Registration Dossier

Administrative data

Description of key information

The following stdies are available for assessing the repeated dose Oral toxicity of Dibromoneopentyl Glycol:
1.      National Toxicology program, (May 1996): NTP Technical Report on the Toxicology and Carcinogenesis Studies of 2,2-bis(bromomethyl)-1,3-propanediol (FR-1138, CAS No. 3296-90-0) in F344/N Rats and B6C3F1 Mice.
 2.      ELWELL et al. (1989): ‘Kidney and Urinary Bladder Lesions in F344/N Rats and BN6C3F1 mice, after 13 weeks of 2,2-Bis(bromoneopentyl-1,3-propanediol administration’.
 4.      Keyes et al. (1980): ‘Results of a two year toxicity and oncogenicity study of rats ingesting diets containing dibromoneopentyl glycol (FR-1138)’.
values for DNEL clculations were taken from the NTP report (1996). NOAEL could not be achieved for neither rat or mice. Therefore, LOAEL value was used.
Studies on the repeated dose toxicity via the dermal or inhalation routes are not available.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEL
35 mg/kg bw/day
Study duration:
chronic
Species:
mouse

Additional information

National Toxicology program, (May 1996):

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.

The NOAEL for rats could not be achieved. LOAEL was found to be L 2500 ppm . The NOAEL for mice was not achieved as well. The LOAEL was 312 ppm. 

Ellwell etal. (1989)

The paper describes 13- week toxicity studies of BMP administered orally (by gavage or feed) to F344/N rats and B6C3F1 mice to determine target organ toxicity. The chemical was administered by oral gavage in corn oil 5 days per week for 13 weeks to rats at doses of 0, 50, 100, 200, 400, and 800mg/kg and to mice at doses of 0, 25, 50, 100, 200, and 400 mg/kg, or in the feed for 13 weeks at 0, 1250, 2500, 5000, 10,000, and 20,000 ppm.

There was a dose related decrease in body weight gain in rats and mice after chemical administration. Mortality attributed to toxicity of BMP was seen in the gavage study in 2/10 high dose (800mg/kg) male rats and 3/10 high dose (400mg/kg) male mice. No dose related death occurred in the feed study.

Minimal generation in the renal papilla was seen in male rats at 800mg/kg in the gavage study and at doses of 5000 ppm or more in the feed study. This was also present in one female rat at the 20,000ppm dose. In male mice renal papillary necrosis occurred at 400mg/kg after dosing by the gavage route and at 2500, 5000 and 10,000 ppm in the dose feed study. In female mice papillary necrosis occurred only in the 10,000ppm dose in the feed study. Tubular cell regeneration of the renal cortex was also present in mice at the same dose levels at which the papillary necrosis was observed. Transitional cell hyperplasia of the urinary bladder was seen in male rats at 400 and mg/kg and in both sexes of mice 200 and 400 mg/kg.

The kidney and urinary bladder were the target organs when BMP is administered by gavage or the dose feed route. Mice were more sensitive than rats for the development of kidney and bladder lesions. Male rats and mice were more sensitive than females for the development of renal papillary degeneration or necrosis.

Keyes et al. (1980):

In a 2 year repeated dose toxicity and carcinogenicity, males and female rats were orally administered the test substance through feeding, continuously for two years. The concentrations used were 0, 50, 100mg/kg/day. 5 animals/sex were used as satellite groups after a year and additional 10 animals/sex/ group were used for tissue analysis.

Mortality- Male rats given 50 or 100mg/kg/day test substance showed no differences in mortality between treatment and control groups. Female rats receiving 100mg/kg/day had statistically increased mortality rates in months 17 and 17, but, this was considered to be questionable toxicological significance.

Body weight, food consumption, clinical findings- No toxicologically significant differences in body weight were detected. No consistent deviations in food consumption of males or females noted at either dose levels during the study. No toxicologically significant differences haematologic or clinical findings between controls and treatment groups were noted. 

Gross pathology- 6/11 female rats given 100mg/kg/day showed bilateral diffuse opacity of the lenses. This was not noted in the control or in the 5 mg/kg/d group.

Organ weight changes- male rats given 100mg/kg/day test substance showed statistically significant increase in relative liver weights, After 1 year of treatment. This was the only toxicologically significant difference between control and treatment groups. 

Histopathology- male rats given 100mg/kg/day, showed statistical increase in the incidence of thyroid retention cyst formation. Female rats given 100mg/kg/day showed 6/11 with bilateral lenticular degeneration of the interior cortex graded as moderate in degree. In addition, some rats showed bilateral degeneration of the posterior cortex and basophilic staining material within this region of lens. There were several observations noted on examination of the livers of female rats given 100mg/kg/day, that were considered to be related to treatment. These include heaptocellular degenerative changes consisting of increased eosinophilic cytoplasmic homogeneity accompanied by a slight increase of livers having several foci or a single area of heaptocellular alteration. Statistical analysis of the incidence of tumors found at necropsy showed there were no significant differences between control and treatment groups. Based on the findings of the study, the NOAEL was found to be 5mg/kg/day and the LOAEL 100mg/kg/day.

 


Repeated dose toxicity: dermal - systemic effects (target organ) urogenital: kidneys; urogenital: urinary bladder

Justification for classification or non-classification

Based on the information gained, the test substance Dibromoneopentyl glycol does not need to be classified for repeated dose toxicity according to Directive 67/548/EEC or Regulation (EC) No 1272/2008.