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Administrative data

Description of key information

Since progesterone is a naturally occurring hormone in humans, no relevant tumorigenic potential has to be assumed for this compound. However, also during the handling of progesterone it has to be kept in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.

Key value for chemical safety assessment

Justification for classification or non-classification

It has to be taken into account that gestagens in general can promote the growth of specific hormone dependent tissues and tumours.

Classified according to German legislation (TRGS-905) for gestagenic steroids as Carc. Cat. 3 (EEC criteria).

Classified as Category 3, R40 according to Directive 67/548/EEC.

Classified as Category 2 according to Regulation (EC) 1272/2008/EC (CLP).

Additional information

Carcinogenicity Animal Data

Test system

Substance

Application

Test concentration

End point/Effect

Literature

16 ovariectomized

C3H mice with

mouse tumor

virus

[MTV+]

Progesterone

Intramuscular

weekly

intravaginal

applications

of 1%

solution of

DMBA

0.2 mg twice

weekly

Incidence of squamous-

cell carcinomas

increased

from 5/15 to 9/16; no

change in the

incidence of

mixed carcinomas (3/8 to 4/16)

Glucksmann, A & Cherry, C.P.

(1962) The effect of castration

and of additional hormonal

treatments on the induction of

cervical and vulval tumours in

mice. Br. J. Cancer 16, 634-652.

C3H female

mouse [MTV+]

Progesterole in peanut oil

Subcutaneous

5 times/week/19 weeks

2.5 mg

 

Incidence of breast

tumors induced by 3-

methyl-cholanthrene

to 23/23, compared

with 5/24 for 3-

methylcholanthrene

alone & 2/25 for

progesterole alone.

IARC. Monographs on the

Evaluation of the Carcinogenic

Risk of Chemicals to Man.

Geneva: World Health

Organization, International

Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V6 139 (1974)

BALB/C mouse

Progesterone

Subcutaneous

implantation,

18 months

treatment

59-900 µg/day

Ovarian granulosa cell

tumors were found in

27/83 balb/c mice;

most of them

measuring less than

0.5 mm in diameter.

One microscopic

tumor occurred among 33 control mice killed after 18 months.

IARC. Monographs on the

Evaluation of the Carcinogenic

Risk of Chemicals to Man.

Geneva: World Health

Organization, International

Agency for Research on Cancer,

1972-PRESENT. (Multivolume

work)., p. V6 141 (1974)

BALB/C

mouse

Progesterone

Subcutaneous

Implantation,

18 months

treatment

18-900 µg/day

Sarcomas of the

endometrial stroma in

15/142 mice after 18

months. No tumors in

the 33 control animals

Lipschütz, A., Iglesias, R,

Panasevich, V.I. & Salinas, S.

(1967). Granulosa-cell tumors

induced in mice by progesterone.

Br. J. Cancer 21, 144-152;

Lipschütz, A., Iglesias, R,

Panasevich, V.I. & Salinas, S.

(1967). Pathological changes

induced in the uterus of mice withnthe prolonged administration of

progesterone and 19-nor-

contraceptives. Br. J. Cancer 21, 160-165.

Neonatal female

Balb/cfC3H

mouse [MTV+]

Progesterone

Subcutaneous

100 µg/day, alone or in

combination

with 5 or 20

µg/day

Oestradiol 17β

Persistent vaginal

cornification in all 32

mice treated with

progesterone alone;

simultaneous

administration

reduced occurrence of vaginal cornification

significantly. Mammary tumor

incidence was enhanced by

progesterone alone

(23/32) or in

combination with

oestradiol (5 µg, 20/32; 20 µg, 33/44),

when compared to

control animals /5/17).

Age of onset was

significantly lower in

mice given progesterone.

Jones, L.A. & Bern, H.A. (1977) Long-term effects of neonatal treatment with progesterone, alone or in combination with estrogen, on the mammary gland and reproductive tract of female

BALB/cfC3H mice.

Cancer Res. 37, 67-75.

