Reaction mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane

Endpoint summary

Description of key information

There are no available acute toxicity data for the registered substance "Reaction Mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane". Therefore, data have been read-across from its constituents, HMDS, L3, L4 and L5.

Oral route:

- In a 28-day repeated oral gavage study (Shin-Etsu Chemical Company, 1994) in rats, conducted according to the appropriate OECD Test Guideline 407 and in compliance with GLP, the NOAEL for hexamethyldisiloxane (HMDS) was 160 mg/kg bw/day based on reduced food consumption, reduced body weight gain, increase organ weights (liver, spleen and brain), changes to white cell count and corpuscular parameters in male rats that received 640 mg/kg bw/day.  

- In an OECD Test Guideline 407 study (Harlan, 2010), performed in compliance with GLP in rats, the potential oral toxicity of octamethyltrisiloxane (L3) was evaluated in Sprague Dawley rats. Animals were exposed to target concentrations of 0, 5, 25, 250 and 1000 mg/kg bw/day by oral gavage for 28 days. Based on the findings in the liver (brown pigment accumulation accompanied by periportal chronic inflammation and bile duct proliferation), it was concluded that males were more affected than the females by treatment with octamethyltrisiloxane (L3). Under polarised light some pigment accumulations show birefringence, but this finding was not consistent in size or between animals. Pigment accumulation was considered to be an adverse finding due to observed secondary periportal chronic inflammation and bile duct proliferation. In the absence of clear reversibility of microscopic liver findings, the NOAEL of the test item was considered to be 25 mg/kg/day in the males and 250 mg/kg/day in the females.

- In a key 28-day oral gavage study conducted according to OECD Test Guideline 407 and in compliance with GLP (Dow Corning Corporation, 2010a) the NOAEL for decamethyltetrasiloxane (L4) was 25 mg/kg bw/day based on significantly elevated mean absolute liver weights, mean liver-to-body weight ratios and mean liver-to-brain weight ratios in males and females treated with 250 mg/kg bw/day and 1000 mg/kg bw/day (p<0.05 or p<0.01) and brown pigment accumulation which was considered to be an adverse finding, due to secondary periportal chronic inflammation and bile duct proliferation.

- In a 28-day oral study performed according to OECD Test Guideline 407 (DCC, 2010), 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.

Inhalation route:

- In a two-generation reproductive toxicity study on hexamethyldisiloxane (HMDS), conducted according to OECD Test Guideline 416 and in compliance with GLP (reliability score 2) (WIL Research, 2006), there were microscopic liver findings in the F0 males of the 5000 ppm group and F1 males and females in the 5000 and 1600 ppm groups. These hepatic findings were considered to be human relevant and adverse, therefore the repeat dose NOAEC was considered to be 400 ppm (2657 mg/m³).

- Whole body exposure of SD rats to octamethyltrisiloxane (L3) at 95, 400 or 3200 ppm for 90 days resulted in liver and kidney changes (Harlan, 2011). In the liver hepatocyte hypertrophy and accumulation of brown pigment in the bile ducts with associated periportal inflammation and bile duct proliferation were noted. In the kidneys tubular hypertrophy was noted and associated with minor changes in salt balance and plasma protein levels. Hyaline droplets noted represented alpha-2u-globulin accumulation. Based on the secondary effects of pigment accumulation noted in the liver at 3200 ppm the NOAEC was considered to be 400 ppm.

- In the 90-day inhalation study (Dow Corning Corporation, 2010b) conducted according to OECD Test Guideline 413 and in compliance with GLP, inhalation of decamethyltetrasiloxane (L4) at concentrations of 70 and 400 ppm did not result in any effects attributable to treatment. The NOAEC was therefore considered to be at least 400 ppm, the highest concentration tested.

Dermal route:

- In a 28-day repeated dose dermal toxicity study in rats (Dow Corning Corporation, 1993) for HMDS, conducted according to a protocol similar to OECD Test Guideline 410, and in compliance with GLP, the NOAEL was considered to be 1000 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

25 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

As a worse-case the lowest NOAEL 25 mg/kg/day based on adverse effects in male rats is selected for Reaction Mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane was based on a 28 day repeated oral toxicity study for the constituent L3. The oral DNEL is derived based on NOAELfrom this study.

