1-bromopropane

Carcinogenicity

Description of key information

Two studies are available for the chronic  inhalation toxicity / carcinogenicity endpoint:
USA National Institutes of Health (2011) (2 year) –NOAEC (rat): < 125 ppm (estimated at <0.64 mg/L**). Corrected T25 = 673 mg/m3 (0.67 mg/L) for Pancreatic Islet:  Adenoma and Carcinoma
USA National Institutes of Health (2011) (2 year) –NOAEC (mice): < 62.5 ppm (estimated at <0.32 mg/L**)
Corrected T25 = 357 mg/m3 (0.36 mg/L) for Alveolar/bronchiolar Adenoma and Carcinoma.

Key value for chemical safety assessment

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

T25

357 mg/m³

Study duration:

chronic

Species:

mouse

Quality of whole database:

Following Chapter R8 guidance (R.8.5.2), the data is not suitable to derive the preferred BMD endpoints (absence of a good linear fit for tumours). T25s for the relevant tumour type in each study are therefore derived. There is insufficient information to support use of a non-linear response, therefore simple linearity (tumour incidence proportional to dose) is assumed. T25s have been derived accordingly.

Justification for classification or non-classification

The neoplastic findings in rats and mice ( NTP sudy report TR 564 ) give rise to some concern for carcinogenicity. If each occurrence of tumours were isolated given additional considerations as the non-genotoxic Mode of Action, chronic stimulation of cell proliferation by cytotoxicity (where appropriate e.g. mouse lung tumour)(CLP Annex I § 3.6.2.2 ), the evidence would not be sufficiently convincing to place 1-BP in Category 1B.

By reference to the data summarised within this dataset and according to section 4.2.1 of Annex VI of Directive 67/548/EEC, the substance meets criteria for classification as a Category 3 carcinogen (Xn, R40). Under the CLP Regulation, the substance meets the criteria for classification as a Category 2 carcinogen (GHS08, H351).

Additional information

The 2-year mouse repeat dose inhalation study was selected as the key study for chronic repeat-dose toxicity and carcinogenicity. The substance was found to possess carcinogenic activity in male and female rats, and in female mice.

 

Groups of 50 male and 50 female rats were exposed to 1-bromopropane vapor at concentrations of 0, 125, 250, or 500 ppm, 6 hours per day, 5 days per week for 105 weeks. Survival of 500 ppm males was significantly less than that of the chamber control group. Mean body weights of exposed groups were similar to those of the chamber controls. Increased incidences of macroscopic, soft, pale-yellow to green, variably sized nodules were seen predominantly in the nose and skin of exposed rats. The number of animals with multiple masses was increased in the 500 ppm groups. In most cases, these lesions were microscopically shown to be suppurative inflammation, many with Splendore-Hoeppli material. The incidence of adenoma of the large intestine (colon or rectum) was significantly greater in 500 ppm females than in the chamber control group. The incidence of adenoma of the large intestine in 250 ppm males exceeded the historical control ranges for inhalation studies and all routes. The incidences of keratoacanthoma, basal cell adenoma, basal cell carcinoma, or squamous cell carcinoma (combined) were significantly greater in all exposed groups of males than in the chamber control group and exceeded the historical control range for inhalation studies. The incidences of keratoacanthoma and of keratoacanthoma or squamous cell carcinoma (combined) in ≥125 ppm males were also significantly increased and exceeded the historical control ranges for inhalation studies. In 500 ppm females, the incidence of squamous cell papilloma, keratoacanthoma, basal cell adenoma, or basal cell carcinoma (combined) exceeded the historical control range for inhalation studies.  The incidence of malignant mesothelioma was significantly greater in 500 ppm males than in the chamber control group.   The incidences of pancreatic islet adenoma in all exposed groups of males and of pancreatic islet adenoma or carcinoma (combined) in 125 and 250 ppm males were significantly increased.  Treatment-related nonneoplastic lesions were observed in the respiratory system of exposed male and female rats. In the nose, the incidences of suppurative chronic inflammation, chronic active inflammation, glandular hyperplasia, respiratory epithelial hyperplasia (females), and respiratory metaplasia of the olfactory epithelium (females) were increased in all exposed groups. In the larynx, the incidences of chronic active inflammation and squamous metaplasia (except 125 ppm females) were increased in all exposed groups, and the incidences of suppurative chronic inflammation were increased in the 500 ppm groups. Also, chronic inflammation of the lung was observed in the 500 ppm females. In the trachea, there were increased incidences of chronic active inflammation in all exposed groups of females and 500 ppm males, and the incidence of epithelial hyperplasia was increased in 500 ppm females.  The No Observed Adverse Effect Concentration (NOAEC) was therefore identified as <125 ppm.

