1,2-dichloropropane

Carcinogenicity

Description of key information

In an NTP study, equivocal evidence of an increase in morphologically atypical mammary tumors was reported in female rats in the presence of a marked reduction in survival and body weight. Some evidence of an increased incidence of hepatic adenocarcinomas was found in male and female mice relative to concurrent (but not historic) controls in the presence of liver damage and decreased body weight (females only). It is considered that other factors such as spontaneous biological variation may have contributed to the increased incidence of mouse liver tumors.
In the Umeda study, papillomas were observed in the nasal cavity of  male rats exposed to 200 ppm and male and female rats exposed to 500 ppm DCP.  No papillomas were noted in the nasal tissues of male or female rats exposed to 80 ppm or female rats exposed to 200 ppm DCP for 2 years.  Two esthesioneuroepitheliomas were observed in male rats exposed to 80 ppm, one rat exposed to 200 ppm DCP, and none in males exposed to the highest concentration, 500 ppm, nor in female rats at any exposure levels.  There was no increase in the tumor incidence noted in other tissues.
In the study Matsunoto (2013), tumor responses were seen in single sexes. In the females, the combined incidence of bronchiolo-alveolar adenomas/carcinomas reached significance at the highest dose level of 200 ppm PDC and exceeded the JBRC historical control data (the incidence ranges not given). For males exposed to 200 ppm PDC, the incidence of benign Harderian gland adenomas of the eye exceeded the maximum incidences of the JBRC historical control data (ranges also not given). There is no Harderian gland in men and Harderian gland adenomas have no human relevance. The remaining tumor incidences were within the incidences of the JBRC historical control data. 

Key value for chemical safety assessment

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The publication does not state whether the study was conducted according to guidelines but was conducted according to GLPs. The report contains sufficient data for interpretation of study results

Principles of method if other than guideline:

Publication does not state whether any guidelines were followed. Animals were exposed to test material for 2 years. Animals were weighed weekly for the first 14 weeks and then every 4 weeks thereafter. Blood was obtained for hematology and clinical chemistry determinations (specific tests not stated in publication) at necropsy. A complete gross necropsy was performed and histopathological examination of tissues conducted (only nasal tissues specified in methods section of publication although results from other tissues were reported in the results section).

GLP compliance:

yes

Species:

rat

Strain:

Fischer 344/DuCrj

Sex:

male/female

Details on test animals or test system and environmental conditions:

F344/DuCrj (SPF) rats of both sexes were obtained at 4 wk of age from Charles River Japan, Inc. (Kanagawa, Japan). After 2 wk quarantine and acclimation, the animals were allocated by a stratified randomization procedure into body-weight matched, DCP-exposed, and clean air-exposed groups. The
2-year study consisted of three DCP-exposed groups and one control group, each comprising 50 rats of each sex. The animals were housed individually in stainless-steel wire hanging cages (150 mm [W] × 216 mm [D] × 176 mm [H]) in stainless-steel inhalation exposure chambers maintained at a temperature of 23 ± 2°C and at a relative humidity of 55 ± 15% with 12 ± 1 air changes/h. Fluorescent lighting was controlled automatically to give a 12-h light/dark cycle. All rats had free access to sterilized water and γ-irradiation sterilized commercial pellet diet (CRF-1, Oriental Yeast Co., Ltd., Tokyo, Japan).

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

For the 2-year study, groups of 50 rats of each sex were exposed to DCP at 0 (clean air control), 80, 200, or 500 ppm for 6 h/day, 5 days/ wk for 104 wk (2 years). The highest exposure concentration of DCP for the 2-year study was chosen as 500 ppm on the basis of the nasal toxicity and growth retardation induced by the 13-wk inhalation exposure to DCP, according to the criteria of maximum tolerated dose (MTD) setup by both National Cancer Institute (NCI) and IARC guidelines (Sontag et al., 1976; Bannasch et al., 1986).