System:

gastrointestinal tract

Organ:

liver

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

1 335 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

The NOAEC for Reaction Mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane is selected based on a 2 -generation reproductive toxicity study for the constituent HMDS. In this study, the repeated dose inhalation route systemic toxicity NOAEC was considered to be 400 ppm (2657 mg/ m³) based on the adverse hepatoxicity findings observed in the F1 generation.
The following correction was made to the NOAEC: Modification for experimental exposure duration (6 h in study to 8 h in workers): 0.75. Modification for respiratory volume (rat to human): 6.7/10. Therefore the corrected NOAEC for repeat dose effects via the inhalation route is: 2657*0.75*(6.7/10) = 1335 mg/ m³.

System:

other: gastrointestinal

Organ:

liver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

664 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

The following correction was made to the NOAEC: Modification for experimental exposure duration (6 h in study to 24 h in General Population): 6/24 = 0.25. Therefore the corrected NOAEC for repeat dose effects via the inhalation route is: 2657*0.25 = 664 mg/ m³(based on a 2 -generation reproductive toxicity study for the constituent HMDS).

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

Study duration:

subacute

Species:

rat

Additional information

There are no available repeated toxicity studies for the registered substance "Reaction Mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane". Therefore, data have been read-across from its following four constituents:

 

1) HMDS: hexamethyldisiloxane (CAS 107-46-0)

2) L3: octamethyltrisiloxane (CAS 107-51-7)

3) L4: decamethyltetrasiloxane (CAS 141-62-8)

4) L5: dodecamethylpentasiloxane (CAS 141-63-9

For each endpoint, several studies are available for the above constituents of the registered substance.The most relevant and the recent key studies are selected for this assessment.

Oral studies:

In the repeated dose study for the oral route (Shin-Etsu Chemical Company, 1994) Sprague-Dawley rats (6 animals/sex/dose) were given HMDS (in olive oil) by oral gavage at a dose of 0, 8, 40, 160 or 640 mg/kg bw/day, 7 days/week for 28 days. The exposure period was followed by a 14 -day observation period for the control, 160 and 640 mg/kg bw/day groups. The animals were observed throughout for signs of toxicity, their body weights and food consumption were measured, and haematology, clinical chemistry, urinalysis, macroscopic and microscopic examinations were conducted. Body weight gain and food consumption were reduced from day 19 to 28 in males of the highest dose group. Additionally, in males of the highest dose group, white blood cell count was increased and mean corpuscular volume and mean corpuscular haemoglobin were decreased at the end of the exposure period. At the end of the recovery period white blood cell count and platelet count were increased, and haemoglobin concentration and haematocrit value were decreased in this same group of animals. At the end of the dosing period absolute and relative liver weights, relative spleen weight and relative brain weight were increased in males of the 640 mg/kg bw/day group. At the end of the recovery period absolute and relative spleen weights and relative liver weight were increased in males of the 640 mg/kg bw/day group. There were also effects in male rats that were related to alpha- 2u-globulin nephropathy and can therefore be dismissed as species-specific and therefore not relevant to humans (Dow Corning Corporation, 2007). The NOAEL was 160 mg/kg bw/day.

In an OECD Guideline 407 study (Harlan 2010), performed to GLP, the potential oral toxicity of octamethyltrisiloxane was evaluated in Sprague Dawley rats. Animals were exposed to target concentrations of 0, 5, 25, 250 and 1000 mg/kg bw/day by oral gavage for 28 days.Based on the findings in the liver (brown pigment accumulation accompanied by periportal chronic inflammation and bile duct proliferation), it was concluded that males were more affected than the females by treatment with octamethyltrisiloxane (L3).Under polarised light some pigment accumulations show birefringence, but this finding was not consistent in size or between animals. Pigment accumulation was considered to be an adverse finding due to observed secondary periportal chronic inflammation and bile duct proliferation.In the absence of clear reversibility of microscopic liver findings, the NOAEL of the test item was considered to be 25 mg/kg/day in the males and 250 mg/kg/day in the females.

