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EC number: 201-071-2 | CAS number: 77-94-1
The calculation of the DNELs is performed in accordance with the principles given in ECHA (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.” and including the advice given in the "Guidance on Assessment factors to derive a DNEL", ECETOC Technical Report No. 110, October, 2010.
Available dose descriptors:
For tributyl citrate, DNELs are needed for chronic exposure by the oral (only for consumers), dermal (for workers and consumers) and inhalation routes of exposure (workers and consumers). Inhalation is not relevant route of exposure due to the low vapour pressure of the substance. Since tributyl citrate does not represent an acute hazard (not classified for acute toxicity), no DNELs for acute systemic toxicity need to be derived.
No DNELs are needed for local effects because there is no dose-response and route-specific information on these endpoints. Long-term systemic DNELs cover sufficiently local effects.
From all available data for the different human health endpoints it is clear that tributyl citrate exerts its effect by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the related substances, reflecting the routes, duration and frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment. There are following annotations for each endpoint:
- Since the substance is not acutely toxic by dermal route of exposure, no DNEL needs to be derived. This is based on a LD50 greater than 2000 mg/kg bw (as evident from all weight of evidence pieces).
- Acute DNELs for inhalation (systemic and local) are not necessary since there is no acute toxic hazard by inhalation.
- A qualitative approach in hazard assessment for eye and skin irritation/corrosion and skin sensitization is used because no dose descriptors are available on these endpoints.
- For the non-threshold endpoints (mutagenicity and carcinogenicity) no DNELs can be derived because a No-Effect Level could not be established from the relevant studies. Hence, the hazard characterization is based on a qualitative approach.
- There is no animal data on repeated dermal or inhalation exposure. To cover this endpoint, NOAEL established in a 13 -week feeding study in rats (Rosner, 2003) has been used to calculate the long-term DNELs by route-to-route extrapolation.
- No DNELs for reprotoxic effects are needed because tributyl citrate is not toxic for reproduction.
First of all, available dose descriptors were converted into a correct starting point to take into account differences in routes of exposure between experimental animals and humans and differences in human and animal exposure conditions. Consecutively, the assessment factors have been applied to the correct starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.
The assessment factors are applied in accordance with ECETOC Technical Report No 110 (recent document) (ECETOC Report No 86 is referenced in Table R.8-19 of ECHA guidance document).
Modification of the relevant dose descriptors to the correct starting point:
Based on physico-chemical properties as well as on the available toxicity data, 100% dermal absorption is considered for the target substance (worst case). The dermal absorption in rats and in humans is assumed to be the same since no information for dermal absorption of target chemical in rats and in humans is available. In case of oral-to-inhalation extrapolation, 50% oral absorption is assumed for oral absorption in rats and 100% absorption for inhalation is assumed in humans (worst case; according to the ECETOC Report No 110, 100% absorption for inhalation can be used in case of absence of substance specific data for absorption).
Oral-to-inhalation extrapolations are performed to assess long-term inhalation effects in humans. In addition, oral-to-dermal extrapolations are conducted to assess long-term dermal effects in humans.
Exposure time differed in workers and in the 13 -week range-finding feeding study in rat. Rats were exposed to the test substance once daily via diet, while workers are exposed 8h daily (5days/week). However, the dose descriptor (the NOAEL of 1000 mg/kg bw) was not adjusted to 8h exposure because exposure time is not really relevant for the systemic dose resulting from only dermal exposure.
Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the 13 -week feeding study in rats was used to assess inhalation exposure in humans. 0.38 m³/kg/day is the standard respiratory volumes in rats during 8h exposure. 6.7 and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, respectively.
Applying of assessment factors:
The species-specific default assessment factor of 4 for allometric scaling for rats is applied in case of usage of the oral NOAEL to derive dermal DNEL.
No allometric scaling factor is applied in case of oral-to-inhalation extrapolation.
No additional assessment factor is applied for remaining interspecies differences in toxicodynamics between rats and humans. This is the approach described in the ECETOC report, which states that this is already covered by the factor introduced for allometric scaling.
Assessment factor of 3 is applied for workers for all endpoints and for all exposure routes. The factor of 5 is used in the process of DNEL-calculation for general population.
