Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
484 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
12.5
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:
265 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
5
Dose descriptor:
NOAEC
Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
200 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Additional information - workers

Acute / short-term exposure, systemic effects

 

Dermal route

 

A DNEL for short term duration (short term event, peak exposure) will not need to be derived in the case where an acute toxicity hazard (leading to C&L) has not been identified.

 

In non-guideline studies (Smith et al., 1968), the dermal LD50in rats is about 40,000 mg/kg bw. Based on these data, no classification for acute dermal toxicity has to be applied for DMSO according to EU Directive 67/584/EEC and EU regulation (EC) No 1272/2008 (CLP).

 

Inhalation route

 

A DNEL for short term duration (short term event, peak exposure) will not need to be derived in the case where an acute toxicity hazard (leading to C&L) has not been identified.

 

In a guideline acute inhalation study performed following the OECD TG 403 (, 1998), the LC0in rats was higher than 5.3 mg/Lfor a 4-hour exposure to an aerosol of DMSO. Based on these data, no classification for acute inhalation toxicity has to be applied for DMSO according to EU Directive 67/584/EEC and EU regulation (EC) No 1272/2008 (CLP).

 

 

Acute / short-term exposure, local effects

 

Dermal route

 

A DNEL for short term duration (short term event, peak exposure) will not need to be derived in the case where an acute toxicity hazard (leading to C&L) has not been identified.

 

A skin irritation assay performed in rabbit according to the OECD TG 404 (Sire, 2007) revealed no more than a very slight or well-defined erythema, which disappeared in 3 days. In humans, repeated application of DMSO solution for up to several months could induce transient erythema, burning, stinging and itching, which returned to normal after discontinuation of treatment. In one study in humans, occlusive exposure to DMSO caused cell death of the outer epidermis, followed by rapid regeneration. Based on these data, classification for skin irritation is not warranted according to EU Directive 67/584/EEC and EU regulation (EC) No 1272/2008 (CLP).

 

Sensitization tests performed in guinea pigs and mice following methods comparable to the OECD TG 406 were uniformly negative. A skin sensitization assay performed in humans was also negative. Based on these data, classification for skin sensitisation is not warranted according to EU Directive 67/584/EEC and EU regulation (EC) No 1272/2008 (CLP).

 

Inhalation route

 

A DNEL for short term duration (short term event, peak exposure) will not need to be derived in the case where an acute toxicity hazard (leading to C&L) has not been identified.

 

No signs of respiratory tract irritation were observed in an acute inhalation toxicity study with DMSO (, 1998). Rats were exposed to an aerosol concentration of 5.3 mg/L for 4 hours. Based on these data, classification for respiratory tract irritation is not warranted according to EU Directive 67/584/EEC and EU regulation (EC) No 1272/2008 (CLP).

 

 

Long-term exposure, systemic effects

 

Dermal route

 

Studies performed with several species have shown that DMSO is of low toxicity after repeated dermal administration. Typical findings after prolonged treatment of experimental animals with very high dose levels of DMSO include skin irritation at the site of application, halitosis, increased diuresis and changes in the refractive power of the lens in sensitive species. These ocular changes were observed at dose levels 1650 mg/kg bw/d in rabbits for 6 months (Noel et al., 1975), 3300 mg/kg bw/d in dogs for 17 weeks (Smith et al., 1969) and 1650 mg/kg/bw/d to pigs for 58 weeks (Noel et al., 1975). Similar ocular changes were never observed in monkeys at dose levels up to 8910 mg/kg bw/d for 18 months (Vogin et al., 1970), a dose level that caused marked ocular toxicity in the sensitive species. Significant clinical signs of systemic toxicity and the alterations of the lens have never been observed or reported in clinical and epidemiological studies performed in humans, even after exposure to high dose levels (1000 mg/kg bw/d for 13 weeks (Brobyn, 1975) or up to 2600 mg/kg bw/d for 12 weeks (Shirley et al., 1989)) or for a long period of time (1 to 45 ml/day for 1 to 21 months (Gordon, 1967)). Therefore, the NOAEL by dermal route used for the DNEL derivation will be 1000 mg/kg bw/d based on the 13-week study in humans.

 

Step 1) Relevant dose-descriptor:

 

NOAEL: 1000 mg/kg bw/d in humans

 

Step 2) Modification of starting point:

 

None.

 

NAELworkers= 1000 mg/kg bw/d

 

Step 3) Assessment factors

 

Interspecies:1

 

The dose-descriptor is based on a human study.