In a 28-day oral gavage study conducted to OECD 407 and to GLP (Dow Corning Corporation, 2010a) the NOAEL for L4 was 25 mg/kg bw/day in males and females based on significantly elevated mean absolute liver weights, mean liver-to-body weight ratios and mean liver-to-brain weight ratios in males and females treated with 250 mg/kg bw/day and 1000 mg/kg bw/day (p<0.05 or p<0.01). In addition, some hepatic brown pigment accumulation in the bile duct was observed after four weeks of treatment in five males at 1000 mg/kg bw/day and one male at 250 mg/kg bw/day. Under polarised light some pigment accumulations show birefringence, but this finding was not consistent in size or between animals. Pigment accumulation was considered to be an adverse finding due to the secondary periportal chronic inflammation and bile duct proliferation observed in five males at 1000 mg/kg bw/day. In females at 1000, 250 and 25 mg/kg bw/day, periportal fatty change was not accompanied by degeneration or inflammation and was considered to be non-adverse. After the recovery period, the severity of perilobular fatty change was reduced in the females previously treated at 1000 mg/kg bw/day.

In a GLP study performed according to OECD Test Guideline 407 with L5, 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 L5 via the oval (gavage) route for 28 days. Doses of 0, 25, 250 or 1000 mg/kg bw/day were administered. Over the course of the study, a range of parameters were investigated (mortality, clinical signs of toxicity, food consumption, body weight, behaviour). During week 4, a functional observation battery was carried out and grip strength and locomotor activity tests were performed. Necropsy was performed immediately after treatment at 28 days, or after a recovery period of 14 days (satellite groups), and macro- and microscopic analyses were performed. Blood and urine were taken for analysis immediately after treatment and after the recovery period. Under the conditions of this study, no biologically-significant, treatment-related effects were observed at any dose. A NOAEL of >=1000 mg/kg bw/day was determined for this study.

Inhalation route:

In a two-generation reproductive toxicity study (WIL Research Laboratories, 2006) conducted via the inhalation route, Sprague-Dawley rats (30 animals/sex/dose) were exposed to HMDS at a concentration of 100, 400, 1600 or 5000 ppm, 6 hours/day, 7 days/week. Exposure started at least 70 days prior to mating, throughout mating, during gestation through to gestation day 20, therefore animals were exposed for at least 90 -days. The NOAEC for parental toxicity relevant to humans was 400 ppm (2657 mg/m3) based on microscopic liver findings (golden-brown pigment in the periportal areas) in the F0 males of the 5000 ppm group and F1 males and females in the 5000 and 1600 ppm groups. Although this was a reproductive toxicity study, endpoints relevant to repeat dose toxicity were evaluated and among the many repeat dose inhalation studies for HMDS, the hepatic findings observed in this study were recorded at the lowest exposure concentration.

Whole body exposure of SD rats to octamethyltrisiloxane at 95, 400 or 3200 ppm for 90 days resulted in liver and kidney changes (Harlan, 2011). In the liver hepatocyte hypertrophy and accumulation of brown pigment in the bile ducts with associated periportal inflammation and bile duct proliferation were noted. In the kidneys tubular hypertrophy was noted and associated with minor changes in salt balance and plasma protein levels. Hyaline droplets noted represented alpha-2u-globulin accumulation. Based on the secondary effects of pigment accumulation noted in the liver at 3200 ppm the NOAEC was considered to be 400 ppm for L3.

 

In a 90-day inhalation study conducted to OECD 413 and to GLP (reliability score 1) inhalation of L4 at concentrations of 70 and 400 ppm were well tolerated. 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 NOAEL for L4 for systemic toxicity in male and female rats is at least 400 ppm.

Dermal route:

In a dermal repeated dose toxicity study (Dow Corning Corporation, 1993) Sprague-Dawley rats (10 animals/sex/dose) were exposed to undiluted HMDS under occlusive conditions at a dose of 0, 100, 500 or 1000 mg/kg bw/day, 6 hours/day, 5 days/week for 28 days. The animals were then observed and examined according to OECD test guideline 410, except that urinalysis was not included. Overall, the NOAEL is considered to be ≥1000 mg/kg bw/day. Although the observed body weight gain and food consumption differences from control were greater than 10%, the difference in absolute body weight between the control and 1000 mg/kg bw/d group was less than 10%. There were also significantly lower liver and kidney weights when compared to brain weight. However, based on the weight of evidence evaluation of the effects observed at 1000 mg/kg/day, these are not considered adverse and therefore, the NOAEL is 1000 mg/kg/day.

Read-across justification

 

Reaction Mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane (EC No 946-797-7) belongs to the structural class of siloxanes. Studies for toxicity endpoints are available for all of its constituents. The available studies, as well as key physicochemical properties, are summarised in Table 1. The most recent and reliable studies for the substance’s constituents were chosen for weight of evidence.