Airflow containing DCP at designated target concentrations was prepared by a vaporization technique. The saturated vapor–air mixture was generated by bubbling clean air through the DCP liquid in a temperature-regulated glass flask (25°C), and by cooling it through a thermostatted condenser at 18°C. The airflow containing the saturated vapor was diluted with clean air, and then warmed to 23°C in a thermostatted circulator, which served to stabilize the vapor concentration by complete gasification of the DCP. The flow rate of the vapor–air mixture was regulated with a flowmeter, further diluted with humidity- and temperature-controlled clean air in a spiraling line mixer, and then supplied to an inhalation exposure chamber. Four inhalation exposure chambers of 4300 l, each accommodating 100 individual cages for 50 male and 50 female rats, were used for the 2-year study.

References:
Bannasch P, Griesemer RA, Anders F, Becker R, Cabral JR, Della Porta G, Feron VJ, Henschler D, Ito N, Kroes R. 1986. Long-term assays for carcinogenicity in animals. IARC Sci Publ:13–83.

Sontag JM, Page NP, Saffiotti U. 1976. Guidelines for Carcinogen Bioassay in Small Rodents. NCI-CG-TR-1. Washington DC: DHEW.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Chamber concentrations of DCP were monitored by gas chromatography every 15 min throughout the entire exposure periods, and maintained at 80.2 ± 0.5, 200.5 ± 1.3, and 500.2 ± 2.4 ppm for the 2-year study. No additional information provided in report.

Duration of treatment / exposure:

6 hours/day

Frequency of treatment:

5 days/week for 104 weeks

Post exposure period:

No data.

Remarks:

Doses / Concentrations:
0 (clean air control), 80, 200, or 500 ppm
Basis:
nominal conc.

Remarks:

Doses / Concentrations:
80.2 ± 0.5, 200.5 ± 1.3, and 500.2 ± 2.4 ppm for the three exposed groups.
Basis:
analytical conc.

No. of animals per sex per dose:

50 rats of each sex/dose level

Control animals:

yes

Details on study design:

For the 2-year study, groups of 50 rats of each sex were exposed to DCP at 0 (clean air control), 80, 200, or 500 ppm for 6 h/day, 5 days/ wk for 104 wk (2 years). The highest exposure concentration of DCP for the 2-year study was chosen as 500 ppm on the basis of the nasal toxicity and growth retardation induced by the 13-wk inhalation exposure to DCP, according to the criteria of maximum tolerated dose (MTD) setup by both National Cancer Institute (NCI) and IARC guidelines (Sontag et al., 1976; Bannasch et al., 1986).

References:
Bannasch P, Griesemer RA, Anders F, Becker R, Cabral JR, Della Porta G, Feron VJ, Henschler D, Ito N, Kroes R. 1986. Long-term assays for carcinogenicity in animals. IARC Sci Publ:13–83.

Sontag JM, Page NP, Saffiotti U. 1976. Guidelines for Carcinogen Bioassay in Small Rodents. NCI-CG-TR-1. Washington DC: DHEW.

Positive control:

No data.

Observations and examinations performed and frequency:

The animals were observed daily for clinical signs and mortality. Body weight and food consumption were measured once a week for the first 14 wk and once every 4 wk thereafter in the 2-year study.

Sacrifice and pathology:

All rats, including those found dead or moribund, received complete necropsy. For hematology and blood biochemistry, blood was collected under ether at terminal necropsy after overnight fasting. The blood sample was analyzed with an automatic blood cell analyzer (ADVIA120, Bayer Co. NY, USA) and an automatic analyzer (Hitachi 7080, Hitachi, Ltd., Ibaraki, Japan) for blood biochemistry.

Organs were removed, weighed, and examined for macroscopic lesions at necropsy. All organs and tissues and the entire respiratory tract including nasal cavity, pharynx, and larynx were examined for histopathology in all the animals. The organs and tissues were fixed in 10% neutral buffered formalin. The nasal cavity was decalcified in formic acid-formalin solution before trimming, and was transversely trimmed at three levels according to the procedure described in our previous paper (Nagano et al., 1997): at the level of the posterior edge of the upper incisor teeth (Level 1), at the incisive papilla (Level 2), and at the level of the anterior edge of the upper molar teeth (Level 3). The tissues were embedded in paraffin,
and 5 μm-thick sections were prepared and stained with hematoxylin and eosin (H&E). Nasal lesions were diagnosed with reference to the criteria of the International Classification of Rodent Tumours (IARC, 1992) and the International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice (Renne et al., 2009).