 

Intraspecies:5

 

Default assessment factor for workers.

 

Exposure duration:1

 

The dose-descriptor is based on a 3-month human study supported by a clinical studies with exposure up to 21 months. In addition, the NOAEL higher than 8910 mg/kg bw/d in the 18-month dermal study in primates allows considering that the dose level of 1000 mg/kg bw/d will be safe for a long-term exposure in humans. Therefore, no assessment factor will be used to extrapolate from the 3-month exposure to the long-term exposure.

 

Dose response:1

 

The DNEL derivation is based on a NOAEL.

 

Quality of database:1

 

DNEL Value = 1000 mg/kg bw/day x 1/(1 x 5 x 1 x 1 x 1)

= 200 mg/kg bw/day

 

Remark: starting from the NOAEL of 8910mg/kg bw/din the 18-month dermal study in primates and applying the default assessment factors (5 x 5 x 1 x 1 x 1) leads to a DNEL of 356 mg/kg bw/d.

 

Inhalation route

 

According to the results of a 13-week inhalation toxicity study compliant with the OECD TG 413 (Kenny, 2000a), the No Adverse Effects Concentration (NOAEC) for DMSO could be established at 964 mg/m3(the highest concentration attainable as vapour) for respiratory tract irritation and is higher than 2783 mg/m3(the highest concentration tested) for systemic toxicity. As the highest concentration tested didn’t induce systemic toxicity, the derivation of the DNEL from this NOAEC will lead to an underestimation of the DNEL. Therefore, the inhalation DNEL for the systemic effects will be extrapolated from the oral toxicity studies.

 

Studies performed with several species have shown that DMSO is of low toxicity after repeated oral administration. Typical findings with prolonged treatment at high dose levels leads to changes of the refractive power of the lens in some sensitive species, decrease of the body weight gain and modifications of some haematological parameters. The ocular changes were observed at doses of 9900 mg/kg bw/d in rats for 18 months and 1100 mg/kg bw/d in dogs for 2 years (Noel et al., 1975). Similar ocular changes were not observed in monkeys following oral administration at doses of up to 8910 mg/kg bw/d for 18 months (Vogin et al., 1970), a dose level that caused marked ocular toxicity in sensitive species, and in dermal clinical and epidemiological studies performed in humans, even after exposure to high dose levels (1000 mg/kg bw/d for 13 weeks (Brobyn, 1975), up to 2600 mg/kg bw/d for 12 weeks (Shirley et al., 1989)) and for a long period of time (1 to 45 ml/day for 1 to 21 months (Gordon, 1967)).

 

Therefore, excluding the species-specific ocular effects, the NOAELs for the other systemic effects were 3300 mg/kg bw/d in rats, 1100 mg/kg bw/d in dogs, and 2970 mg/kg bw/d in monkeys. Considering that the monkey is the most representative animal species for the evaluation of the potential toxicity of DMSO in humans, the DNEL derivation will be based on the NOAEL of 2970 mg/kg bw/d in monkeys (Vogin et al., 1970).

 

 

Step 1) Relevant dose-descriptor

 

NOAELmonkey: 2970 mg/kg bw/d

 

Step 2) Modification of starting point:

 

The oral absorption of DMSO in monkeys is estimated to be 70% (Layman et al., 1985), therefore the oral NOAEL is equivalent an internal NOAEL of 2079 mg/kg bw/d.

 

For a 24-hour exposure by inhalation, the equivalent NOAEC will be:

2079 mg/kg bw/d / 0.23*m3/kg bw = 9039 mg/m3.

 

After correction for activity driven differences of respiratory volumes in workers (10 m3) compared to workers in rest (6.7 m3):

 

NAECworkers= 6,056 mg/m3

 

Step 3) Assessment factors

 

Interspecies: 2.5

 

Intraspecies: 5

 

Default assessment factor for the general population.

 

Exposure duration: 1

 

The dose-descriptor is based on an 18-month toxicity study in monkeys.

 

Dose response:1

 

The DNEL derivation is based on a NOAEC.

 

Quality of database:1

 

DNEL Value= 6,056 mg/m3x 1/(2.5 x 5 x 1 x 1 x 1)

= 484 mg/m3(150 ppm)

 

*based on a minute volume of 2.4 L/min. (REACH guidance R7c) and a mean body weight of 5 kg (http://pin.primate.wisc.edu/factsheets/entry/rhesus_macaque).