 

Groups of 50 male and 50 female mice were exposed to 1-bromopropane vapor at concentrations of 0, 62.5, 125 or 250 ppm, 6 hours per day, 5 days per week for 105 weeks. Survival of exposed groups was similar to that of the chamber controls. Mean body weights of all exposed groups were similar to those of the chamber controls throughout the study. In the females, there were increased incidences of alveolar/bronchiolar adenoma, alveolar/bronchiolar carci-noma, and alveolar/bronchiolar adenoma or carcinoma (combined); the incidences of alveolar/bronchiolar adenoma or carcinoma (combined) were significantly increased in all exposed groups of females (P=0.010). There were significantly increased incidences of cytoplasmic vacuolization of the bronchiolar epithelium in all exposed male groups and regeneration of the bronchiolar epithelium in all exposed groups of males and females. In the nose, there were significantly increased incidences of cytoplasmic vacuolization of the respiratory epithelium in all exposed groups of males and in 125 and 250 ppm females. There were significantly increased incidences of respiratory epithelial hyperplasia in all exposed female groups and in 62.5 and 250 ppm males. There were significantly increased incidences of respiratory metaplasia of olfactory epithelium in 62.5 and 125 ppm males and 125 and 250 ppm females. There were significantly increased incidences of cytoplasmic vacuolization of respiratory epithelium in the larynx and trachea of all exposed male groups and in the trachea of 62.5 and 125 ppm females.  The No Observed Adverse Effect Concentration (NOAEC) was therefore identified as <62.5 ppm.

Tumours were seen in both rats and mice down to the lowest doses tested (125ppm in rats, 62.5ppm in mice). Of the rat carcinogenicity and the mouse carcinogenicity studies available, the mouse carcinogenicity study (USA National Institutes of Health, 2011), was selected as the key study for this endpoint, producing the lowest T25. The study was conducted in a similar manner to the OECD 451 guideline (carcinogenicity studies) on mice (male and females). The dose levels used were 62.5 ppm, 125 ppm and 250 ppm.

A statistically significant (trend test) increasing incidence of tumors was seen in both rats and mice down to both the lowest test concentrations. The LOAEC was therefore set at 62.5ppm (mouse) based upon these results.

Following Chapter R8 guidance (R.8.5.2), the data is not suitable to derive the preferred BMD endpoints (absence of a good linear fit for tumours). T25s for the relevant tumour type in each study are therefore derived. There is insufficient information to support use of a non-linear response, therefore simple linearity (tumour incidence proportional to dose) is assumed. In the following table, T25s are derived.

Table 27. Derivation of T25s from carcinogenicity studies

Rat

Species, sex,  tumour/ site, reference	% Incidence^a(n=50)			T25 (ppm)^c	Corrected^dT25 (ppm)	Corrected T25 (mg/m3)
	125 ppm	250 ppm	500 ppm
Rat, female, colon or rectum adenoma	2.3	4.7	13.3	940	671	3439
Rat, male, Keratoacanthoma	7.4	15.4	16.2	422	302	1545
Rat, male, Keratoacanthoma or Squamous Cell Carcinoma	7.4	13	19	422	302	1545
Rat, male, Keratoacanthoma, Basal Cell Adenoma, Basal Cell Carcinoma, or Squamous Cell Carcinoma	14.6	20.2	24.3	214	153	783
Rat, male, Malignant Mesothelioma	4.9	5.2	10.8	638	456	2334
Rat, male, Pancreatic Islet: Adenoma	12.2	10.4	13.9	256	183	937
Rat, male, Pancreatic Islet: Carcinoma	9.8	5.8	1.1	318	228	1167
Rat, male, Pancreatic Islet: Adenoma and Carcinoma	17	15.9	15	184	131	673

Mouse

Species, sex,  tumour/ site, reference	% Incidence^b(n=50)			T25 (ppm)^c	Corrected^dT25 (ppm)	Corrected T25 (mg/m3)
	62.5 ppm	125 ppm	250 ppm
Mouse, female, Alveolar/bronchiolar Adenoma (includes multiple)	10.6	6.7	18.6	147	105	539
Mouse,fe male, Alveolar/bronchiolar Carcinoma (includes multiple)	14	10	8	112	80	408
Mouse, female, Alveolar/bronchiolar Adenoma or Carcinoma	16^e,f	14^f	26^f	98	70	357

^a Corrected for treatment related mortality and control incidence (% survival probability [Kaplan Meier] to end of study = 46, 52, 36, 26 for control, low, mid and high doses respectively).

^{b C}orrected for background (control) incidence no correction required for treatment related mortality.

^c Based on linear extrapolation from lowest tumorigenic dose.

^d Factors relevant to dose correction (Appendix R 8-6): Dosing 5 days/week. No correction required for study duration (104 weeks).

^e Significantly different the control at the 1% level,

^f Signification dose response identified from a trend test: P<0.001

Justification for selection of carcinogenicity via inhalation route endpoint:
Tumours were seen in both rats and mice down to the lowest doses tested (125ppm in rats, 62.5ppm in mice). Of the rat carcinogenicity and the mouse carcinogenicity studies available, the mouse carcinogenicity study (USA National Institutes of Health, 2011), was selected as the key study for this endpoint, producing the lowest T25. The study was conducted in a similar manner to the OECD 451 guideline (carcinogenicity studies) on mice (male and females). The dose levels used were 62.5 ppm, 125 ppm and 250 ppm.
A statistically significant (trend test) increasing incidence of tumours was seen in both rats and mice down to both the lowest test concentrations.