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Carcinogenicity

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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.

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

% Incidencea (n=50)

T25 (ppm)c

CorrecteddT25 (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

% Incidenceb (n=50)

T25 (ppm)c

CorrecteddT25 (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

16e,f

14f

26f

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 Corrected 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.

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).