 

Table 1: Key data for constituents

Substance	HMDS	L3	L4		L5
Chemical name	Hexamethyldisiloxane	Octamethyltrisiloxane	Decamethyltetrasiloxane		Dodecamethylpentasiloxane
CAS number	107-46-0	107-51-7	141-62-8		141-63-9
Molecular weight	162.38	236.54	310.69		384.84
Water solubility (mg/l)	0.93	0.034	6.7E-03		7.5E-05
Log Kow	5.1	6.6	8.1		9.4
Vapour pressure (Pa at 25°C)	5500	530	73		7.8
Acute oral toxicity (LD50,mg/kgbw)	>12,000 (BRRC, 1982)	>2000 (Dow Corning Corporation, 2004a)	-		-
Acute inhalation   toxicity (LC50,mg/l)	approximately 106 (Dow Corning Corporation,1997)	>22.6 (Dow Corning Corporation, 2004c)	-		-
Acute dermal toxicity   (LD50,mg/kgbw)	>2000 (IFREB, 1982)	>2000 (Dow Corning Corporation, 2004b)	>2000 Corning Corporation, 2009c)	(Dow	>2000 Corning Corporation, 2009a)	(Dow
Skin irritation	Not irritant (Dow Corning Corporation, 1996)	Not irritant (Dow Corning Corporation, 1999)	Not irritant Corporation, 2009e)	(Dow Corning	Not irritant Corporation, 2009b)	(Dow Corning
Eye irritation	Not irritant(Stauffer, 1973)	-	Not irritant (Dow Corning Corporation, 2000)		-
Skin sensitisation	Not sensitising (Dow Corning Corporation,1992)	Not sensitising(RCC, 1999)	-		-
Repeated      dose toxicity
oral	NOAEL:  160 mg/kg bw/day in rats  (Shin-EtsuChemical Company,1994)	NOAEL: 25 mg/kg/ day in males and 250 mg/kg/day in females rats (Harlan, 2010)	NOAEL: 25 mg/kg bw/day in males and at least 1000 mg/kg bw/ day in femalesrats (Dow Corning Corporation, 2010a)		NOAEL of >=1000 mg/kg bw/day in rats (Dow Corning Corporation, 2010)
Inhalation	NOAEC: 400 ppm (Wil       Research, 2006)	NOAEC: 400 ppm (Harlan, 2010)	NOAEL: >= 400 ppm (Dow          Corning Corporation, 2010)		-
Dermal	NOAEL:              1000 mg/kg  bw/day (Dow    Corning Corporation, 1993)	-	-		-
Mutagenicity
Bacterial	Negative              (Hita Laboratories, 1994)	Negative (BioReliance, 2008)	Negative (BioReliance, 2005)		-
In          Vitro Mammalian Cytogenicity	Negative              (Hita Laboratories, 1995)	Negative (BioReliance, 2008)	-		Negative (Bioservice, 2014)
In          Vitro Mammalian Mutagenicity	Negative              (Litton Bionetics, 1978a)	-	Negative   (Harlan, 2010)		-
In Vivo Genotox	Negative                                           in chromosome aberration                         assay (Dow              Corning Corporation, 1982)	-	-		-
Toxicity             to reproduction
Fertility	NOAEC: 5000 ppm (OECD 416) (Will Research, 2006)	NOAEC: >= 3146 ppm  (OECD 422) (Dow    Corning Corporation, 2008)	NOAEC: >= 400 ppm (OECD 422) (Dow Corning Corporation, 2007)		-
Developmental toxicity	NOAEC: 1600 ppm (OECD  416) (Will Research, 2006)	NOAEC:750      mg/ kg         bw/day              ppm (OECD 414) (Dow Corning Corporation, 2017)	NOAEC: >= 400 ppm (OECD 422) (Dow Corning Corporation, 2007)		-

-   No data

 

Acute toxicity:

There is no evidence from any of the available studies that the substances in this group have any potential for acute toxicity (in terms of either lethality or adverse clinical effects) by any route up to and exceeding the maximum dose levels tested according to current OECD guidelines. It is therefore valid to read-across the registered substance with the available studies. The data do not suggest that the reaction mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane will have any potential for acute toxicity.

