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Carcinogenicity

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Description of key information

Three carcinogenicity studies are available. Two 2-year oral gavage studies, conducted in rats and mice according to OECD Test Guidelines (TG) 451 were reported (NTP, 1986a). In addition, one 2-year inhalation (whole body) rat study (Umedaet al. 2010) was included. No test guidelines are reported for the inhalation study. All studies were conducted using 1,2-dichloropropane (DCP).

 

1)   In the 2-year oral rat study, no significant or treatment-related increase in tumour incidence was observed in male rats given 62 or 125 mg/kg bw/day, while female rats given 125 or 250 mg/kg bw/day showed a positive trend for mammary adenocarcinoma (incidence rates adjusted for survival were 3%, 5% and 27% at 0, 125 and 250 mg/kg, respectively). These tumours consisted of highly cellular fibroadenomas which were not metastatic, anaplastic, or highly invasive, but were significantly increased in the high dose group. High dose females showed a marked decrease in survival and a significant reduction in bodyweight, indicating that the maximum tolerated dose (MTD) was exceeded.

 

2)   In the 2-year oral mouse study (doses were 0, 125 and 250 mg/kg bw/day for both sexes) incidences of liver adenoma were increased in high dose males (45%) and at both doses in females (17 and 19%, respectively). Control incidences were 20% in males and 3% in females.

An increased incidence of thyroid tumours was also observed in females at the high dose (21% compared with 3% in control, 0% in low dose). Liver changes (hepatocytomegaly, focal necrosis) occurred in all treatment groups, which may have affected the metabolic and hormonal state of the animal. In addition, the concurrent control incidence of hepatocellular adenomas was lower than the mean historical control incidence while the highest incidences in the treated mice were below the upper bounds of the historical control incidence (mean 33%, range 14-58% in males; mean 14%, range 2-28% in females).

 

3)     In the 2-year inhalation rat study (Umeda et al., 2010; concentrations of 0, 80, 200 and 500 ppm (v/v), 50 rats/sex/concentration) there was a clear increased incidence of nasal papillomas in the highest dose groups of both sexes. Three cases of olfactory esthesioneuroepitheliomas were also seen in males exposed to 80 and 200 ppm. Concentration-dependent increased incidences in hyperplasia of the transitional epithelium and in squamous cell hyperplasia were also seen in both sexes, as well as atrophy of the olfactory epithelium, inflammation of the respiratory epithelium and squamous cell metaplasia.

(RAC opinion, 2014)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2003
Reliability:
1 (reliable without restriction)
Qualifier:
no guideline followed
Principles of method if other than guideline:
standard NTP gavage study
GLP compliance:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
corn oil
Duration of treatment / exposure:
103 wk
Frequency of treatment:
5 d/wk
Remarks:
Doses / Concentrations:
males 0, 62 or 125 mg/kg bwt/d
Basis:

Remarks:
Doses / Concentrations:
females 0, 125 or 250 mg/kg bwt/d
Basis:

Body weight and clinical signs

Treated animals showed a dose-related reduction in body weight. Final body weights were approx. 5% lower than control for low dose animals, and 14% and 24% lower then control in the high dose male and female groups, respectively. (Female body weight was decreased by >20% from wk 76 of the study.) No clinical signs are described.

Survival

The survival of high dose females (250 mg/kg bwt/d) was significantly (P<0.001) below that of the low dose females and controls (32%, 86% and 74% survival to the end of the study). Mortality and morbidity were especially marked at wk 94 of the study. Survival in males was comparable for all groups (78%, 84% and 82% alive at wk 103 for the control, 62 mg/kg bwt/d and 125 mg/kg bwt/d groups, respectively).

Tumor pathology

Because of reduced survival in high dose female rats, statistical procedures that adjust for intercurrent mortality (life table and incidental tumor tests) were regarded as more meaningful than the 'unadjusted' analysis.