 

 

Long-term exposure, local effects

 

Inhalation route

 

Exposure of rats to ca. 1 mg/L DMSO as vapours for up to 90 days didn’t cause any irritation to the respiratory tract (Kenny, 2000a). Irritation in the upper airways (slight inflammation and hyperplasia in the nasal epithelium and pharynx), which was slowly reversible, was only observed when rats were exposed to a DMSO aerosol (Kenny, 1999 and 2000b).

 

The irritation in the upper respiratory airways was evaluated in 3 snout-only repeated-dose inhalation toxicity studies.In a 14-day study, rats were exposed to DMSO at concentrations of 0.52 mg/L as vapours and 1.39 and 5.36 mg/L as aerosols, in a 28-day study, at 0.507 mg/L as vapours and 0.132 and 1.886 mg/L as aerosols and in the 90-day study, at 0.310, 0.964 mg/L as vapours and 2.783 mg/L as aerosols.

Vapours of DMSO didn’t cause any irritation to the respiratory system in rat following 14 days to 0.52 mg/L, 28 days to 0.507 mg/L and 90 days to 0.964 mg/L. Irritation in the upper airways (slight inflammation and hyperplasia in the nasal epithelium and pharynx), slowly reversible, was observed at different concentrations of aerosols:

 

Exposure time

Non irritating concentration (mg/l)

Lowest irritating concentration (mg/l)

14 days

1.39 (aerosol, 64% < 7µm)

5.36 (aerosol, 69% < 7 µm)

28 days

1.884 (aerosol, 75% < 7 µm)

nd

90 days

0.964 (vapor)

2.793 (aerosol, 63% < 7 µm)

 

 

The irritating effects are related to thedeposit of the non-respirable fraction of the DMSO aerosol in the upper respiratory tract when the animals are exposed to very high concentrations. The NOAEC for the nasal irritation after deposition of the non-respirable fraction of a DMSO aerosol is higher than 1,884 mg/m3for a 28-day exposure in rats and between 964 and 2,793 mg/m3 for a 90-day exposure.

 

Step 1) Relevant dose-descriptor:

 

The DNEL derivation will be based on the NOAEC of 1,884 mg/m3 for the nasal irritation in rats exposed for 28-days to DMSO aerosols.

 

Step 2) Modification of starting point:

 

Correction of exposure duration in study (6 hrs/day, 7 days/week) to default worker exposure (8 hrs/day, 5 days/ week); and correction for activity driven differences of respiratory volumes in workers (10 m3) compared to workers in rest (6.7 m3).

 

NAECworkers (8h)= 1884 mg/m3x 6/8 hrs x 7/5 days x 6.7/10 m3

NAECworkers (8h)= 1,325 mg/m3

 

Step 3) Assessment factors

 

Interspecies: 1

 

The irritating effects of DMSO are related to the deposit of the non-respirable fraction of the DMSO aerosol in the nasal passages when the animals are exposed to very high concentrations. There are significant anatomical and physiological differences relating to the upper airways between rats and humans (REACH Guidance R7c). The relative nasal surface area (nasal cavity surface area/nasal cavity volume) is 6 times higher is rats than in humans, the respiratory rate of rats (0.29 m3/kg-day) leads to a greater burden as compared to humans (0.14 m3/kg-day) and the ratio of the nasal cavity surface area to the minute volume is 4 times higher in rats than in humans indicating an higher chance of aerosol deposition on the nasal epithelium in rats than in humans. Therefore, no additional assessment factor will be added for interspecies extrapolation from rodent to human, considering that the effects observed in rat are exaggerated and provide a “built in” safety margin.

 

Intraspecies :5

 

Default assessment factor for workers.

 

Exposure duration : 1

DMSO aerosols didn’t cause nasal irritation in rat following 14 days at 1,390 mg/m3, 28 days at 1,884 mg/m3and 90 days at a concentration between 964 and 2,793 mg/m3. Between 14 and 90 days of exposure, the NOAEC for the nasal irritation didn’t decrease with the increasing exposure duration. Therefore, as long as the exposure concentration is lower than the saturated vapour concentration (ca. 1,800 mg/m3based on a vapour pressure of 0.56 hPa @ 20°C), no effect is expected whatever the exposure duration.

 

Dose response:1

 

The DNEL derivation is based on a NOAEC.

