Chemical name: Aziridine, 1,1',1''-phosphinylidynetris-

Final regulatory action has been taken for the category: Industrial

Final regulatory action: The chemical is Severely Restricted

Use or uses prohibited by the final regulatory action:

The placing on the market of textiles containing TEPA and which are carried directly or indirectly on the skin (clothes, wigs, costumes etc) or which are intended to be used as decoration (bedsheets, table clothes, carpets, curtains etc.) is banned.

The final regulatory action was based on a risk or hazard evaluation: Yes

Summary of the final regulatory action:

The placing on the market of textiles containing Tris(1-azridinyl) phosphine oxide (TEPA) and which are carried directly or indirectly on the skin (clothes, wigs, costumes, etc) or which are intended to be used as decoration (bed sheets, table clothes, carpets, curtains, etc) is banned (Ordinance on the Reduction of Risks linked Chemical products, ORRChem).

TEPA is considered as a substance particularly dangerous for human health. According to the article 79 of the Ordinance on Chemicals (OChem), which is not specific for TEPA, a particularly dangerous substance can only be supplied to adults or authorized persons.

The reasons for the final regulatory action were relevant to: Human health

Summary of known hazards and risks to human health:

Metabolism After intraperitoneally administraion of 32-P-TEPA to mice, radioactivity was not localized selectively in any of the tissues examined. During the first 24 hours after treatment, some 60 to 75% of dose was excreted via urine, compared with only 2-5% in faeces. In urine, 80% of the radioactivity was identified as inorganic phosphate, the remainder as an unidentified metabolite which could be hydrolysed to give organic phosphate. In rats, 80% of the radioactivity in blood was associated with haemoglobin. During the first 24 hours, 89-90% of the radioactivity was excreted in urine. However, in contrast with the mouse, 50-70% of urinary radioactivity was present as unchanged TEPA. Pattern of metabolism in dogs is essentially similar to that of rats. Recovery of unchanged TEPA in urine was about 25-30% of the dose over the same period. Tissue distribution studies showed retention was uniformly low, with exception of bone marrow in which a selective uptake resulted in a concentration of 6-10 times that in other tissues.

The most importan pharmacological actions of the alkylating agents as TEPA are those that disturb the fundamental mechanisms concerned with cell growth, mitotic activity, differentiation and function. The capacity of thse drugs to interfere with normal mitosis and cell division in all rapidly proliferating tissues provides the basis for their therapeutic applications and for many of their toxic properties.

Animal carcinogenicity data TEP produced a low incidence of benign and malignant tumours in rats following oral administration, the only species and route tested. The available data are insufficient for evaluation of the carcinogenicity of this compound.

Human carcinogenicity data No case reports or epidemiological studies are available.

Animal toxicity: Sherman rats were treated intraperitoneally with 5-10 mg/kg bodyweight on the 11th day of pregnancy. Higher doses were toxic to mothers and caused some fetal resorptions and decreased fetal and placental weight. At doses tolerated by mothers, many resorptions were observed, but no malformations were seen. Freshly prepared suspensions of 5 mg/kg TEPA in sesame oil given intramuscularly to Wistar rats on the 4th and 5th, 7th and 8th or 11th adn 12th day of gestation cause resorption of almost all fetuses.

TEPA induces back-mutations of auxotrophic strain of Schjizosaccharomyces pombe. dominant lethal mutations in Musca domestica and dominant lethal, sex-linked recessive lethal mutations and chromosome translocations in Drosophila melanogaster.,

Frequencies of dominant lethals were significantly increased in progeny of male Swiss mice given intraperitoneally injections of TEPA. Doses ranging from 0.156 - 20 mg/kg body weight gave similar results in A/L and C57B1/6J mice. CD rats given intraperitoneal injections of 10 mg/kg bodyweight TEPA had chromatid aberrations in 87.5% of bone-marrow cells. Induction of transmissable translocations has been found after single intraperitoneal injections of TEPA in male Swiss albino and A/L mice.

Acute and oral symptoms in wild bird species: Ataxia, wing drop, tachypnea, dyspnea, mutations, tremors, prostration, repeated wing-beat convulsions. Mortality occurred 4 hours to 10 days after treatment.

The 30 day empirical minimum lethal dosage (EMLD): for chukars, lowest daily oral dosage that produced 1 or 2 deaths by end of the 30-day period is more that 1.0 mg/kg/day. But survivors of this level later produced markedly less fertile eggs than a control group receiving empty gelatin capsules for 30-day dosage period.

A study on 6 groups of weanling male and female Fisher rats, given daily doses of 0.001 - 0.3 mg TEPA in steroid suspending vehicle, by gavage, 5 days/week for 1 year, showed that the average survival times were between 240 and 500 days for 2 highest dose groups and 560 days for other treated groups. Of 58 treated animals, 34 developed tumors: 1 adenocarcinoma, 1 fibrosarcoma and 6 fibroadenomas of mammary gland, 10 interstitial cell tumors and 1 mesothelioma of testis, 1 fibroma and 1 fibrosarcoma, 1 lung adenoma, 1 hepatoma, 2 bronchial adenomas, 2 squamous cell carcinomas of ear, 1 skin papilloma, 3 lymphomas, 2 others and 1 basal-cell carcinoma of the lip, which was the only tumor observed. Area of application: in 653 controls, there were only 56 tumors observed. The incidence of interstitial-cell tumors of testis was 25/26 examined. Over 600 days, mammary fibroadenomas were infrequent, being found mostly in old females.

A number of TEPA analogues of established chemosterility containing different numbers of aziridine rings and with side chains of various lengths are available. Eight analogues, including TEPA and HEMPA, were tested for their ability to produced chromosomal aberrations in Vicia faba root-tip cells. TEPA and 6 analogues at 7.5 x 10^{-4 and 10-3 moles produced a significant increased in the chromosomal aberration yield.}

^{Human toxicity: A high frequency of chromosome aberrations was observed in vitro after treatment of human leucocyte cultures with TEPA.}

^{The frequency of sister chromatid exchanges (SCE) and chromosome aberrations and the dynamics of cell division in peripheral blood lymphocytes of 4 patients with Fanconi's anemia were studies after in vitro exposure to the alkylating agents TEPA and mitomycin. SCE frequency was significantly increased only after high doses (10-5 moles TEPA)}

^{IARC (1972 - present) Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.}

^{Gilman AG, Goodman LS and Gilman A (eds) (1980) Goodman and Gilman's the Pharmacological Basis of Therapeutics 6th ed. p. 1260}

^{Novotna B et al (1979). Effects of alkylating agents on lymphocytes from controls and from patients with Fanconi's anemia: studies of sister chromatid exchanges, chromosome aberrations and kinetics of cell division. Hum. Genet. 49(1): 41-50}

^{US Dept. of the Interior, fish and Wildlife Service, Bureau of Sport Fisheries and wildlife. Handbook of Toxicity of Pesticides to Wildlife. 1970, p. 111}

^{Hartley-Asp B. Comparative clastogenicity of analogues of the insecticide TEPA in Vicia faba root-tip cells. Mutat. Res 85(4) 300 (1981).}

^{Hazardous Substances Data Bank.}

Date of entry into force of the final regulatory action: 01/08/2005