Female C3HXA

hybrid mouse

[MTV+]

 

Implantation

(subcutaneous)

every 28

days during

104 weeks)

14 mg pellets

Breast carcinomas

significantly earlier

age higher incidence

(88% at 70 week) than among 58 untreated control mice (62% at 93 week). No mammary tumors in 27 progestrone- treated, intact males.

IARC. Monographs on the

Evaluation of the Carcinogenic

Risk of Chemicals to

Geneva: World Health

Organization, International

Agency for Research on Cancer, 1972-present.

(Multivolume work)., p. V6 141(1974)

27 C3H mice

[MTV-]

Progesterone

42 weeks

 

No induction of

tumors

IARC. Monographs on the

Evaluation of the Carcinogenic

Risk of Chemicals to Man.

Geneva: World Health

Organization, International

Agency for Research on Cancer,

1972-PRESENT. (Multivolume

work)., p. V6 139 (1974)

Mouse

 

Subcutaneous

 

Tumors : mammary

gland; ovaries; uterus

IARC Monographs on the

Evaluation of the carcinogenic

Risk of Chemicals to Humans,

International Agency for Research on Cancer,,, P. V6

135 Y74]/[IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, International Agency for Research on Cancer, Lyon,

France, P. V21 491 Y79

BALB/cCrgl

female mouse

Progesterone

Subcutaneous,

5 days after

birth

100 µg/ 0.02

ml sesame oil

Induction of genital

tract lesions in 15/24

mice [MTV-] at about

1.5-2 years of age. No lesions in control

animals.

Jones, H.A. & Wong,

L.M. (1977) Cervicovaginal and mammary gland abnormalities in old BALB/cCrgl mice treated

neonatally with progesterone. J.Toxicol. Environ. Health´3, 360 -361.

13 CBA mouse

with mouse

tumor virus

Progesterone

Subcutaneous,

weekly until

death

10 mg

Mice were given an

intrauterine

implantation of 0.1 mg

3-methylcholanthrene,

mice were ovariectomized. At

week 20-29, 2 sarcomas of the

uterine horn in 4 mice,

2 sarcomas in 4 other

mice that died at 40-

49 weeks. In control

mice only receiving

MCA, 5 adenocarcinomas, 2

squamos carcinomas

and 1 sarcoma were

observed.

Kaslaris, E. & Jull, J.W. (1962) The induction of tumours following the direct implantation of four chemical carcinogens into the uterus of mice and the effect of strain and hormones thereon.

B. J. Cancer 16, 479-483.

C57BL6 mouse

Progesterone

Every 3

weeks for 9

weeks

15 mg after

local

application of

MCA

Increased incidence of

vaginal-cervical

invasive squamous-

cell carcinomas, from

6/50 with MCA alone

to 45/50.

Muñoz, N. (1973) Effect of

herpesvirus type 2 and hormonal imbalance on the uterine cervix of the mouse. Cancer Res. 33, 1504 -1508.

AXC rat

Progesterone

Implantation

(subcutaneous)

40 weeks

20 mg /100 g

body wt

An INCR incidence of liver cell carcinomas induced by N-2 - fluorenyldiacetamide

observed in intact

male rats (11/11 VS

7/12), in castrated

males (5/13 VS 1/9) & in ovariectomized

females (4/12 vs 0/14)

IARC. Monographs on the

Evaluation of the Carcinogenic

Risk of Chemicals to Man.

Geneva: World Health

Organization, International

Agency for Research on Cancer,

1972-present. (Multivolume

work). p. V6 142 (1974)

Female AXC rat

 

Progesterone

/and/or

diethylstilbestrol

(DES) plus

irradiation

Intramuscular

implantation

20 mg / plus

irradiation

Development of

mammary tumors

inhibited by

progesterone.

Incidence reduced

from 12/21 with DES

& irradiation to 1/21

with DES &

progesterone +

irradiation; incidence

0/11 with progesterone &

irradiation.

IARC. Monographs on the

Evaluation of the Carcinogenic

Risk of Chemicals to Man.

