No. 1031 - Miljøstyrelsen

46
D4 is on the list of potential PBT and vPvB (very persistent and very bioaccumulative)
substances selected on the basis of screening criteria in the EU
(DEPA 2003).
In the following a short review of the findings in literature about the substances
are presented. An overview of the studies and their results are presented
in Annex 7.
3.2.1 Toxicokinetics
A number of studies in rats using unlabelled or 14C labelled D4 show that the
level of absorption following inhalation of this substance is low and independent
of gender and dose. The substance is distributed to most tissues and the
highest concentrations were found in fat and the lowest in the reproductive
tissues. Parent D4 is eliminated via the lungs and metabolised D4 via urine
and faeces. The elimination profile from tissues except from fat and lung resembles
that from blood and follows a two-compartment model (EPA DCN
86970000024 1996).
The elimination half-life for D4 has been shown to vary from 68 hours in
plasma to approximately 150 hours in skin. Higher values are seen in testes.
Blood clearance in human volunteers was non-linear and more rapid than by
rats, whereas the elimination from the lungs resembled that from rats (BAuA
2001).
D4 has unusual distribution properties that have become apparent after examination
of the time course data for blood and tissues using a quantitative
physiological model (PBPK). Despite the very high lipophilicity, D4 does not
show prolonged retention because of high pulmonary and hepatic clearance
coupled with induction of metabolising enzymes at high exposure concentrations
(Andersen et al. 2001). This avoids accumulation of free D4.
Pharmacokinetics of D4 administered to rats by inhalation and dermal route
are similar and differs from the intravenous and oral route (Sarangapani et al.
2003).
Percutaneous absorption of neat D4 in humans following topical application
between 1 and 24 hours has been shown at levels of 0.57 – 1.09% (EPA DCN
86980000153 1998 and EPA DCN 8601000003 2000).
In in vitro studies with percutaneous absorption following 24 hours exposure
to 14C-D5 the absorption was found to be 0.8 – 1.08% (EPA DCN
86960000593 1996 and EPA DCN 86970000009 1996).
In rats administered HMDS orally and intravenously no parent HMDS was
found in the urine. Metabolites from this linear siloxane appear to be structurally
different from those obtained for cyclic siloxane except for the commonly
present Me(2)Si(OH)(2).
3.2.2 Acute toxicity
In general the acute toxicity of siloxanes is considered low. LD 50 following oral
administration of D4 in rats is reported to be more than 4,500 mg/kg and
more that 5,000 mg/kg for HMDS. LC 50 in rats exposed to D4 was >12.17
mg/l and >48 mg/l when exposed to HMDS (European Commission 2000).
LC 50 in rats exposed to HMDS for four hours was 15,956 ppm (EPA DCN
86970000724 1997).