References:
International Agency for Research on Cancer (IARC). 1992. Respiratory system. In: Mohr U (ed.) International Classification of Rodent Tumours. Part I: The Rat. 1. IARC Scientific Publications, No 122. Lyon: IARC.

Nagano K, Katagiri T, Aiso S, Senoh H, Sakura Y, Takeuchi T. 1997. Spontaneous lesions of nasal cavity in aging F344 rats and BDF1 mice. Exp Toxicol Pathol 49:97–104.

Renne R, Brix A, Harkema J, Herbert R, Kittel B, Lewis D, March T, Nagano K, Pino M, Rittinghausen S, Rosenbruch M, Tellier P, Wohrmann T. 2009. Proliferative and nonproliferative lesions of the rat and mouse respiratory tract. Toxicol Pathol 37:5S–73S.

Other examinations:

No additional information available.

Statistics:

Peto's test (1980) was used to evaluate statistically significant relationships between incidences of neoplastic lesions and the level of exposure to DCP. Fisher’s exact test was used to evaluate the statistical significance of the differences in the incidences of neoplastic lesions between DCP exposed groups and the clean air-exposed control group. The Chi-square test was used to evaluate the statistical significance of the differences in the incidences of pre and nonneoplastic lesions between DCP-exposed groups and the clean air-exposed control group. Survival curves were plotted according to the method of Kaplan and Meier (1958), and the log-rank test (Peto et al., 1977) and Fisher’s exact test were used to test for statistically significant differences in survival rates between any DCP-exposed rat group of either sex and the clean air-exposed control group. Body and organ weights were analyzed by Dunnett’s test. Two tailed tests were used for all statistics except for Peto’s test. In all cases, a P-value of 0.05 was used as the level of significance. In analyzing results for uncommon tumors in the DCP-exposed groups that were not statistically significant, the tumor incidence was tested for biological significance using a range of minimum and maximum tumor incidences in the JBRC’s historical control data, which were compiled from 2-year inhalation studies of rodent carcinogenicity conducted by the JBRC during the 23-year period from 1987 to 2009.

References:
See below.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The growth rates of the DCP-exposed groups of male rats were slightly suppressed in a concentration-related manner.

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

An anemic tendency was evident in the female rats exposed to 500 ppm, as indicated by a slight decrease (~4%) in red blood cell count.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

γ-GTP levels in the blood significantly increased only in female rats exposed to 500 ppm DCP.

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Microscopic examination revealed that 2-year inhalation exposure to DCP induced lesions in the nasal cavity.

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Microscopic examination revealed that 2-year inhalation exposure to DCP induced tumors in the nasal cavity.

Details on results:

Microscopic examination revealed that 2-year inhalation exposure to DCP induced lesions in the nasal cavity (Table 1), concentrations that also caused inflammation and cytotoxicity of the olfactory epithelium. While inflammation was seen at all exposure concentrations, incidences of papillomas increased in both male (200 and 500ppm) and female (500ppm) rats compared to controls, but were only statistically significant at the 500 ppm dose. The papillomas were characterized by expansile, nodular masses which protruded into the nasal cavity and were located in the dorsal region at Levels 1 and 2. Most papillomas were composed primarily of transitional epithelium-like tissue and contained squamous epithelium-like or glandular tissue. A few papillomas were composed primarily of a glandular structure consisting of nonciliated, cuboidal to low columnar cells. A total of three cases of esthesioneuroepitheliomas were observed in the nasal cavity of male rats exposed to 80 (two cases) and 200 (one case) ppm DCP; none were observed in high dose males, in any female rats or in controls of either sex or reached statistical significance. Since JBRC’s historical control data showed no cases of esthesioneuroepithelioma in 2399 male F344 rats in 48 two-year carcinogenicity studies, the authors concluded that the esthesioneuroepitheliomas were induced by inhalation exposure to DCP. The esthesioneuroepitheliomas were characterized by a rosette-like structure and located in the dorsal region of Levels 2 and 3. Incidences of hyperplasia of the transitional epithelium were significantly increased in all DCP- exposed groups of both sexes, and incidences of squamous cell hyperplasia were significantly increased in male rats exposed to 200 and 500 ppm and in female rats exposed to 500 ppm DCP. The severities of these two types of hyperplasias were increased in an exposure concentration-related manner. Hyperplasia of the transitional epithelium was characterized by an increased number of nonciliated cuboidal, epithelial cells in a focal area. Squamous cell hyperplasia was characterized by a thickening of five or more epithelial layers. These two hyperplasias, which were assessed by the authors as being preneoplastic, were similar to the papillomas but were not clearly expanding into the surrounding tissue and were accompanied by hyperplasia of the submucosal gland. Incidences of nonneoplastic lesions, squamous cell metaplasia, and inflammation in the respiratory epithelium, were significantly increased in all DCP- exposed groups and in both sexes. Atrophy of the olfactory epithelium was often accompanied by necrosis of the olfactory sensory cells and respiratory metaplasia of the olfactory epithelium, and located in the dorsal region of Levels 2 and 3, and its severity scores increased in a concentration-related manner. No exposure-related lesions were observed in any other organs in the DCP-exposed rat groups of either sex.

Relevance of carcinogenic effects / potential:

Papillomas were observed in the nasal cavity of male rats exposed to 200 ppm and male and female rats exposed to 500 ppm PDC. No papillomas were noted in the nasal tissues of male or female rats exposed to 80 ppm or female rats exposed to 200 ppm PDC for 2 years. Although two esthesioneuroepitheliomas were observed in male rats exposed to 80 ppm and one rat exposed to 200 ppm PDC which the authors considered to be due to PDC exposure, there were no tumors of this type noted in male rats exposed to the highest concentration, 500 ppm, nor were any of these tumors noted in female rats at any exposure levels. As the authors stated that there was no effect on survival at any concentration of PDC, and given the lack of an exposure-response relationship for these tumors in male rats and no esthesioneuroepitheliomas in the females, it is unclear whether the esthesioneuroepitheliomas are related to PDC exposure. There was no increase in the tumor incidence noted in other tissues.

Dose descriptor:

NOEC

Effect level:

80 ppm (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOEC

Effect level:

200 ppm (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No papillomas were noted in the nasal tissues of female rats exposed to 200 ppm DCP for 2 years.

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

LOEC

Effect level:

80 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Histopathological changes and inflammation were noted in the nasal tissue of rats exposed to 80 ppm, the lowest concentration examined.

Remarks on result:

other: Effect type: toxicity (migrated information)

Table 1. Number of rats bearing the selected histopathological lesions of the nasal cavity in the rats exposed by inhalation to DCP or clean air for 2 years.

	Male				Female
Group (ppm)	0	80	200	500	0	80	200	500
Number of animals examined	50	50	50	50	50	50	50	50
Neoplastic lesions
Papilloma	0	0	3	15^##	0	0	0	9^##
Esthesioneuoepithelioma	0	2	1	0	0	0	0	0
Total nasal tumors	0	2	4	15^##	0	0	0	9^##
Pre-neoplastic lesions
Hyperplasia: transitional epithelium	0	31** [1.1]	39** [1.1]	48** [1.8]	2 [1.0]	21** [1.2]	39** [1.1]	48** [1.5]
Squamous cell hyperplasia	0	2 [1.0]	6* [1.0]	27** [1.1]	0	0	3 [1.0]	20** [1.3]
Total pre-neoplastic lesions	0	31**	39**	50**	2	21**	39**	48**
Non-neoplastic lesions
Squamous cell metaplasia: respiratory epithelium	5 [1.0]	31** [1.0]	41** [1.0]	49** [1.2]	3 [1.0]	15** [1.0]	37** [1.2]	46** [1.5]
Inflammation: respiratory epithelium	20 [1.0]	35** [1.0]	47** [1.0]	47**[1.2]	10 [1.0]	30** [1.0]	39** [1.0]	40** [1.1]
Atrophy: olfactory epithelium	0	48** [1.1]	50** [1.9]	49** [2.0]	0	50** [1.0]	50** [1.9]	50** [2.0]

Note: The values in brackets indicate the averaged severity grade index of the lesion in affected animals, according to the following equation. [E(grade × number of animals with grade)]/number of affected animals. Grade: “slight” scored as 1, “moderate” as 2, “marked” as 3, and “severe” as 4.

