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Carcinogenicity

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Description of key information

The Joint FAO/WHO Expert Committee on Food Additives (JECFA) has assessed the carcinogenicity data from a 2 year drinking water study in Wistar Rats using Benchmark dose analysis. They concluded that the BMDL10 for tumour incidence was 3.3 mg/kg bw/day. This value has been taken forward to calculate the DMEL for the substance.

In addition both the European Commission and IARC have designated the substance as a known carcinogen in animals with possible carcinogenicity in humans.

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:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
no guideline required
Principles of method if other than guideline:
The paper presents the BMDL10 values calculated for the substance based upon the results of a 2 year carcinogenicity study conducted in rats.
GLP compliance:
no
Remarks:
GLP status is not appplicable to review documents
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Wistar KFM/Han
Sex:
male/female
Route of administration:
oral: drinking water
Vehicle:
water
Dose / conc.:
27 mg/L drinking water
Dose / conc.:
80 mg/L drinking water
Dose / conc.:
240 mg/L drinking water
No. of animals per sex per dose:
80 (eighty)
Control animals:
yes, concurrent vehicle
Key result
Dose descriptor:
BMDL10
Effect level:
ca. 3.3 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: tumour incidence
Dose descriptor:
BMD: 10
Effect level:
ca. 5.4 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: tumour incidence

BMD10s and BMDL10s varied within the range of 5.4 to 7.5 and 3.3 to 6.1 mg/kg

bw per day, respectively. This proves the required independency of results from the

chosen model. Modelling for malignant tumours only gave similar results (not

shown) with BMD10 and BMDL10 ranges of 8.3 to 10.1 mg/kg bw per day and 5.6 to

8.4 mg/kg per day, respectively.

Modelling results for female rats (animals with treatment-related tumours)

are shown in Table 4. As for male rats, several models gave reasonable fits and

BMD10s and BMDL10s varied only within a narrow range: the ranges obtained were

7.6 to 10.3 mg/kg bw per day for BMD10 and 6.6 to 7.7 mg/kg bw per day for BMDL10.

Table 5 gives a summary of the modelling of data for individual tumour sites.

Modelling was performed on incidence data for tumour-bearing animals for benign

and malign kidney tumours (males only), hepatocellular tumours (males and

females) as well as tumours of the tongue (males and females) (see Table 1 and 2 for

incidence data for males and females, respectively). Incidence data for thyroid

tumours showed no clear dose–response relationship and were unsuitable for

modelling.

Table 1. Number of male rats bearing tumours after receiving drinking-water

containing 1,3-dichloro-2-propanol for 2 years

Tumour site                                   Concentration (mg/kg)

                                                      0             2.1         6.3        19

Kidney

Tubular adenoma                                  0/50       0/50      3/50       9/50

Tubular carcinoma                                 0/50      0/50        0/50       1/50

Combined                                              0/50      0/50       3/50       9/50a

Liver

Hepatocellular                                       1/50        0/50      0/50        0/50

adenoma

Hepatocellular                                       0/50        0/50       2/50       8/50

carcinoma

Combined                                             1/50        0/50      2/50        8/50

Thyroid gland

Follicular adenoma                                0/50       0/50       2/50       3/48

Follicular carcinoma                              0/50        0/50      2/50       1/48

Combined                                             0/50       0/50       4/50        4/48

Tongue

Papilloma                                              0/50        1/50       0/49        6/50

Carcinoma                                            0/50        0/50      0/49       6/50

Combined                                              0/50       1/50       0/49       12/50

All treatment-affected sites: kidney tubular adenoma and carcinoma, hepatocellular

adenoma and carcinoma, follicular adenoma and carcinoma of the thyroid, papilloma and

carcinoma of the tongue

Benign tumours                                     1/50      1/50        5/50      17/50

Malign tumours                                      0/50       0/50       4/50       14/50

Combined                                              1/50      1/50        8/50b         29/50c

 

a Male No. 274 had an adenoma and a carcinoma and was counted only once

b Male No. 201 had a benign and a malign tumour and was counted only once

c Males Nos 269 and 274 each had a benign and a malign tumour; both animals were counted

only once

Table 2. Number of female rats bearing tumours after receiving drinking-water

containing 1,3-dichloro-2-propanol for 2 years

Tumour site                                           Concentration (mg/kg)

