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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
24 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
37.5
Dose descriptor:
LOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

General remarks:

Trioxane is a cyclic trimer of fomaldehyde and is a volatile solid at room temperature with a characteristic chloroform-like odor. Trioxane is primarily used as a monomer in the production of polyacetals and secondarily as a chemical intermediate. Only a small amount of the total production of trioxane is used in consumer applications (Toxicology and Regulatory affairs (2000), 1,3,5-Trioxane. US EPA HPV Challenge Program Submission).

Acute toxicity:

The RIP 3.2.2, R8 (2008) proposes, that a DNEL for acute toxicity should only be derived in case an acute toxicity hazard (leading to C&L) has been identified and there is a potential for high peak exposures. No mortality and no systemic signs of toxicity were observed up to the highest dose levels tested (3200 mg/kg bw for oral route, 39.2 mg/l for inhalation route and 3980 mg/kg bw for dermal route) and hence no systemic DNELs need to be derived for acute toxicity.

Furthermore trioxane is not a skin or eye irritant or a skin sensitizer.

Repeated dose/long term exposure:

In a 90-day guideline gavage study in rats performed under GLP, no adverse signs of systemic toxicity were observed in the highest tested dose level of 300 mg/kg bw (RCC, 2002). 

Non adverse effects on hematopoietic parameters (e.g. reticulocytes) and spleen weight were consistently observed in the high dose group of this 90-day gavage study and in the high dose group (1000 mg/kg bw) of a preceding 28-day gavage study in rats. The adverse character of these effects is questionable and therefore the oral NOAEL for systemic effects of 300 mg/kg bw derived from the 90-day gavage study in rats is very conservative.

This NOAEL is also covering maternal toxicity and the developmental effects observed at matenal toxicity in an oral developmental study in rats (HMR, 1998).

The database concerning repeated inhalation exposure to trioxane vapors is not extensive and a subchronic study is not available. Altough a reliable 14-day inhalation study is supported by several studies of lower reliability.

In this 2-week whole body inhalation key-study in rats, mild transient signs of respiratory tract irritation were observed in the lowest tested vapor concentration of 0.38 mg/l (Bio/Dynamics, 1983). Animals were exposed for 6 hrs/day, five days/week to test atmospheres of 0.38, 3.62, 18.18 mg/l.

Therefore an inhalation LOAEC of 0.38 mg/l for local effects on the respiratory tract was identified.

Based on mild effects on the hematopoietic system and changes in clinical parameters in the highest dose level tested (18.18 mg/l) a very conservative inhalation NOAEC of 3.62 mg/l for systemic effects was identified, since the adverse character of these effects are arguable and may, at least partly, be due to primary irritation of the respiratory tract.

Signs of respiratory irritation were also observed in an acute inhalation study (secretion, respiratory distress). The LOAEC for local effects at the respiratory tract was 30.8 mg/l air (Bio/Dynamics Inc. 1986).

Additionally assessing the mutagenic potential in vitro and in vivo provide convincing evidence that trioxane does not possess mutagenic or genotoxic activity. In an incompletely reported long term assay in rats no evidence of a carcinogenic potential was found.

 

The derivation of DNELs was performed according to the ECHA Guidance on information requirements and chemical safety assessment - chapter R.8 (May 2008), adapted by partial justified variations.

Acute/short-term exposure – systemic effects – dermal DNEL

Not quantifiable; see above

 

Acute/short-term exposure – systemic effects – inhalation DNEL

Not quantifiable; see above

 

Acute/short-term exposure – local effects – dermal DNEL

Not quantifiable; see above

 

Acute/short-term exposure – local effects – inhalation DNEL

To obtain a ceiling limit value for acute effects at the portal of entry the DNELinhal., local, chronic of 10 mg/m3 (ca. 1.34 ppm, see below) can be extrapolated with a factor of 2.

DNELinhal., local, acute: 20 mg/m3 (ca. 5.3 ppm).

 

Long-term exposure – systemic effects – dermal DNEL

Since no repeated dose study is available for the dermal route of exposure, a route-to-route extrapolation from the oral NOAEL seems to be appropriate. No dermal penetration study is available. In the absence of data on differences in kinetics and metabolism of both, the starting route and the end route, the ECHA Guidance on information requirements and chemical safety assessment - chapter R.8, p.25 (May 2008) recommends worst case assumptions. Limited absorption for the starting route and maximum absorption for the end route should be assumed. On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation. However, the proposed first pass effect following oral administration of trioxane was not considered in this approach. 

NOAELrat, oral, systemic = NOAELrat, dermal, systemic = 300 mg/kg bw

Corrected NOAELrat, dermal:       300 mg/kg bw

Subchronic → chronic:                   1/2

Rat → human (allometric scaling):   1/4

remaining differences:                     2/5

Worker:                                         1/5

Quality of whole database:              1

Dose-response:                              1

DNELdermal, systemic, chronic:     3 mg/kg bw day

 

Long-term exposure – systemic effects – inhalation DNEL

The derivation of the DNEL was performed according to the ECHA Guidance on information requirements and chemical safety assessment - chapter R.8 (May 2008). Allometric scaling does not need to be applied in cases where doses in experimental animal studies are expressed as concentrations (mg/m3). In case of differences between experimental and worker exposure conditions (8h each day), a conversion of an inhalatory rat NOAEC into a corrected inhalatory NOAEC is required:

corrected inhalatory NOAEC = 3620 mg/m3 x 6/8 h/day x 6.7/10 m3 (difference between 8h breathing volume at rest against light activity) = 1819 mg/m3

Subacute → chronic:                      1/6

Rat → human (allometric scaling):   1

remaining differences:                     2/5

Worker:                                         1/5

Quality of whole database:              1

Dose-response:                              1

DNELinhal., systemic,chronic:         24.4 mg/m3 (6.5ppm)

 

Long-term exposure – local effects – dermal DNEL

Not quantifiable; see above

 

Long-term exposure – local effects – inhalation DNEL

In case the starting point for the DNEL calculation is a LOAEL, R8 is suggesting to apply an assessment factor between 1/3 and 1/10 when the BMD-approach can not be taken into account. Since the character of the respiratory irritation observed in the low dose group of the animal experiment was mild, reversible and not accompanied by histopathological findings (see above), applying a factor of 1/5 is sufficiently conservative.

A factor for remaining uncertaintieswas applied according to the ECHA recommendations for substances with local effects at the portal of entry (ECHA Guidance on information requirements and chemical safety assessment - chapter R.8, p.32; May 2008).Additionally a factor of 3 was applied for worker intraspecies differences according to the ECETOCrecommendations(Guidance on Assessment Factors to Derive DNELs;final draft, ECETOC, 2010).

Adaptation of dose descriptor:

LOAECrat, inhal., local = 380mg/m3for local effects

NOAECcorrected = LOAECrat, inhal., local / 5 = 380mg/m / 5 = 76 mg/m3

Following assessment factors were applied:

allometric scaling

1

local effects are independent of metabolic rate

remaining uncertainties

2/5

for quantitative differences in deposition, airflow patterns, clearance rates and protective mechanisms, in case e.g. local irritation due to physicochemical property is the cause of toxicity

Intraspecies worker

1/3

respiratory tract irritation is independent of individual metabolic variances

Exposure duration

1

for concentrations leading to an unpronounced effect without specific pathology local effects on the respiratory tract are more related to the concentration than to the total dose

Quality of whole database

1

 

Dose-response

1

 

DNELinhal., local, chronic:     10 mg/m3 (ca. 2.65 ppm)

 

 

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

No exposure of the general population needs to be supported by the CSR/CSA.