Significant difference: *p < 0.05; **p < 0.01 by χ2-test, #p < 0.05; ##p < 0.01 by Fisher’s Exact test T: p < 0.05, Tt: p < 0.01 by Peto’s test.

Conclusions:

Papillomas were observed in the nasal cavity of male rats exposed to 200 ppm and male and female rats exposed to 500 ppm PDC. No papillomas were noted in the nasal tissues of male or female rats exposed to 80 ppm or female rats exposed to 200 ppm PDC for 2 years. Although two esthesioneuroepitheliomas were observed in male rats exposed to 80 ppm and one rat exposed to 200 ppm PDC which the authors considered to be due to PDC exposure, there were no tumors of this type noted in male rats exposed to the highest concentration, 500 ppm, nor were any of these tumors noted in female rats at any exposure levels. As the authors stated that there was no effect on survival at any concentration of PDC, and given the lack of an exposure-response relationship for these tumors in male rats and no esthesioneuroepitheliomas in the females, it is unclear whether the esthesioneuroepitheliomas are related to PDC exposure. There was no increase in the tumor incidence noted in other tissues.

Executive summary:

The toxicity and carcinogenicity of 1,2-dichloropropane (DCP) were examined by inhalation exposure of male and female F344 rats to DCP for 2 years. In the 2-year study the DCP concentrations were 80, 200, or 500 ppm (v/v). Two-year exposure to DCP significantly increased incidences of papilloma in the nasal cavity of male and female rats exposed to 500 ppm DCP. In addition, three cases of esthesioneuroepithelioma were observed in the DCP-exposed male rats. Total nasal tumors increased in a concentration-dependent manner. Hyperplasia of the transitional epithelium and squamous cell hyperplasia, both of which were morphologically different from the hyperplasia of the respiratory epithelium observed in the 13-wk exposure study, occurred in a concentration-dependent manner and were associated with inflammation; these lesions are considered to be preneoplastic lesions. Atrophy of the olfactory epithelium, inflammation of the respiratory epithelium, and squamous cell metaplasia were also seen in the 2-year study al all doses. These results demonstrate that DCP is a nasal carcinogen in rats.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

370 mg/m³

Study duration:

chronic

Species:

rat

Quality of whole database:

Acceptable

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Equivocal evidence of an increase in morphologically atypical mammary tumors (adenocarcinoma or highly cellular fibroadenoma) was reported in female rats in the presence of a marked reduction in survival and body weight, while some evidence of an increased incidence of hepatic adenocarcinomas was found in male and female mice relative to concurrent (but not historic) controls in the presence of liver damage and decreased body weight (females only). Overall it is considered that DCP is not a direct-acting carcinogen, that there is equivocal evidence of an increase in mammary tumors in female rats, and that other factors (such as spontaneous biological variation) may have contributed to the increased incidence of mouse liver tumors.

Based on the NTP study, IARC concluded in 1987 that 1,2-dichloropropane is not classifiable as to its carcinogenicity to humans (Group 3).

In the Umeda study (2010), papillomas were observed in the nasal cavity of male rats exposed to 200 ppm and male and female rats exposed to 500 ppm DCP. No papillomas were noted in the nasal tissues of male or female rats exposed to 80 ppm or female rats exposed to 200 ppm DCP for 2 years. Although two esthesioneuroepitheliomas were observed in male rats exposed to 80 ppm and one male rat exposed to 200 ppm DCP which the authors considered to be due to DCP exposure, there were no tumors of this type noted in male rats exposed to the highest concentration, 500 ppm, nor were any of these tumors noted in female rats at any exposure level. As the authors stated that there was no effect on survival at any concentration of DCP, and given the lack of an exposure-response relationship for these tumors in male rats and no esthesioneuroepitheliomas in the females, it is unclear whether the esthesioneuroepitheliomas are related to DCP exposure. There was no increase in the tumor incidence noted in other tissues.

