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Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subchronic
Species:
rat
Quality of whole database:
NOAEL=25ppm

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Study duration:
subchronic
Species:
dog
Quality of whole database:
NOAEL=75ppm

Additional information

Repeated dose Oral toxicity

Two studies are available on the repeated dose oral toxicity of dibromomethane: A Fourteen Day Repeated Dose Oral Range-Finding study for the ‘Oral (Gavage) Reproduction/Development Toxicity Screening Test in the Rat’ (Dhinsa and Fulcher 2007) and unpublished study by the DOW reported in the review by Torkelson and Rowe 1981.

1.               A Fourteen Day Repeated Dose Oral Range-Finding study for the ‘Oral (Gavage) Reproduction/Development Toxicity Screening Test in the Rat’ was chosen to be the key study for the repeated dose oral toxicity (Dhinsa and Fulcher 2007). The study was conducted in accordance with the OECD TG 421 and TSCA OPPTS TG 870.3550, and with GLP standards (for full details see section 3.1.8) thus, it was rated klimisch 1. This range finding study was selected to represent the repeated dose oral toxicity endpoint also in the IUCLID data Set of dibromomethane HPV dossier for EPA in 2006.  

Dosages of 1000, 500, 150 or 75 mg/kg/day of the test material (99.4% purity, dibromomethane) were administered by gavage to groups consisting of three male and three female Sprague-Dawley Crl:CD® (SD) IGS BR strain rats. A control group of three male and three female rats was dosed with the vehicle (Polyethylene Glycol 400). The following parameters were observed:

 Mortality: Animals were examined for signs of ill health twice daily, early and late  during the working period, thought the study. Animals at 1000 mg/kg/day killed on day 4 due to the early termination of this dosage group were subjected to full macroscopic necropsy.

Clinical signs: All animals were examined for signs of toxicity, ill health or behavioural change immediately before and after dosing and one hour after dosing. All observations were recorded.

Bodyweight: Individual bodyweights were recorded on Days 1, 4, 8 and 15 of the treatment period.

Necropsy: On completion of the treatment period, all animals were killed by cervical dislocation and immediately subjected to an internal and external macroscopic examination. No tissues were retained.

Evaluation of the data: Clinical observations, bodyweights, bodyweight change and necropsy data were examined for any adverse effects resulting from treatment. The data obtained were used to provide the basis for selection of dose levels for the main study. In view of the preliminary nature of this phase of the study and the small group size no statistical analyses were performed.

Results: No deaths were observed in any of the groups. Treatment at 1000 mg/kg/day was associated with notable bodyweight loss (>10%) and a decline in the clinical condition of all three males on Day 4 of the study. One male showed ataxia and piloerection and the other two males showed hunched posture; all three males also showed red/brown staining around the eyes. One female at 1000 mg/kg/day also showed ataxia and red/brown staining around the eyes and a slight bodyweight loss on Day 4. No clinical signs were apparent for the remaining two females at this dosage and there was no obvious adverse effects of treatment on bodyweight gain of these animals to Day 4.

This dosage was considered to be unsuitable for use in the main reproductive screening investigation and therefore the animals were terminated on Day 4 of the study, having received three consecutive daily doses. Macroscopic necropsy examination did not reveal any obvious cause for the decline in the condition of the animals.

Control animals and animals receiving 75, 150 or 500 mg/kg/day were dosed for fourteen consecutive days. There was no adverse effect on body weight gain at these doses. The incidence of clinical signs observed at 75, 150 or 500 mg/kg/day did not indicate any obvious adverse effect of treatment. All animals survived to scheduled termination (Day 14) and necropsy examination did not reveal any effect of treatment at any of these dosages. At 500 mg/kg/day, red staining of the cage tray paper was observed for males during Days 7-10; the significance of this observation is unclear but, as it did not persist and was not associated with any decline in the condition of the animals, it was considered not to preclude this dosage from further investigation.

An initial bodyweight loss to Day 4 was apparent for one male and one female at 150 mg/kg/day, although an initial loss was not apparent for the remaining animals at this dosage or for either sex at 500 mg/kg/day. Isolated incidences of bodyweight loss were observed for a few treated animals during the remainder of the study but were considered to reflect normal biological variation rather than an adverse effect of treatment.

2.     Limited information on repeated dose oral toxicity of dibromomethane is reported in a review by Torkelson and Rowe 1981 (unpublished study by the DOW). The information is also cited in the US EPA Health and Environmental Profile for Methylene Bromide, 1987. Due to the limited information on this study it was identified as a supporting study (klimisch rating 4). 

  When 300 mg/kg of dibromomethane were administered orally to rats and rabbits (60 doses/92 days), no effects on weight gain, general appearance or liver histology were observed. However marked anesthesia, was observed in rabbits with 400mg/kg dibromomethane for 60/92 days.

 Conclusion

Based on the available information, NOAEL for repeated dose oral toxicity can be considered to be 500 mg/kg   bw/day.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Reliability

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Reliability

Justification for classification or non-classification