Extrapolation of duration:
An assessment factor of 2 was applied in case of the 13 -week feeding study to extrapolate to a chronic study.
Quality of whole data base:
An assessment factor for uncertainties in the quality of the data base is regarded to be 2, which is mainly based on the use of read-across substances to cover the data gaps of tributyl citrate, or because the data available for tributyl citrate were very old and without detailed information.
Issues related to dose response:
Assessment factor of 1 was used.
Calculation of endpoint-specific DNELs for workers
Long-term exposure - systemic effects (dermal)
NOAEL of 1000 mg/kg bw from 13 -week feeding study in rats (Rosner, 2003) has been used for the DNEL derivation:
1. Corrected NOAEL = oral rat NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal rat/ ABS dermal human) = 1000 mg/kg bw x (100%/100%) x (100% / 100%) = 1000 mg/kg bw. There are no human and rat values for dermal absorption available therefore dermal absorption in rats and humans is assumed to be the same and equal 100% (worst case).
2. DNEL = 1000 mg/kg bw /(4 x 3 x 2 x 2) = 20.8 mg/kg bw/day. AFs are: 4 -interspecies, 3 - intraspecies, 2 -subchronic study, 2- for quality of data base as read-across substance data is used.Overall AF amounts to 48.
Long-term exposure - systemic effects (inhalation)
13 -week range-finding feeding study in rats (Rosner, 2003) has been used for the DNEL derivation:
1.Corrected NOAEC = oral rat NOAEL x (1/0.38m³) x (ABS oral-rat/ABS inh-human) x (6.7/10)m³ = 1000 mg/kg bw x (1/0.38m³) x (50%/100%) x (6.7/10)m³ = 881.6 mg/m³.
2. DNEL = 881.6 mg/m³/ (3 x 2 x 2) = 73.5 mg/m³. AFs are: 3 - intraspecies; 2 - subchronic study, 2 - for quality of data base as read-across substance data is used.Overall AF amounts to 12.
The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are additional considerations or deviations for:
Modification of the starting point:
The oral absorption in rats and in humans is assumed to be the same since no information for oral absorption for target chemical in rats and in humans is available.
- No differences in the respiratory volumes under normal conditions and by light activity in humans were taken into account. Standard respiratory volume of 1.15 m³ for rats during 24 hours was applied in case of oral-to-inhalation extrapolation.
- A higher assessment factor of 5 (in place of 3 for workers) for intraspecies variation/differences of human population was used.
Calculation of endpoint-specific DNEL for general population
Long-term exposure - systemic effects (oral)
13 -week feeding study in rats (Rosner, 2003) has been taken for the DNEL derivation:
1. Corrected NOAEL = oral rat NOAEL x (ABS oral-rat/ABS oral-human) = 1000 mg/kg bw x 1 = 1000 mg/kg bw.
2. DNEL = 1000 mg/kg bw /(4 x 5 x 2 x 2) = 12.5 mg/kg bw/day. AFs are: 4 -interspecies, 5 - intraspecies, 2 - subchronic study, 2 - for quality of data base as read-across substance data is used. Overall AF amounts to 80.
1. Corrected NOAEL = oral rat NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal rat/ ABS dermal human) = 1000 mg/kg bw x 1 x 1 = 1000 mg/kg bw. There are no values for dermal absorption available therefore dermal absorption in rats and humans is assumed to be the same.Dermal absorption = oral absorption (worst-case)
2. DNEL = 1000 mg/kg bw /(4 x 5 x 2 x 2) = 12.5 mg/kg bw/day. AFs are: 4 -interspecies, 3 - intraspecies, 2 - subchronic study, 2 - for quality of data base as read-across substance data is used.Overall AF amounts to 80.
1.Corrected NOAEC = oral rat NOAEL x (1/1.15m³/kg bw/day) x (ABS oral-rat/ABS inh-human) = 1000 mg/kg bw x (1/1.15m³) x (50%/100%)= 575 mg/m³ (1.15 is standard respiratory volume (m³/kg bw) of rats during 24 h exposure.)
2. DNEL = 575 mg/m³/ (5 x 2 x 2) = 28.8 mg/m³. AFs are: 5 - intraspecies; 2 - subchronic study, 2 - for quality of data base as read-across substance data is used. Overall AF amounts to 20.
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