Irritation/corrosion

The available studies for the linear siloxanes from this analogue group are summarised in the Table 1. There is no evidence from any of the available studies that the substances in this group have any potential for skin or eye irritation. It is therefore valid to read-across the registered substance with these studies. The data do not suggest that the reaction mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane will have any potential for skin or eye irritation.

 

Sensitisation

In vivo skin sensitisation data are available for a number of these substances. The available studies for the linear siloxanes from this analogue group are summarised in the Table 1. There is no evidence from any of the available studies that the substances in this group have any potential for skin sensitisation. The data do not suggest that the reaction mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane will have any potential for skin sensitisation.

Mutagenicity

The available studies for the linear siloxanes from this analogue group are summarised in the Table 1. There is no evidence from any of the available studies that the substances in this group have any potential for genetic toxicity or mutagenicity. The data do not suggest that the reaction mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane will have any potential for mutagenicity.

 

Reproductive and developmental toxicity

The available studies for the linear siloxanes from this analogue group are summarised in the Table 1. There is no evidence from any of the available studies that the substances in this group have any potential for reproduction or developmental toxicity. It is therefore valid to read-across the registered substance. The available studies do not suggest that the reaction mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane any adverse effects on fertility or offspring development.

 

 

Conclusion

Considering all of the above data, the data from the structural class of siloxanes (HMDS, L3, L4 and L5) can be read-across to Reaction Mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane.

Reaction Mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane is a multiconstituent substance with four constituents:

•       HMDS, hexamethyldisiloxane, CAS 107-46-0: 3-15%

•       L3, octamethyltrisiloxane, CAS 107-51-7: 40-70%

•       L4, decamethyltetrasiloxane, CAS 141-62-8: 10-30%

•       L5, dodecamethylpentasiloxane, CAS 141-63-9: 5-15%

Repeated dose toxicity data (28-day or 90-day or both) are available for all four constituents.  

 

 

 (i) Structural similarity

HMDS, L3, L4 and L5 form a homologous series of fully methylated linear siloxanes with two to five silicon atoms. They are part of the structural class of siloxanes. L4 has four silicon atoms connected by three oxygen atoms and L5 has five silicon atoms connected by four oxygen atoms.

 

(ii) Similar toxicokinetics

The read-across of data within the structural class of siloxanes is justified by the similarities in structure and physicochemical properties of the substances. They have extremely low water solubility and high octanol-water partition coefficients. These properties indicate that absorption of these substances is likely to be low via oral and dermal routes of exposure. Absorption following dermal exposure is unlikely for these substances. Once absorbed these substances are likely to distribute into tissues, particularly fatty tissues. These substances belong to the structural class of siloxanes (alkyl, vinyl, aryl or hydrogen substituted) and are hydrolyse slowly at pH 7 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, and these 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 absorbed onto food present in the stomach and thus the true rate of degradation in the stomach is difficult to predict.

 

(ii) Acute toxicity

Toxicity studies indicate that none of the linear siloxanes are acutely toxic. Nor are they irritating or sensitising in reliable studies.

 

(iv) Repeated dose toxicity

Repeated sub-acute oral toxicity studies are available for all constituents. Some of the linear siloxane substances eg. L4 and L5 led to fatty changes in the liver, and L4 caused brown hepatic pigment accumulation in the bile ducts, 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 brown hepatic pigment accumulation was considered to be adverse. 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.

Since L4 was more toxic than L5 in the repeated dose 28-day oral toxicity studies, reading across from L4 to L5 for long-term toxicity endpoints can be considered as a worst case. The NOAEC of 400 ppm in the OECD 413 and 422 studies for L4 would not be achievable for L5 due to the lower vapour pressure.

 

(v) Mutagenicity

The available studies indicate that there is no evidence that the substances in this group have any potential for genetic toxicity or mutagenicity.

 

(vi) Reproductive and developmental toxicity

There is no evidence from any of the available studies that the substances in this group have any potential for reproduction or developmental toxicity.

 

(vii) Conclusion

Overall, HMDS, L3, L4 and L5 have similar toxicological profiles. After considering all of the above factors it is deemed appropriate to read-across data and fulfil the toxicological endpoints for Reaction Mass   of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane

Justification for classification or non-classification

There is no evidence to suggest that Reaction Mass of decamethyltetrasiloxane; dodecamethylpentasiloxane; hexamethyldisiloxane; octamethyltrisiloxane should be classified for adverse effects following repeated exposure by any route according to Regulation (EC) 1272/2008.