A quantitative increased tumor incidence in one or both treatment groups relative to control, or a positive trend in the absence of any statistically significant difference between the treated and control groups, was seen for the following tissues and tumor types:

* mammary gland mammary gland hyperplasia was increased, and there was a positive trend for mammary adenocarcinoma (adjusted rates: 2,7%, 4.7%, 26.7%; significantly increased in high dose group), both in females only; the overall incidence of fibroadenomas showed a negative trend in females. Tumor incidence in the high dose group was strongly influenced by findings in 4 of 16 animals that survived to the end of the study. A historical incidence of 2% (3/150) was reported for the laboratory conducting this study, with an overall historical incidence of 1.2% (11/895).

* uterus

enometrial stromal polyps occurred with a significant positive trend, although the incidence in the individual treatment groups was not increased relative to control.

* thyroid follicluar cell carcinoma were found in two low dose females (but not in control or high dose females) at study termination; historic range 0.2-0.7%.

* stomach or forestomach a non-significant increase in squamous cell papillomas was found in two high dose females (none in control); historic range 0-0.3%.

* pancreas islet cell carcinomas occurred with a positive trend in males, however the incidence of adenomas was greatest in the control group and the combined incidence (adenoma + carcinomas) was not different between the groups.

* pituitary while the incidence of adenomas was significantly increased in low dose females, the survival-adjusted incidence was unremarkable; the incidence of pituitary carcinomas was greatest in control females; the incidence of combined (adenomas + carcinomas) was not increased significantly.

* adrenal glands pheochromocytomas showed a negative trend in males, and there was no difference in the incidence in combined pheochromocytoma + malignant pheochromocytoma).

No tumors were present in liver, a tissue showing signs of non-neoplastic changes (see above). Note: Significant increases were observed in virus antibody titers. The report notes that the relationship between these increases and occurrence of non-neoplastic- and neoplastic changes is unclear.

Conclusions:
NTP concluded that under the conditions of this study there was no evidence that PDC was a carcinogen in male rats treated by gavage at doses up to 125 mg/kd bwt/d or 250 mg/kg bwt/d, respectively, for up to 103 wk. There was equivocal evidence of an increase in mammary tumors in high dose females, but no other tissues were affected.
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2003
Reliability:
1 (reliable without restriction)
Qualifier:
no guideline followed
Principles of method if other than guideline:
standard NTP gavage study
GLP compliance:
yes
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Route of administration:
oral: gavage
Duration of treatment / exposure:
103 wk
Frequency of treatment:
5 d/wk
Remarks:
Doses / Concentrations:
0, 125 or 250 mg/kg bwt/d
Basis:

Body weight and clinical signs

Mean body weights of treated and vehicle control animals were comparable, and no compound-related clinical signs were noted.

Survival

The survival of high dose females (250 mg/kg bwt/d) was significantly (P<0.035) less than that of the low dose females and controls, with 70%, 58% and 52% of the control, low and high dose animals surviving to termination. Survival in males was comparable for all groups (70%, 66% and 70% alive at wk 103 for the control, 125 mg/kg bwt/d and 250 mg/kg bwt/d groups, respectively). The report notes that the lowered survival in female mice was related to an increased incidence of reproductive tract infections in animals which died before the end of the study (45% of controls affected versus 64% of both the low and high dose females that died during the study).

Non-tumor pathology

Hepatocytomegaly (6%, 10% and 30% for control, low dose and high dose animals, respectively) and hepatic focal necrosis (4%, 10% and 20%) were seen in male mice only. Acanthosis of the surface epithelium of the forestomach occurred at increased incidence in high dose males (0%, 0%, 4%) and both groups of treated females (0%, 10%, 8%). Suppurative inflammation (affecting ovary, uterus or multiple organs) was found in 5/11 control, 9/14 low dose and 14/22 high dose females that died before the end of the study.

Tumor pathology

Tumors were found in the following tissues, although the increase was not always statistically significant and/or dose-related:

* liver There was a positive trend for liver adenomas in male (20%, 29%, 45%, adjusted for intercurrent mortality) and female (3%, 17%, 19%, adjusted) mice. Tumor incidences in high dose males (P=0.017, lifetable test) and both low (0.064, lifetable test) and high dose (P=0.047, lifetable test) females were increased significantly relative to control.

