Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Additional information - workers

Identity of the substance and approach to meeting the data requirements

The substance Polyol TD consists of three components:

CTF (5 -ethyl-1,3 -dioxane-5 -methanol)

DMP (2-ethylpropane-1,3-diol)

TMP (propylidynetrimethanol)

The relevant toxicological data requirements are met by a combination of data for Polyol TD and data for the individual components. The components DMP and TMP are considered to be sufficiently similar for read-across to be appropriate. Therefore, for each relevant data requirement, data are provided for Polyol TD or DMP/TMP and CTF.

Toxicokinetics

No specific studies are required. According to Column 1 of Annex VIII of the REACH regulation, Assessment of the toxicokinetic behaviour of the substance (to the extent that can be derived from the relevant available information) is required and this is provided. An adequate assessment of the basic toxicokinetics of the components of the substance can be made from the existing toxicity data and theoretical considerations, without the need for additional specific testing.

The substance consists of three components, therefore the likely toxicokinetic behaviour of each of the components therefore needs to be considered.

CTF

Based on an assessment of its physicochemical properties, CTF is likely to be extensively absorbed following oral and inhalation exposure. Dermal absorption is also likely but may be less extensive. The substance satisfies Lipinski's rule of 5 (OECD QSAR Toolbox). CTF is a water-soluble small molecule and is therefore is likely to be rapidly and extensively distributed in the blood following oral, dermal or inhalation exposure. DMP can be predicted to be extensively metabolised by a combination of hydrolytic and oxidative reactions. The OECD QSAR Toolbox predicts a total of 44 low molecular weight hepatic metabolites. Rapid urinary excretion of the low molecular weight and water-soluble metabolites of CTF is predicted; bioaccumulation is therefore unlikely

TMP

Based on an assessment its physicochemical properties, TMP is likely to be extensively absorbed following oral and inhalation exposure. Dermal absorption is also likely but may be less extensive. The substance satisfies Lipinski's rule of 5 (OECD QSAR Toolbox). TMP is a highly-water soluble small molecule and is therefore is likely to be rapidly and extensively distributed in the blood following oral, dermal or inhalation exposure. TMP can be predicted to be metabolised by sequential oxidation of the alcohol groups, in common with related substances; OECD QSAR Toolbox predicts a total of 10 low molecular weight and water-soluble hepatic metabolites. Rapid urinary excretion of the low molecular weight and water-soluble metabolites of TMP is predicted; bioaccumulation is therefore unlikely.

DMP

Based on an assessment of its physicochemical properties, DMP is likely to be extensively absorbed following oral and inhalation exposure. Dermal absorption is also likely but may be less extensive. The substance satisfies Lipinski's rule of 5 (OECD QSAR Toolbox). DMP is a highly water-soluble small molecule and is therefore is likely to be rapidly and extensively distributed in the blood following oral, dermal or inhalation exposure. DMP can be predicted to be metabolised by sequential oxidation of the alcohol groups, in common with related substances; OECD QSAR Toolbox predicts a total of 14 low molecular weight and water-soluble hepatic metabolites. Rapid urinary excretion of the low molecular weight and water-soluble metabolites of DMP is predicted; bioaccumulation is therefore unlikely.

Acute toxicity

The substance Polyol TD is of low toxicity. An acute oral LD50 of >2000 mg/kg bw is reported. The dermal LD50 of TMP is reported to be >10000 mg/kg bw. A waiver is proposed for acute inhalation toxicity in accordance with Column 2 of Annex VIII of the REACH Regulation as acute toxicity data are available for the oral and dermal routes. Inhalation is not predicted to be a significant route of exposure based on the physicochemical properties of the substance.

Irritation/corrosion

Only very slight skin irritation was seen in a rabbit skin irritation study performed with CTF; a negative EpiSkin assay is available for DMP. An in vivo eye irritation study with CTF indicates that this component is an eye irritant; no additional testing is proposed for animal welfare reasons and it is assumed that Polyol TD is an eye irritant and will therefore be classified as such.

