Registration Dossier

Administrative data

Description of key information

There are no repeated dose toxicity data on tetradecamethylhexasiloxane (L6), so good quality data for the related substances, dodecamethylpentasiloxane (L5, 161-53-9) and decamethyltetrasiloxane (L4, 141-62-8), have been used to assess the repeated dose toxicity of tetradecamethylhexasiloxane.

In a 28-day study performed according to OECD Test Guideline 407 (Dow Corning Corporation, 2010a) with dodecamethylpentasiloxane, no biologically significant, treatment-related effects were reported in rats given dodecamethylpentasiloxane (L5) by oral gavage at 25, 250 or 1000 mg/kg bw/day. A NOAEL of >=1000 mg/kg bw/day was derived.

In a 90-day inhalation study performed according to OECD Test Guideline 413 (Dow Corning Corporation, 2010b) with decamethyltetrasiloxane (L4), no biologically significant, treatment-related effects were reported in rats given decamethyltetrasiloxane (L4) by inhalation at 70 and 400 ppm. A NOAEC of >=400 ppm was derived, which is equivalent to 5083 mg/m³

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
5 083 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
5 083 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No data are available for the registration substance, tetradecamethylhexasiloxane (L6), so reliable data for the related substances, dodecamethylpentasiloxane (L5, 141-63-9) and decamethyltetrasiloxane (L4, 141-62-8) have been used to assess the repeated dose toxicity of tetradecamethylhexasiloxane.

In the key repeated dose oral toxicity study with dodecamethylpentasiloxane, groups of five male and five female rats (with additional satellite groups of five males and five females given the top and the control dose) were treated with dodecamethylpentasiloxane (L5) via the oral (gavage) route for 28 days (Dow Corning Corporation, 2010). The study was conducted according to OECD 422 and in compliance with GLP. Doses of 25, 250 or 1000 mg/kg bw/day were administered, with a concurrent control group treated with the vehicle alone (corn oil) at 5 ml/kg bw. Hepatocellular hypertrophy was observed in the liver which was considered to be an adaptive change and therefore not adverse with respect to human health hazard assessment, so the NOAEL was considered to be at least 1000 mg/kg bw/day, the highest dose tested.

In the key 90-day inhalation study conducted according to OECD 413 and in compliance with GLP (Dow Corning Corporation, 2010) inhalation of decamethyltetrasiloxane (L4) at concentrations of 70 and 400 ppm were well tolerated. There were no clinical signs or treatment-related effects associated with exposure in the ophthalmologic endpoints, body weights, food consumption and rat neurobiological function. Certain changes in serum chemistry and haematology parameters, urinary volumes and organ weights (absolute and relative) may be treatment-related, but not toxicologically significant. The only treatment-related microscopic finding in Group 3 females was an increased incidence of alveolar macrophages, though not considered an adverse effect. Based on the results of this study the NOAEC for decamethyltetrasiloxane for systemic toxicity in male and female rats is at least 400 ppm, which is equivalent to 5083 mg/m³.

In the supporting repeated dose inhalation study conducted according to OECD 422 and in compliance with to GLP (Dow Corning Corporation, 2007), whole body exposure of rats to decamethyltetrasiloxane for 28 days did not result in any adverse effects attributable to treatment. Therefore the NOAEC for systemic toxicity of the adult rats was considered to be at least 400 ppm (the highest concentration tested), which is equivalent to 5083 mg/m³.

Read-across justification

To reduce animal testing REACH recommends to make use of a read-across approach where appropriate based on the high accordance in properties relevant for the specific endpoint. In the case of repeated dose toxicity and reproductive toxicity relevant properties are structural similarity as well as physical-chemical and basic toxicological parameters in the same range. In the following paragraphs the read-across approach for L6 is evaluated point by point. Further information can be found in the supporting report (PFA, 2013u) attached in Section 13 of the IUCLID 6 dossier.  

Read-across hypothesis

The hypothesis is that the target (registered) source substance and the (read-across) substances have similar toxicological properties because they are fully methyl-substituted linear siloxanes with similar physicochemical properties and are structurally similar with similar hydrolysis rates. Hydrolysis rates have been compared based on predicted values, as measured hydrolysis half-lives are available only for L3, and these are consistent with the predicted values.