* thyroid Two high dose females had follicular cell carcinomas, and 3 had follicular cell adenomas. The combined incidence of adenomas or carcinomas in high dose females (21% adjusted) was increased significantly (P=0.040, lifetable test) relative to the controls (3% adjusted), with a historical rate of 1%-3.8%. There were no tumors in the controls.

* forestomach Squamous cell papillomas occurred at an incidence of 0%, 2% and 6% in control, low dose and high dose male mice, and at 0%, 4% and 4% in the equivalent female groups. Historical rates for this tumor are in the range 0-0.2% for male B6C3F1 mice and 0-0.3% for females. One high dose female had a squamous cell papilloma (2% incidence, historical range of 0-0.3%).

* lung Alveolar/bronchiolar adenomas and alveolar/bronchiolar adenomas or carcinomas (combined) showed a significant negative trend in female mice.

* external surface Subcutaneous fibromas or fibrosarcomas and fibromas or fibrosarcomas of the skin or subcutaneous tissue occurred with a significant negative trend in male mice. Note: Significant increases were observed in virus antibody titers. The reports notes that the relationship between these increases and occurence of the non-neoplastic- and neoplastic changes is unclear.

Conclusions:
NTP concluded that under the conditions of this study PDC increased the incidence of hepatic adenomas in B6C3F1 mice treated with 125 mg/kd bwt/d or 250 mg/kg bwt/d by gavage for up to 103 wk.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
125 mg/kg bw/day
Study duration:
chronic
Species:
mouse
System:
hepatobiliary
Organ:
liver

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:
2010
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
no guideline available
Principles of method if other than guideline:
Umeda et al., 2010; concentrations of 0, 80, 200 and 500 ppm (v/v), 50 rats/sex/concentration
GLP compliance:
not specified
Species:
rat
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Details on exposure:
concentrations of 0, 80, 200 and 500 ppm (v/v)
Duration of treatment / exposure:
2 years
No. of animals per sex per dose:
50 rats/sex/concentration
Key result
Dose descriptor:
LOAEC
Effect level:
80 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
ophthalmological examination
histopathology: neoplastic
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
80 ppm
System:
respiratory system: upper respiratory tract
Organ:
other: olfactory esthesioneuroepitheliomas
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Three cases of olfactory esthesioneuroepitheliomas were also seen in males exposed to 80 and 200 ppm. Concentration-dependent increased incidences in hyperplasia of the transitional epithelium and in squamous cell hyperplasia were also seen in both sexes, as well as atrophy of the olfactory epithelium, inflammation of the respiratory epithelium and squamous cell metaplasia

Conclusions:
In the 2-year inhalation rat study (Umeda et al., 2010; concentrations of 0, 80, 200 and 500 ppm (v/v), 50 rats/sex/concentration) there was a clear increased incidence of nasal papillomas in the highest dose groups of both sexes. Three cases of olfactory esthesioneuroepitheliomas were also seen in males exposed to 80 and 200 ppm. Concentration-dependent increased incidences in hyperplasia of the transitional epithelium and in squamous cell hyperplasia were also seen in both sexes, as well as atrophy of the olfactory epithelium, inflammation of the respiratory epithelium and squamous cell metaplasia.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Study duration:
chronic
Species:
rat
System:
respiratory system: upper respiratory tract
Organ:
not specified
other: olfactory esthesioneuroepitheliomas, hyperplasia of the transitional epithelium and squamous cell hyperplasia, atrophy of the olfactory epithelium, inflammation of the respiratory epithelium and squamous cell metaplasia

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

According to COMMISSION REGULATION (EU) 2016/1179 of 19 July 2016 amending, for the purposes of its adaptation to technical and scientific progress, Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures (9th ATP of CLP), 1,2 -dichloropropane is calssified as Carc. 1B, H350.