In the study Matsunoto (2013), tumor responses were seen in single sexes. In the females, the combined incidence of bronchiolo-alveolar adenomas/carcinomas reached significance at the highest dose level of 200 ppm PDC and exceeded the JBRC historical control data (the incidence ranges not given). For males exposed to 200 ppm PDC, the incidence of benign Harderian gland adenomas of the eye exceeded the maximum incidences of the JBRC historical control data (ranges also not given). There is no Harderian gland in men (Albert et al., 1986) and Harderian gland adenomas have no relevance to humans (Cohen, 2004). The remaining tumor incidences were within the incidences of the JBRC historical control data.

 

Based on the inhalation cancer bioassay results demonstrating an increased incidence of nasal tumors in rats in combination with epidemiological data, PDC is self-classified as a Category 2 carcinogen according to DSD/DPD criteria; this equates with a GHS Category 1B cancer classification, according to Directive 67/548/EEC, EU CLP (Regulation (EC) No. 1272/2008).

Additional information

The carcinogenic potential of DCP has been investigated in two long term oral gavage studies using F344 rats and B6C3F1 mice (NTP, 1986). Due to poor survival, statistical analysis of tumour incidence was adjusted for survival in both species.

No significant or treatment-related increase in tumour incidence was observed in male rats given 0, 62 or 125 mg/kg bw/day for 103 wk. Female rats given 125 or 250 mg/kg bw/day showed a positive trend for mammary adenocarcinoma incidence (adjusted rates: 3%, 5%, 27%), which was increased significantly in the high dose group. These were neither metastatic, anaplastic, nor highly invasive, and were diagnosed by some NTP pathologists as highly cellular fibroadenomas (NTP, 1986). Affected high dose females showed a marked decrease in survival (32% alive at study end versus 74%-86% in the control and low dose groups) and a significant reduction (>20%) in body weight, suggesting that 250 mg/kg bw/day was in excess of the Maximum Tolerated Dose for DCP; compromised metabolic, immune, or hormonal status was possible under such conditions (NTP, 1986). It is pertinent that there was no increase in liver tumours despite the occurrence of chronic histopathological changes, including foci of clear change and necrosis. Based on these findings, NTP concluded that there was no evidence for the carcinogenicity of DCP in male rats, while in females given 250 mg/kg bw for 103 wk, there was equivocal evidence of an increased incidence of mammary adenocarcinoma; these were considered borderline malignant lesions by NTP, which occurred concurrently with significantly decreased survival and reduced body weight gain.

In mice, there was a positive trend for liver adenoma (adjusted for survival) in both sexes given 0, 125, or 250 mg/kg bw/day for 103 weeks. Tumour incidences in high dose males (45%) and both groups of treated females (17-19%) were increased significantly relative to the controls (20% in males, 3% in females). The findings in male mice occurred in the presence of hepatocytomegaly and hepatic focal necrosis in both treatment groups. The incidence of liver tumours in female mice was essentially identical in the two treated groups, despite a 2-fold difference in dose. High dose females also showed an increased incidence of thyroid tumours but this was not clearly dose-related (combined follicular cell carcinomas and adenomas, adjusted rates 3%, 0%, or 21% in control, low, and high dose groups), and occurred in the presence of liver changes (hepatocytomegaly, focal necrosis, tumours), which may have affected the metabolic and/or hormonal status of the animals. Body weights (both sexes) were unaffected by treatment, while survival at week 103 was reduced in treated females due to reproductive tract infection (70%, 58% and 52% for control, low and high dose animals; males unremarkable). NTP concluded that there was some evidence of carcinogenicity for DCP in male and female mice, based upon an increased incidence of hepatocellular neoplasms, primarily adenomas (thyroid tumours disregarded). While the mechanism underlying these changes is unknown, the occurrence of histopathological liver lesions in male mice (LOAEL 125 mg/kg bw/day) suggests that chronic target organ toxicity may have played a contributing role in the expression of these benign tumours.