Skin sensitisation

Negative LLNA results are reported for the components DMP and CTF. There is no evidence from experience of use that the substance Polyol TD or its components has the potential to cause respiratory sensitisation in exposed workers.

Repeated dose toxicity

Oral studies are available for the component TMP and therefore (by read-across) for the component DMP. A 90-day oral repeat toxicity study with CTF in the rat (OECD 408) is proposed in order to address the toxicity of this component and fully characterise the toxicity of the substance. Waivers are proposed for repeated dermal and inhalation toxicity, in accordance with Column 2 of Annex VIII/IX of the REACH Regulation. The repeated dose toxicity of the substance has been adequately elucidated by the oral route, with additional testing proposed for CTF. Further testing by the additional routes of exposure is not required.

The oral toxicity of trimethylolpropane (TMP 99) was determined in a 90 day feeding study with male and female rats (de Knecht-van Eekelen & van der Meulen, 1969). The test substance was fed at 0, 0.03, 0.1, 0.3 and 1.0% in stock diet to groups of 10 male and 10 female rats. Rats were sacrificed and subject to necropsy at the end of the feeding period. General appearance and behaviour, body weight gain, food intake and efficiency, blood serum enzyme activities, serum protein content and urine composition were not affected by treatment. Haemoglobin content was decreased in 1.0% females, whilst packed cell volume and red blood cell counts were decreased in females at 0.3 and 1.0%. Blood smears contained normoblasts and white blood cell fragments in both sexes at 1.0% and normoblasts in females at 0.3%. The relative weight of the spleen was increased in both sexes. Liver, kidney and ovary weights were increased in 1.0% females. Pituitary weight was increased in males at 1.0%. Gross examination at autopsy revealed enlarged dark spleens in both sexes at 1.0%. Histopathology revealed increased numbers of cells in the red pulp of the spleen, and in the liver Kupffer cells laden with pigment, sinusoids containing normoblasts and too many small lymphocytes were revealed in the 1.0% group. It was therefore concluded that the 90 day NOAEL of TMP 99 is 0.1% in the diet, for male and female rats. This dose level is calculated to be equivalent to 100 mg/kg bw/d, using default conversion factors.

A combined repeat dose and reproductive/developmental toxicity screening test was conducted in male and female Slc: SD rats (MHLW, 1994), according to GLP. Trimethylolpropane was administered daily to the rats by gavage, at doses of 0 (vehicle control; distilled water), 12.5, 50, 200, 800 mg/kg bw/day. The rats were dosed for 2 weeks prior to mating, during the mating period and pregnancy until day 4 of lactation (approximately 45 days). There were no deaths or abnormal clinical signs attributable to treatment. The body weights of males and females in the 800 mg/kg group were lower than those of the control group during the pre-mating period. Food consumption was not affected by treatment. Haematology and clinical chemistry investigations did not reveal any treatment-related abnormalities. Absolute and relative liver weights were significantly elevated in the 800 mg/kg males, and increased but not significantly in the 800 mg/kg females. Necropsy revealed hypertrophy of the liver in 3 male 800 mg/kg rats. Histopathological examination revealed no definite morphological lesions. Slight basophilic alteration of the renal tubular epithelial cells was observed in 1 female receiving 50 mg/kg, in 2 females receiving 200 mg/kg, and in 5 females receiving 800 mg/kg. These changes were not unequivocally attributable to the test substance administration, because of their limited distribution and limited degree, and because similar lesions were observed in male rats of all groups including the controls. The NOAEL was therefore considered to be 200 mg/kg bw/d in both sexes. The oral toxicity of trimethylolpropane (TMP) was studied in a 28 -day range finding test (Wijnands & Feron, 1969). The substance was fed at 0, 0.3, 1.0, 2.0 and 4.0% in the diet to albino rats, for a period of 28 days.

