 13 weeks.
One control female, two males and one female receiving 625ppm, one female receiving 1250ppm, one female receiving 2500ppm, one female receiving 5000ppm, and 3 males receiving 10,000 pop died during the study. The final mean body weights and weight gain
1250, 2500, 5000 ppm and of females receiving 1250, 2500, 5000 and 10,000ppm and of females receiving 625ppm were significantly lower than those of the controls. Feed consumption by exposed mice was generally higher than that by controls thought the study.
Clinical findings included abnormal posture and hypoactivity in 10,000 ppm male and female mice. Blood urea nitrogen concentration concentrations of 5000 ppm females and 10,000 males and females were greater than those of controls. Also, urine specific gravity was lower in 10,000 ppm females. Differences in organ weights generally followed those in body weights. Papillary necrosis, renal tubule regeneration, and fibrosis were observed in the kidneys of 2,500 and 5000 ppm males and 10,000 ppm males and females. Urinary bladder hyperplasia was observed in 5,000 and 10,000 ppm males and females.
 
Executive summary:

Groups of male and female F344/N rats and B6C3F mice were exposed to technical grade of 2,2-bis(bromoneopentyl)-1,3-propanediol (78%) pure) in feed for 13 weeks.

Rats:Groups of 10 male and 10 female rats were fed diets containing 0, 1250, 2500, 5000, 10000, 20000 ppm, of test substance for 13 weeks. No rats died during the study. The final mean body weights and weight gain of 5000, 10,000, and 20,000 ppm males and females were significantly lower than those of the controls. Feed consumption by exposed animals was lower than that by controls at week 1, but was generally similar to slightly higher than that by controls at week 13. No chemical related clinical findings were observed. Chemical related differences in clinical pathology parameters included increase in urine volumes accompanied by decreased urine specific gravity and minimally increased protein excretion in 10,000, and 20,000 ppm males. In females, urine parameters were less affected than males. Water deprivation tests demonstrated that male and female rats were able to adequately concentrate their urine in response to decreased water intake. Serum protein and albumin concentrations in female rats exposed to 2,500 ppm and higher were slightly lower than those of the controls. Renal papillary degeneration was present in 5000 and 10,000 ppm males, and in 20,000 ppm males and females. Hyperplasia of the urinary bladder was present in 20,000 ppm males.

Mice: Groups of 10 male and 10 female mice were fed diets containing 0, 625, 1250, 2500, 5000 ppm., of test substance for 13 weeks.

One control female, two males and one female receiving 625ppm, one female receiving 1250ppm, one female receiving 2500ppm, one female receiving 5000ppm, and 3 males receiving 10,000 pop died during the study. The final mean body weights and weight gain

1250, 2500, 5000 ppm and of females receiving 1250, 2500, 5000 and 10,000ppm and of females receiving 625ppm were significantly lower than those of the controls. Feed consumption by exposed mice was generally higher than that by controls thought the study.

Clinical findings included abnormal posture and hypoactivity in 10,000 ppm male and female mice. Blood urea nitrogen concentration concentrations of 5000 ppm females and 10,000 males and females were greater than those of controls. Also, urine specific gravity was lower in 10,000 ppm females. Differences in organ weights generally followed those in body weights. Papillary necrosis, renal tubule regeneration, and fibrosis were observed in the kidneys of 2,500 and 5000 ppm males and 10,000 ppm males and females. Urinary bladder hyperplasia was observed in 5,000 and 10,000 ppm males and females.