                                                               0            3.4          9.6         30

Liver

Hepatocellular                                       1/50        1/50      1/50       5/50

adenoma

Hepatocellular                                       0/50        0/50      1/50        36/50

carcinoma

Combined                                              1/50      1/50        2/50       41/50

Thyroid gland

Follicular adenoma                                1/50      0/50        3/50      3/49

Follicular carcinoma                              0/50       0/50        0/50      2/49

Combined                                             1/50       0/50       3/50       5/49

Tongue

Papilloma                                               0/50       0/50       0/50      7/49

Carcinoma                                            0/50        1/50       1/50      4/49

Combined                                             0/50        1/50      1/50        11/49

 

All treatment-affected sites: hepatocellular adenoma and carcinoma, follicular adenoma and

carcinoma of the thyroid, papilloma and carcinoma of the tongue

Benign tumours                                    2/50       1/50        4/50       12/50

Malign tumours                                      0/50       1/50      2/50       37/50

Combined                                             2/50       2/50       6/50       42/50a

 

aSeveral animals had both benign and malign tumours and were counted only once.

Table 3. BMD10, BMDL10 and statistical parameters obtained from fitting

models to dose–response data for male rats with treatment-related tumours

after receiving drinking-water containing 1,3-dichloro-2-propanol for 2 years

Model                  pvalue   Chi squared        AIC         BMD10(mg/kg           BMDL10(mg/kg

                                                                               bw per day)           bw per day)

 

Gamma                0.507     0.44                 138.1      5.4                         3.5

Logistic                0.248     2.79                 138.5      7.5                         6.1

Logistic (log dose)    .534     0.39                   138.0     5.4                          3.5

Probit                  0.366    2.01                   137.7      6.8                          5.6

Probit (log dose)     0.731    0.12                   137.7       5.4                          3.6

Quantal-quadratic  0.493     1.42                   136.9       6.5                          5.6

Weibull                0.620    0.43                  138.3       5.4                          3.4

Multistage (2nd       0.343      0.90                  138.6       5.7                         3.3

degree polynomial,

betas>=0)

AIC: Akaike’s information criterion; BMD10: benchmark dose for 10% extra risk of tumours;

BMDL10: 95% lower confidence limit for the benchmark dose. Extra risk is defined as the

additional incidence divided by the tumour-free fraction of the population in the controls.

Multistage stands for a specific mathematical model applied.

Table 4. BMD10, BMDL10and statistical parameters obtained from fitting

models to dose–response data for female rats with treatment-related tumours

after receiving drinking-water containing 1,3-dichloro-2-propanol for 2 years

 

Model                                    pvalue  Chi-squared          AIC         BMD10                   BMDL10

                                                                                            (mg/kg bw              (mg/kg bw

                                                                                           per day)                 per day)

Gamma                                  0.967     0.00                120.2     10.2                        7.2

Logistic                                  0.810     0.42                 118.6      9.4                         7.5

Logistic (log dose)                 0.953      0.00                120.3      10.1                       7.4

Probit                                    0.588     1.06                 119.2      8.5                         6.9

Probit (log dose)                    0.996     0.00                120.2     10.1                        7.7

Quantal-quadratic                   0.41      1.77                 120.1       7.6                        6.7

Weibull                                  0.888      0.02                120.3      10.3                       7.0

Multistage (3rd                         0.854     0.03                 120.3       10.3                      6.6

degree polynomial,

betas 0)

AIC: Akaike’s information criterion; BMD10: benchmark dose for 10% extra risk of tumours.

BMDL10: 95% lower confidence limit for the benchmark dose. Extra risk is defined as the

additional incidence divided by the tumour-free fraction of the population in the controls.