The LOEL = ca. 965 mg/kg bw/day (1%). Reduced body weights and decreased food efficiency were observed at the 4% level in both sexes. Haematology analyses conducted on day 25 revealed reduced haemoglobin values at the 2% and 4% levels. Red blood cell counts were decreased dose-dependently in the 1%, 2% and 4% groups. White blood cell counts were increased in the 4% group. Enlargement of the spleen and liver was observed at necropsy in the 2% and 4% animals. Relative liver, kidney, heart and spleen weights were significantly and dose-dependently increased in the 1%, 2% and 4% groups. Histopathological examination revealed treatment-related abnormalities in the spleen and liver of rats in the 1%, 2% and 4% group. Slight abnormalities in the kidney were noted in the 2% and 4% males.

The 28 day NOAEL is considered to be 0.3% (ca. 275 mg/kg bw/day).

Genetic toxicity

The genetic toxicity of Polyol TD is adequately characterised using a combination of studies on the substance and its components. A negative Ames test is reported for Polyol TD (May, 2010). Negative results are reported for the components CTF and DMP in studies of clastogenicity in CHO cells in vitro (Murie, 2010); negative results are also reported for the components CTF and DMP in mouse lymphoma assays (Riach, 2010). All studies are modern and compliant with GLP and the appropriate guidelines and involved testing up to the respective limit concentrations. The available studies therefore adequately demonstrate the absence of genotoxicity of Polyol TD: read-across is proposed from the DMP to the other component, TMP. No further studies are therefore required.

Toxicity to reproduction

No evidence of any effects on reproduction were seen in a combined reproductive /developmental toxicity screening study with the component TMP at a dose level of 800 mg/kg bw/d. The absence of histopathological changes in reproductive organs in repeated dose toxicity studies with TMP and the absence of specific reproductive effects in a screening study indicate that the substance will not have any adverse effects on fertility. By read-across, no effects are predicted for the component DMP. There are currently no data on the repeated dose toxicity of the component CTF, however a testing proposal for a 90-day study is included in this dossier. This study will include full assessment of relevant reproductive system tissues, and the need for specific testing for reproductive toxicity will be reconsidered in light of the findings in this study. Based on these considerations, no further testing is considered to be required for assessment of reproductive toxicity of Polyol TD at present.

The NOAEL for developmental toxicity in the TMP screening study was also 800 mg/kg bw/d. Testing proposals are included for developmental toxicity studies with the components TMP and CTF; the study with TMP is also intended to cover (by read-across) the developmental toxicity of the other component, DMP.

DNEL derivation [Workers]

Based on the data available, the substance is of low acute toxicity, is not a skin irritant or sensitiser and is not mutagenic, a developmental or reproductive toxin. Classification is proposed for eye irritation based on data for the component CTF.

The relevant (lowest) NOAEL for DNEL derivation is the NOAEL of 100 mg/kg bw/d from a 90-day rat study with TMP. No repeated dose toxicity, reproductive or developmental toxicity data are available for the component CTF, however comparable toxicity of CTF with DMP/TMP is assumed. This assumption and any implications for the derivation of the DNEL values will be re-assessed when the proposed 90 -day toxicity study with CTF is available.

Local effects

DNEL values for local effects are not derived. The substance is not a skin irritant or sensitiser but is an eye irritant. However relevant dose-response data are not available and a quantitative dose descriptor cannot be determined. Exposure should be avoided by the use of appropriate protective equipment.

Systemic effects

The substance is of low systemic toxicity. No acute toxicity hazard resulting in classification has been identified, therefore a DNEL for acute systemic effects is not proposed.

The relevant endpoint is the NOAEL of 100 mg/kg bw/d from the 90-day oral rat study with TMP; no treatment-related adverse effects were seen at this dose level.

The use of assessment factors according to ECETOC guidance is considered below:

Intraspecies: a default value of 4 (allometric scaling: rat) is proposed.