Geneva: World Health

Organization, International

Agency for Research on Cancer, 1972-present. (Multivolume work)., p. V6 142 (1974)

AXC rat,

hysterectomized

and

ovariectomized

Progesteron

Subcutaneous

injection or

implantation

2 mg (injection)

20 mg (implantation)

No affection of

incidence of mammary tumors

induced by simultaneous

administration of DES

by 82 weeks of age

(18/39 or 17/33 vs.

21/38).

Segaloff, A. (974) The role of the ovary in estrogen production of mammary cancer in the rat.

Cancer Res 34, 2708-2710.

Female SD rat

Progesterone

Subcutaneous,

i.g. installation

of 20 mg

DMBA at 55

days

1.25 mg in

0.05 mL

sesame oil, 5

days of age

Tumor development in

23/30 animals by 190

days of age. Incidence

was similar to that in

controls given DMBA

only. (20/33). Local

number of adeno-

carcinomas was higher in progesterone- treated rats (44 vs 27).

Shellabarger, C.J & Soo, V.A.

(1973) Effects of neonatally

administered sex steroids on

DMBA-induced mammary

neoplasia in rats. Cancer Res 33,

1567-1569.

Female rat

Progesterone

Subcutaneous

0.3 mg, three

times weekly

for 21 weeks

Increase of latent

period of induction of

mammary tumors

from 37 to 50 weeks.

No change in tumor

incidence.

Cutts, J.H. (1964) Estrone-

induced mammary tumors in the rat. II. Effect of alterations in the hormonal environment on tumor induction, behaviour and growth.

Cancer Res., 24, 1124-1130.

Rat

Progesterone

Intramuscular

1 mg twice

weekly

Retardation of app. 4

times the induction of

sarcomas of the cervix

and vagina produced by local administration of

DMBA weekly for

life; induction of

papillomas was

promoted by 19

weeks; progesterone

alone did not increase

the effects of the

carcinogen in

ovariectomized

animals; when given

with oestrogen, the

incidence but not the

latent period of tumor

induction was restored to that of intact females.

Glucksmann, A & Cherry, C.P. (1968) The effect of oestrogens, testosterone and progesterone on the induction of cervico-vaginal tumours in intact and castrate rats.

Br. J. Cancer, 22, 545-562.

SD Rat

Progesterone

Subcutaneous

3 mg twice

weekly for 28

weeks

Reduction of age at

onset of mammary

tumors induced by 30

mg DMBA given

intragastrically at 50

days of age (52 vs.

115 days) and increased the number

of tumors per rat when

compared to controls.

Mammary tumor

incidence not affected

(19/20 vs. 16/20).

Jabara, A.G. & Maritz, J.S.

(1973) Effetcts of hypothyroidism and progesterone on mammary

tumours induced by DMBA in

Sparague-Dawley rats. Br. J.

Cancer, 28, 161-172.

SD Rat

Progesterone

Subcutaneous

4 mg daily for

20 days

Injection before and

after a single iv

injection of 5 mg

DMBA resulted in a

lowered incidence

(from 100 to 20) and

almost complete

inhibition of the

tumors for 4 months

after the DMBA

injection. No mammary tumors

appeared in rats

treated with

progesterone in

combination with

oestradiol benzoate (5

µg/day) during the

same period

Kledzik, G.S., Bradley, C.J. &

Meites, J. (1974) Reduction of

carcinogen-induced mammary

cancer incidence in rats by early

treatment with hormones or

drugs. Cancer Res. 34, 2953-

2956.

Female Beagle

dog

Progesterone

Subcutaneous,

 

74 weeks

0.08-22.5 mg

daily

Endometrial

hyperplasia; no tumors in animals killed 24 hr after last dose, but fibro-adenomatous nodules occurred in 2/5 dogs given highest doses

IARC. Monographs on the

Evaluation of the Carcinogenic

Risk of Chemicals to Man.

Geneva: World Health

Organization, International

Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V6 141 (1974)