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Administrative data

Description of key information

In accordance with Column 2 of REACH Annex VIII, the repeated dose toxicity study (required in Section 8.6.1) by the oral route does not need to be conducted as due to the physicochemical properties of the substance the most likely route of exposure is via inhalation.
In accordance with Column 2 of REACH Annex VIII, the repeated dose toxicity study (required in Section 8.6.1) by the dermal route does not need to be conducted as neither significant skin contact is likely nor do the physicochemical properties (high vapour pressure of 14.772 kPa means rapid volatilisation before significant absorption can occur) suggest potential for a significant rate of absorption through the skin. Modelling and the high vapour pressure indicate that the most significant route of exposure is by the inhalation route.
Nine studies are available for the repeat dose inhalation toxicity endpoint:
Labbé. R (1997b) (28 day) - NOAEC (rat): <2 mg/L air
Adamo-Trigiani. M (1997) (90 day) - NOEL (rat): 1 mg/L air
Labbé. R (1997c) (10 day range finding study) - NOEC (rat): <15 mg/L air
Labbé. R (1997d) (10 day range finding study) - NOEC (rat): 5 mg/L air
Moon. Y.H. et al (1998) (8 week study) - NOAEC (rat): 300 ppm
USA National Institutes of Health (2011) (2 week range finding study) – NOAEC (rat): 250 ppm*
USA National Institutes of Health (2011) (2 week range finding study) – NOAEC (mouse): 125 ppm*
USA National Institutes of Health (2011) (3-month) – NOAEC (rat): 125 ppm (estimated at 0.64 mg/L**)
USA National Institutes of Health (2011) (3 month) – NOAEC (mouse): 125 ppm (estimated at 0.64 mg/L**)
*Notwithstanding limited histopathology
**assuming 1 mole gas occupies 24.0056 L at RTP and MW = 122.9917 g/mole

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
640 mg/m³
Study duration:
subchronic
Species:
rat

Additional information

The 90-day repeat dose rat inhalation studies were selected as the key study for subchronic repeat-dose toxicity.

Four groups of Sprague-Dawley rats, each comprising 15 males and 15 females, were subjected to 6 hour "whole-body" exposures daily (5 days/week) of a vapour formulation of 1-bromopropane for 13 weeks at target concentrations of 0.5 mg/L (Group 2), 1.0 mg/L (Group 3), 2.0 mg/L (Group 4) and 3.0 mg/L (Group 5). A similarly constituted control group (Group 1) was similarly restrained, but exposed to room air. The mean overall chamber concentration of 1 -bromopropane, determined by Miran infrared gas analyzer, was 0.5, 1.01, 2.01 and 3.0 mg/L for Groups 2, 3, 4 and 5, respectively. The mean overall analytical chamber concentration for the 4 treated groups was 0.51, 1.01, 2.00 and 2.98 mg/L for Groups 2, 3, 4 and 5, respectively. The mean concentrations obtained were within 2% of the targeted concentrations whether determined by either Miran gas analysis or by gas chromatography.

Whole-body inhalation exposure of Sprague-Dawley rats to a vapour of 1-bromopropane for 6 hours each day, 5 days each week, for a 13-week period, at chamber concentrations of 0.5 to 3.0 mg/L produced no clinical observations which were considered to be related to treatment. Four mortalities occurred during bleeding procedures or anaesthesia but were not considered to be related to treatment. There were no obvious effects on body weight, food consumption, urinalysis, ophthalmology, functional observational battery or motor activity that could be attributed to treatment with 1-bromopropane. No treatment-related trends were evident in hematology, blood biochemistry analysis or gross pathology. There was a marginal increase in relative liver weights in Group 5 (3.0 mg/L- high dose) males. This effect was considered of questionable toxicological significance as intergroup differences were minimal and the effect was not observed in the Group 5 (3.0 mg/L-high dose) females. However, histopathological lesions were present in the liver (vacuolation of centrolobular hepatocytes) when exposed at concentrations of 2.0 mg/L (intermediate/high dose) and 3.0 mg/L (high dose). The No Observed Effect Level (NOEL) was therefore identified as 1.0 mg/L (used as a worst case NOAEC of 1000 mg/m3).

Groups of 10 male and 10 femaleF344/N rats were exposed (whole body) to 1-bromopropane vapor at concentrations of 0, 62.5, 125, 250, 500, or 1,000 ppm, 6 hours per day, 5 days per week for 14 weeks. Additional clinical pathology groups of 10 male and 10 female rats were exposed to the same concentrations for 23 days. All rats survived to the end of the study. Mean body weights of 1,000 ppm males were significantly less than those of the chamber controls. Increases in sorbitol dehydrogenase activities were seen in ≥500 ppm males and 1,000 ppm females. Liver weights of males exposed to 250 ppm or greater and of females exposed to 125 ppm or greater were significantly increased by 10% or more. Spleen and kidney weight changes in males and females were not biologically significantly affected and no dose-response was discernible. Exposure concentration-related decreases in sperm motility and counts were observed at ≥250 ppm ranging from 7 - 28% in sperm motility and 6 - 37% in sperm from 250 ppm to the highest dose of 1,000 ppm. Female rats in all three exposure groups evaluated exhibited altered estrous cycles, spending significantly more time in extended estrus and less time in extended diestrus. The incidences of cytoplasmic vacuolization of the liver were significantly increased in males exposed to 250 ppm or greater and in females exposed to 500 ppm or greater. Hepatocyte degeneration was also observed. in 1,000 ppm females. The No Observed Adverse Effect Concentration (NOAEC) was therefore identified as 125 ppm.

 

Groups of 10 male and 10 female mice (B6CF1) were exposed (whole body) to 1-bromopropane vapor at concentrations of 0, 62.5, 125, 250, or 500 ppm, 6 hours per day, 5 days per week for 14 weeks. One 250 ppm male and four males and five females in the 500 ppm groups died early. Mean body weights of exposed groups were similar to those of the chamber controls. Lethargy was observed in males and females exposed to 500 ppm, and abnormal breathing was observed in moribund mice. The kidney, liver, and lung weights of 500 ppm females were significantly greater than those of the chamber controls. The kidney weights of 500 ppm males were significantly decreased. Sperm counts in the 500 ppm group of male mice were 28% less than that in the chamber controls. Female mice exhibited altered estrous cycles, with females in the 500 ppm group spending significantly more time in extended diestrus and those in the 250 ppm group spending significantly more time in extended estrus compared to the chamber controls. Nonneoplastic lesions were observed in the nose, larynx, trachea, lung, and liver of 500 ppm males and females and in the adrenal cortex of 500 ppm females. The No Observed Adverse Effect Concentration (NOAEC) was therefore identified as 125 ppm.

Justification for classification or non-classification

By reference to the data summarised within this dataset and according to section 3.2.3 of Directive 67/548/EEC, the substance does not meet the criteria for classification as potentially causing serious damage to health by prolonged exposure via the inhalation route (R48/20). However, section 3.2.3.1 states that for certain substances with a high saturated vapour concentration evidence may be available to indicate effects that give cause for concern. Such substances may not be classified under the criteria for health effects. However, where there is appropriate evidence that such substances may pose a risk in normal handling and use then classification on a case-by-case basis in Annex I may be necessary.

The nature of this additional evidence is not known to the registrant but this is assumed to be the basis for the official EU classification as Xn; R48/20 on Annex I of Directive 67/548/EEC and as a STOT RE Category 2 on Annex VI of the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.