Hepatocellular adenoma is a common finding in control B6C3F1 mice. Historical control data for this lesion from contemporaneous NTP studies conducted to 1995 (corn oil, gavage, 16 studies) returned an incidence of 267/813 (33%) in males (range 14-58%) and 111/809 (14%) in females (range 2-28%) (Analytical Services Inc, 1995). Comparison of this historical control information with findings from the NTP study shows that the control incidence for males and females from this study (20%, 3%, respectively) was lower than the mean historical control data, while the incidence for high dose males (45%) and both treated females groups (17%, 19%) was below the upper bound of the historic control data. Spontaneous biological variation in the control data may therefore have influenced the results of this study. When reviewing the rat and mouse tumour findings reported by NTP, IARC (1999) concluded that 1,2-dichloropropane isnot classifiable as to its carcinogenicity to humans (Group 3).

The NTP studies indicate and IARC concluded in 1987 that PDC is not a direct-acting carcinogen via the oral route, that there is equivocal evidence of an increase in mammary tumours in female rats, and that other factors (such as spontaneous biological variation) may have contributed to the increased incidence of mouse liver tumours.

The toxicity and carcinogenicity of 1,2-dichloropropane (DCP) were examined by inhalation exposure of male and female F344 rats to DCP for 2 years (Umeda set al., 2010). In the 2-year study the DCP concentrations were 80, 200, or 500 ppm (v/v). Two-year exposure to DCP significantly increased incidences of papilloma in the nasal cavity of male and female rats exposed to 500 ppm DCP. No papillomas were noted in the nasal tissues of male or female rats exposed to 80 ppm or female rats exposed to 200 ppm DCP for 2 years. In addition, three cases of esthesioneuroepithelioma were observed in the DCP-exposed male rats with no dose-response relationship and none found in female rats; it is unclear whether the esthesioneuroepitheliomas are related to DCP exposure. Total nasal tumors increased in a concentration-dependent manner. Hyperplasia of the transitional epithelium and squamous cell hyperplasia, both of which were morphologically different from the hyperplasia of the respiratory epithelium observed in the 13-wk exposure study, occurred in a concentration-dependent manner; these lesions are considered to be preneoplastic lesions. Atrophy of the olfactory epithelium, inflammation of the respiratory epithelium, and squamous cell metaplasia were also seen in the 2-year study. Inflammation of the respiratory epithelium was seen in all exposed groups. There was no increase in the tumor incidence noted in other tissues. Therefore, the nasal tumors were seen at the site of contact in rat respiratory epithelium that is significantly susceptible to irritation and irritation-based carcinogenicity. These results demonstrate that DCP is a nasal carcinogen in rats.

The carcinogenicity of 1,2-dichloropropane (DCP) at concentrations of 32, 80 or 200 ppm (v/v) in the 2-year study with male and female B6D2F1 mice was investigated. Tumor responses were seen in single sexes. Two years exposure to DCP significantly increased the combined incidence of bronchiolo-alveolar adenomas/carcinomas in females, reaching significance at the highest dose in females.  For males exposed to 200 ppm PDC, the incidence of benign Harderian gland adenomas of the eye exceeded the maximum incidences of the JBRC historical control data (ranges also not given). There is no Harderian gland in men (Albert et al., 1986) and Harderian gland adenomas have no relevance to humans (Cohen, 2004). The remaining tumor incidences were within the incidences of the JBRC historical control data. The incidence of pre-neoplastic bronchiolo-alveolar hyperplasia was not increased in any exposure group. In the liver, there were no changes, including altered cell foci. Anemia and systemic toxicity in chronically exposed animals is inferred from results of subchronic mouse study, indicating that MTD has been exceed.

Justification for selection of carcinogenicity via inhalation route endpoint:
Effects seen in both sexes. Reliable study.

Carcinogenicity: via oral route (target organ): digestive: liver

Carcinogenicity: via inhalation route (target organ): respiratory: nose