Interspecies: a default value of 3 is proposed (default for workers)

Exposure duration: a default value of 2 is proposed for extrapolation from a sub-chronic study to chronic exposure. This represents a conservative approach, as the data indicate low toxicity following single and repeated exposures

Dose-response: a default value of 1 is proposed as, based on the available data, the substance is of low toxicity

Quality of the data base: a default factor of 1 is used

An overall assessment factor of 24 for long-term effects is therefore calculated for workers.

[Dermal]

Following the default (worst case) assumption that dermal absorption will not exceed oral absorption, an equivalent dermal NOAEL of 100 mg/kg bw/d is derived.

Applying the assessment factor of 24 to the dermal NOAEL equivalent NOAEL of 100 mg/kg bw/d gives a dermal DNEL value of 4.2 mg/kg bw/d for long-term effects.

[Inhalation]

Following the default assumption that inhalation absorption is twice oral absorption, an equivalent inhalation NOAEL of 50 mg/kg bw/d is derived. This is equivalent to 350 mg/m3 (assuming 70 kg bodyweight and a breathing rate of 1.25 m3/h, 8h/day).

Applying the assessment factor of 24 to the inhalation NOAEC of 350 mg/m3gives an inhalation DNEL value of 14.6 mg/m3for long-term effects.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

DNEL derivation [General Population]

Based on the data available, the substance is of low acute toxicity, is not a skin irritant or sensitiser and is not mutagenic, a developmental or reproductive toxin. Classification is proposed for eye irritation based on data for the component CTF.

The relevant (lowest) NOAEL for DNEL derivation is the NOAEL of 100 mg/kg bw/d from a 90 -day rat study with TMP. No repeated dose toxicity, reproductive or developmental toxicity data are available for the component CTF, however comparable toxicity of CTF with DMP/TMP is assumed. This assumption and any implications for the derivation of the DNEL values will be re-assessed when the proposed 90 -day toxicity study with CTF is available.

Local effects

DNEL values for local effects are not derived. The substance is not a skin irritant or sensitiser but is an eye irritant. However relevant dose-response data are not available and a quantitative dose descriptor cannot be determined. Exposure should be avoided by the use of appropriate protective equipment.

Systemic effects

The substance is of low systemic toxicity. No acute toxicity hazard resulting in classification has been identified, therefore a DNEL for acute systemic effects is not proposed.

The relevant endpoint is the NOAEL of 100 mg/kg bw/d from the 90-day oral rat study with TMP; no treatment-related adverse effects were seen at this dose level.

The use of assessment factors according to ECETOC Guidance is considered below:

Intraspecies: a default value of 4 (allometric scaling: rat) is proposed.

Interspecies: a default value of 5 is proposed for the general population

Exposure duration: a default value of 2 is proposed for extrapolation from a sub-chronic study to chronic exposure. This represents a conservative approach, as the data indicate low toxicity following single and repeated exposures

Dose-response: a default value of 1 is proposed as, based on the available data, the substance is of low toxicity

Quality of the data base: a default factor of 1 is proposed.

An overall assessment factor of 40 for long-term effects is therefore calculated for the general population.

[Oral]

Applying the assessment factor of 40 to the oral NOAEL of 100 mg/kg bw/d gives an oral DNEL value of 2.5 mg/kg bw/d for long-term effects.

 [Dermal]

Following the default (worst case) assumption that dermal absorption will not exceed oral absorption, an equivalent dermal NOAEL of 100 mg/kg bw/d is derived. Applying the assessment factor of 40 to the dermal NOAEL gives a dermal DNEL value of 2.5 mg/kg bw/d for long-term effects.

 [Inhalation]

Following the default assumption that inhalation absorption is twice oral absorption, an equivalent inhalation NOAEL of 50 mg/kg bw/d is derived. This is equivalent to 175 mg/m3(assuming 70 kg bodyweight and a breathing rate of 20 m3/day).

Applying the assessment factor of 40 to the inhalation NOAEC of 175 mg/m3 gives an inhalation DNEL value of 4.4 mg/m3for long-term effects.