Summary of key physicochemical and repeated dose toxicity data for linear siloxanes

Substance

L4

L5

L6

Chemical name

Decamethyl

tetrasiloxane

Dodecamethyl

pentasiloxane

Tetradecamethylhexasiloxane

CAS number

141-62-8

141-63-9

107-52-8

Molecular weight

310.69

384.85

459

Water solubility (mg/l)

6.7E-03 at 23°C

7.0E-05 at 23°C

2.3E-06 at 20°C

Log Kow

8.21 (measured) at 25.1°C

9.41 (measured) at 25°C

>9.41 (read across from L5) at 20°C

Vapour pressure

73 Pa at 25°C

7.8 Pa at 25°C

0.27 Pa at 20°C

Ultimate hydrolysis products

Dimethylsilanediol and trimethylsilanol

Dimethylsilanediol and trimethylsilanol

Dimethylsilanediol and trimethylsilanol

Hydrolysis half-life (pH 7, 20-25°C, predicted)

630 hours

2000 hours

6300 hours

Hydrolysis half-life (pH 7, 37.5°C)

270 hours

490 hours

1600 hours

Hydrolysis half-life (pH 2, 37.5°C)

19 seconds

60 seconds

108 seconds

Sub-acute oral toxicity NOAEL (mg/kg bw/day

25 mg/kg bw/day (Dow Corning Corporation, 2010c)

≥1000 (Dow Corning Corporation, 2010a)

-

Sub-chronic inhalation toxicity NOAEC (mg/l)

5.1 (Dow Corning Corporation, 2010b)

-

-

(a) Structural similarity

L6, L5 and L4 are closely related substances, consisting of chains of six, five and four silicon atoms joined by five, four and three oxygen atoms, i.e. they have five, four or three Si-O groups and a terminal silicon, substituted with fourteen, twelve and ten methyl groups respectively.

(b) Similar toxicokinetics

The read-across of data from decamethyltetrasiloxane and dodecamethylpentasiloxane to tetradecamethylhexasiloxane is justified by the similarities in structure and physicochemical properties of the two substances. They have extremely low water solubility (6.7E-03 mg/l at 23°C, L4; 7.0mg/l at 23°C, L5 and 2.3E-06 mg/l at 20°C, L6) and high octanol-water partition coefficients (log Kow = 8.21 at 25.1°C, L4; , 9.41 at 25°C, L5; and >9.41 at 25°C, L6 (by read-across from L5)). These properties indicate that absorption of parent is likely to be low via oral and dermal routes of exposure. Once absorbed these substances are likely to distribute into tissues, particularly fatty tissues.

The substances belong to the structural class of siloxanes (alkyl, vinyl, aryl or hydrogen substituted) and the substances hydrolyse slowly at pH 7 (see Table 5.6.3) therefore hydrolysis is not of relevance in terms of toxicological studies by the inhalation route. For the oral route, the hydrolysis rate is predicted to be fast at pH 2 and 37.5°C with half-lives of 19 seconds (L4), 60 seconds (L5) and 108 seconds (L6), and the substances share common ultimate hydrolysis products, trimethylsilanol and dimethylsilanediol. However, in view of the high lipophilicity and poor water solubility of the parent substances it is likely that some unhydrolysed material is adsorbed onto food present in the stomach and thus the true rate of degradation in the stomach is difficult to predict.

(c) Acute toxicity

Toxicity studies indicate that neither L4 nor L5 is acutely toxic via the dermal route (see acute dermal toxicity section). Nor are they irritating in reliable studies (see irritation section).

(d) Repeated dose toxicity

Repeated sub-acute oral toxicity studies are available for decamethyltetrasiloxane and dodecamethylpentasiloxane, in which both substances led to adaptive changes in the liver (25, 250 and 1000 mg/kg bw/day for both substances), and decamethyltetrasiloxane caused accumulation of brown pigment in the bile ducts (250 and 1000 mg/kg bw/day), but other relevant findings were unremarkable and there were no apparent effects on the reproductive organs examined at necropsy. The observed effects with L5 were not considered to be adverse with respect to setting a NOAEL and deriving DNEL for human hazard assessment purposes, whereas for L4 accumulation of brown pigment was considered to be adverse. Further studies are underway to determine the nature of the pigment. A 90-day inhalation study is also available with L4 in which no adverse effects were observed at the highest achievable test concentration of 400 ppm. The study with L5 was selected as read-across for repeated dose toxicity by the oral route because L5 is closer in molecular weight to the registered substance than L4, and the accumulation of brown pigment observed with L4 was not seen in studies on L5. The trend in physicochemical properties from L4 to L6 support read-across from L5 rather than L4.

(e) Conclusion

Overall, these two substances have similar toxicological profiles. After considering all of the above factors it is deemed appropriate to read-across data from L5 to L6.

References

Dow Corning Corporation (2010b). A 90-day subchronic whole body inhalation toxicity study of decamethyltetrasiloxane (L4) with a 28-day recovery period in Sprague-Dawley rats. Testing laboratory: Health and Environmental Sciences, Dow Corning Corporation (no further details). Report no.: 2010-I0000-62271. Report date: 2010-09-17. Dow Corning Corporation (2010c). 28-Day oral (gavage) toxicity study in the Sprague-Dawley rat with decamethyltetrasiloxane (L4). Testing laboratory: Not given. Report no.: 2009-I0000-61677. Report date: 2010-08-03.

PFA, 2013u, Peter Fisk Associates, Analogue report - mammalian toxicity of linear and branched siloxanes, PFA.300.002.008




Justification for classification or non-classification

Tetradecamethylhexasiloxane (L6) is not classified for adverse effects following repeated dose exposures according to Regulation (EC) No 1272/2008.