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Immunotoxicity

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Description of key information

In an in vivo study (Medical College of Virginia, 1997) D4 was administered by oral gavage to Fischer 344 rats for 28 days and the innate and acquired immunity were evaluated. There were no D4 related changes in lymphocyte phenotypes Natural Killer cell activity and allogenic mixed lymphocyte response. Spleen Immunoglobin M response was unaffected except of the female high dose animals. This study showed that an oral dose of up to 300mg/kg bw/day D4 does not suppress the immune system in rats.

In a 28-day repeated inhalation study conducted using a protocol similar to OECD 412, and to GLP (Medical College of Virginia, 1997), the NOAEC for D4 was ≥540 ppm, in rats, assuming that hepatic effects were adaptive. There were no effects on immune system function.

There are no reliable dermal immunotoxicity studies.

Key value for chemical safety assessment

Effect on immunotoxicity: via oral route

Link to relevant study records
Reference
Endpoint:
immunotoxicity: short-term oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
24/03/1994 to 29/12/1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Principles of method if other than guideline:
Immunotoxicological investigations in Fischer 344 rats after subacute oral exposure to D4.
The report encompasses 14 studies and consists of the development of a rat-based model for immunological assessment of test articles, the concurrent validation/evaluation of D4 for any potential immunological events, and studies directed at ascertaining if there was any vehicle dependence on dose.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
corn oil
Duration of treatment / exposure:
28 d
Frequency of treatment:
daily
Dose / conc.:
10 mg/kg bw/day (actual dose received)
Dose / conc.:
30 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes, concurrent vehicle
Body weight and weight changes:
no effects observed
Dose descriptor:
NOAEC
Effect level:
>= 300 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No immunosuppression detected.
Critical effects observed:
no

There was no effect on body weights. There was a slight, but dose-dependent decrease in the erythroid elements in male and female rats. Liver weights were increased and thymus weights decreased as a function of D4 dose. These organ weight changes were more pronounced in the female. Humoral immunity, as measured by the IgM response to the T-dependent antigen sheep erythrocytes (sRBC), was not altered by D4 exposure in male rats as measured by the hemolytic antibody plaque assay (AFC) and serum antibody titers. In female rats there was a dose-dependent increase in the IgM response to sRBC when assessed by the AFC response but not with the antibody titers. There were no changes in cell-mediated immunity as measured by one-way mixed lymphocyte response. There were also no changes in Natural Killer cell activity. Macrophage function as measured by the vascular clearance and phagocytic uptake of 51Cr sRBC into the liver, spleen and lungs showed some slight D4-associated changes. These changes are considered to be related to liver size and, thus, liver blood volume associated with D4. Phenotyping of lymphocytes derived from the blood and spleen showed no biologically significant alterations. In separate studies D4 was delivered in 4 different vehicles. Liver weight was used as an indicator of systemic exposure. D4 produced the greatest increase in liver weight when administered in corn oil, followed by 10 % emulphor and Maalox. No increase in liver weight was noted when D4 was administered in a 35 cs polydimethylsiloxane vehicle.

Conclusions:
In an in vivo study (reliability score 1) D4 was administered by oral gavage to Fischer 344 rats for 28 days and the innate and acquired immunity were evaluated. There were no D4 related changes in lymphocyte phenotypes NK cell activity and allogenic mixed lymphocyte response. Spleen IgM response was unaffected except of the female high dose animals. This study showed that an oral dose of up to 300mg/kg bw/day D4 does not suppress the immune system in rats.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat

Effect on immunotoxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
immunotoxicity: acute oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
No data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
abstract
Principles of method if other than guideline:
A 24 h time course for corticosterone concentration in female B6C3F1 mice was investigated. Details of protocol not available.
GLP compliance:
not specified
Species:
mouse
Strain:
B6C3F1
Sex:
female
Route of administration:
oral: unspecified
Dose / conc.:
1 000 mg/kg bw/day
Dose descriptor:
NOAEL
Basis for effect level:
other: D4 (single oral dose of 1000mg/kg bw/day) or a metabolite induces either directly or indirectly an increase in serum corticosterone levels via centrally mediated pathways in which the catecholaminergic system plays a role.
Remarks on result:
not determinable
Remarks:
no NOAEL identified