Table 5. Result of dose–response modelling (BMD10, BMDL10) for various

treatment-affected tumour sites for male and female rats receiving drinking-

water containing 1,3-dichloro-2-propanol for 2 years

 

Tumour site and type             Models with                          Range of BMD10s                  Range of BMDL10s

                                     acceptable fits                       (mg/kg bw per day)                (mg/kg bw per day)

 

Males

Renal adenoma and              Gamma, log logistic,              11.1–12.2                               7.2–7.7

Carcinoma                            log probit, Weibull,

                                               Multistage

Hepatocellular adenoma       Logistic, probit, log                14.4–16.0                              10.3–12.3

and carcinoma                    probit, quantal-quadr.,

                                     multistage

 

Tongue papilloma and           Gamma, logistic, log              12.4–17.9                              8.7–11.6 

Carcinoma                            logistic, probit, log

                                        probit, quantalquadratic,

                                         Weibull,multistage

 

Females

Hepatocellular adenoma       Gamma, logistic, log              11.2–14.6                               9.1–10.1

 and carcinoma                  logistic, probit, log

                                      probit, Weibull,

                                      multistage

Tongue papilloma and           Gamma, logistic, log             17.1–22.8                              11.5–19.1

Carcinoma                         logistic, probit, log

                                      probit, quantalquadratic,

                                      Weibull, multistage

 

BMD10: benchmark dose for 10% extra risk of tumours. BMDL10: 95% lower confidence limit

for the benchmark dose. Extra risk is defined as the additional incidence divided by the

tumour-free fraction of the population in the controls.

Table 10. BMD10aand BMDL10bvalues obtained from fitting models to

incidence data for all treatment-related tumours and for individual tumour

locations in male and female rats given drinking water containing 1,3dichloro-2-propanol

for 2 years

 

Treatment-affected sites and                Range of BMD10values         Range of BMDL10values

tumour types                                        (mg/kg bw per day)                (mg/kg bw per day)

Males

Tumour-bearing animals/all                  5.4–7.5                                   3.3–6.1

treatment-associated sites

Renal adenoma and carcinoma             11.1–12.2                              7.2–7.7

Hepatocellular adenoma and                 14.4–16.0                              10.3–12.3

carcinoma

Tongue papilloma and carcinoma         12.4–17.9                              8.7–11.6

 

Females

Tumour-bearing animals/all                   8.5–10.3                                 6.6–7.7

treatment-associated sites

Hepatocellular adenoma and                 11.2–14.6                               9.1–10.1

carcinoma

Tongue papilloma and carcinoma         17.1–22.8                              11.5–19.1

 

aBMD10: benchmark dose for 10% extra risk of tumours.

bBMDL10: 95% lower confidence limit for the benchmark dose. Extra risk is defined as the

additional incidence divided by the tumour-free fraction of the population in the controls.

Conclusions:
The Committee concluded that the critical effect of 1,3-dichloro-2-propanol
is carcinogenicity. The substance yielded negative results in two new studies of
genotoxicity, a test for micronucleus formation in bone marrow in vivo and an assay
for unscheduled DNA synthesis in vivo/in vitro in rat hepatocytes, but limitations in
those studies and positive findings in tests for genotoxicity in vitro as well as lack of
knowledge on the modes of action operative at the various tumour locations led the
Committee to the conclusion that a genotoxic mode of action could not be excluded.
Accordingly, the cancer dose–response data were analysed by dose–response
modelling, and the Committee used eight different models to calculate BMD
10 and BMDL10 values. BMDL10 values for the individual tumours ranged from 7.2 to
19.1 mg/kg bw per day and for incidence data on tumour-bearing animals for all
treatment-affected locations from 3.3 to 7.7 mg/kg bw per day.
Endpoint:
carcinogenicity: oral
Type of information:
other: IARC monograph
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
no guideline required
Principles of method if other than guideline:
Review of available genotoxicity and carcinogenicity data
GLP compliance:
no
Remarks:
no required for review documents
Conclusions:
Based upon the evidence provided the Working Group concluded that there was sufficient evidence in experimental animals for the carcinogenicity of 1,3-dichloro-2-propanol. 1,3-dichloro-2-propanol is possibly carcinogenic to humans (Group 2B) .
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
BMDL10
3.3 mg/kg bw/day
Study duration:
chronic
Species:
rat
System:
other: tumor incidence
Organ:
other: tumor incidence

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

The substance has a harmonised classification (Index number: 602 -064 -00 -0) of Carcinogen Category 1B H35): may cause cancer.