A 24 h time course for corticosterone concentration in female B6C3F1 mice reveals a significant increase within 15 minutes after oral exposure (1000 mg/kg). Values remain elevated at 12 h and approach baseline at 24 h. A dose response (1 h post dose) suggests a NOEL between 100 and 250 mg/kg of D4. An intact pituitary gland is required for this response. Blocking prostaglandin synthesis did not alter corticosterone levels in mice. Blockade of ß-adrenergic receptors with propranolol in the brain increased corticosterone.

levels by 20 to 60 %. These studies indicate that D4 or a metabolite induces either directly or indirectly an increase in serum corticosterone levels via centrally mediated pathways in which the catecholaminergic system plays a role.

Conclusions:
An in vivo study (reliability score 4 as details only available as an abstract) in female B6C3F1 mice indicate that D4 (single oral dose of 1000mg/kg bw/day) or a metabolite induces either directly or indirectly an increase in serum corticosterone levels via centrally mediated pathways in which the catecholaminergic system plays a role.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
6 551 mg/m³
Study duration:
subacute
Species:
rat

Effect on immunotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In addition to the key oral study in rats (Medical College of Virginia, 1997; reliability score 1) there is also a reliable human volunteer study (Dow Corning Corporation, 1998c; reliability score 2) in which healthy volunteers ingested either 12 mg per day of D4 in 1 ml corn oil, or corn oil alone for 2 weeks in a double-blind, placebo-controlled, crossover study design. Immunological assays were chosen to screen for an immunotoxic or adjuvant effect. Assays for immunotoxicity included enumeration of peripheral lymphocyte subsets and functional assays using peripheral blood mononuclear cells. Because in humans there is no direct test for adjuvant effect of siloxane exposure, pro-inflammatory cytokines and acute phase reactants in peripheral blood were analysed as surrogate markers of adjuvancy. No immunotoxicity or pro-inflammatory/adjuvant effect of D4 ingestion was observed.

Another supporting study investigated the in vitro immunological effects of siloxanes, including D4, using cultured human immune cells (Dow Corning Corporation, 2001d; reliability score 2). It was found that in the absence of serum, D4 is toxic to peripheral blood mononuclear cells. However, when small amounts of serum or plasma are added, the toxicity is not observed due to lipoprotein content. The study authors therefore concluded that the effects on immune cells systemically are not relevant to humans as there will be sufficient lipoproteins to prevent toxicity. It was speculated that there might be some implications of the toxicity locally in the respiratory mucosa, where concentrations of D4 might become too high compared with lipid availability, thus leading to inflammation or fibrosis.

However, an in vivo study (Wilson & Munson, 1997; reliability score 4 as details only available as an abstract) in female B6C3F1 mice indicates that D4 (single oral dose of 1000mg/kg bw/day) or a metabolite induces either directly or indirectly an increase in serum corticosterone levels via centrally mediated pathways in which the catecholaminergic system plays a role.

To evaluate the response of natural killer (NK) cells activity to exposure to D4, female B6C3F1 mice were administered 1000 mg/kg bw by gavage for 1, 7, 14 or 35 days (Wilson et al., 1995; reliability score 4). After 1 day a minimal suppression of NK activity was apparent. By 7 days a significant enhancement (100 % increase) was there. 50 % enhancement was still present after 14 days. After 35 days NK activity had returned to baseline. Spleen and liver weight were increased by day 7 and remained above controls throughout the exposure period.


Justification for classification or non-classification

Based on the available data D4 does not require classification for immunotoxicity according to Regulation (EC) No. 1272/2008.