 

Quality of database:1

 

DNEL Value= 1325 mg/m3x 1/(1 x 5 x 1 x 1 x 1)

= 265 mg/m3(82 ppm)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
120 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
25
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:
47 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
100 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
60 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Acute / short-term exposure, systemic effects

 

Dermal route

 

A DNEL for short term duration (short term event, peak exposure) will not need to be derived in the case where an acute toxicity hazard (leading to C&L) has not been identified.

 

In non-guideline studies (Smith et al., 1968), the dermal LD50in rats is about 40,000 mg/kg bw. Based on these data, no classification for acute dermal toxicity has to be applied for DMSO according to EU Directive 67/584/EEC and EU regulation (EC) No 1272/2008 (CLP).

 

Inhalation route

 

A DNEL for short term duration (short term event, peak exposure) will not need to be derived in the case where an acute toxicity hazard (leading to C&L) has not been identified.

 

In a guideline acute inhalation study performed following the OECD TG 403 (, 1998), the LC0in rats was higher than 5.3 mg/Lfor a 4-hour exposure to an aerosol of DMSO. Based on these data, no classification for acute inhalation toxicity has to be applied for DMSO according to EU Directive 67/584/EEC and EU regulation (EC) No 1272/2008 (CLP).

 

Oral route

 

A DNEL for short term duration (short term event, peak exposure) will not need to be derived in the case where an acute toxicity hazard (leading to C&L) has not been identified.

 

In non-guideline studies (Willson et al, 1965), oral LD50are 28300 mg/kg in rats and 21400 mg/kg in mice. Based on these data, no classification for acute dermal toxicity has to be applied for DMSO according to EU Directive 67/584/EEC and EU regulation (EC) No 1272/2008 (CLP).

 

 

Acute / short-term exposure, local effects

 

Dermal route

 

A DNEL for short term duration (short term event, peak exposure) will not need to be derived in the case where an acute toxicity hazard (leading to C&L) has not been identified.

 

A skin irritation assay performed in rabbit according to the OECD TG 404 revealed no more than a very slight or well-defined erythema, which disappeared in 3 days. In humans, repeated application of DMSO solution for up to several months could induce transient erythema, burning, stinging and itching, which returned to normal after discontinuation of treatment. In one study in humans, occlusive exposure to DMSO caused cell death of the outer epidermis, followed by rapid regeneration. Based on these data, classification for skin irritation is not warranted according to EU Directive 67/584/EEC and EU regulation (EC) No 1272/2008 (CLP).

 

Sensitization tests performed in guinea pigs and mice following methods comparable to the OECD TG 406 were uniformly negative. A skin sensitization assay performed in humans was also negative. Based on these data, classification for skin sensitisation is not warranted according to EU Directive 67/584/EEC and EU regulation (EC) No 1272/2008 (CLP).

 

Inhalation route

 

A DNEL for short term duration (short term event, peak exposure) will not need to be derived in the case where an acute toxicity hazard (leading to C&L) has not been identified.

 

No signs of respiratory tract irritation were observed in an acute inhalation toxicity study with DMSO (, 1998). Rats were exposed to an aerosol concentration of 5.3 mg/L for 4 hours. Based on these data, classification for respiratory tract irritation is not warranted according to EU Directive 67/584/EEC and EU regulation (EC) No 1272/2008 (CLP).

 

 

Long-term exposure, systemic effects

 

Dermal route

 

Studies performed with several species have shown that DMSO is of low toxicity after repeated dermal administration. Typical findings after prolonged treatment of experimental animals with very high dose levels of DMSO include skin irritation at the site of application, halitosis, increased diuresis and changes in the refractive power of the lens in sensitive species. These ocular changes were observed at dose levels 1650 mg/kg bw/d in rabbits for 6 months (Noel et al., 1975), 3300 mg/kg bw/d in dogs for 17 weeks (Smith et al., 1969) and 1650 mg/kg/bw/d to pigs for 58 weeks (Noel et al., 1975). Similar ocular changes were never observed in monkeys at dose levels up to 8910 mg/kg bw/d for 18 months (Vogin et al., 1970), a dose level that caused marked ocular toxicity in the sensitive species. Significant clinical signs of systemic toxicity and the alterations of the lens have never been observed or reported in clinical and epidemiological studies performed in humans, even after exposure to high dose levels (1000 mg/kg bw/d for 13 weeks (Brobyn, 1975) or up to 2600 mg/kg bw/d for 12 weeks (Shirley et al., 1989)) or for a long period of time (1 to 45 ml/day for 1 to 21 months (Gordon, 1967)). Therefore, the NOAEL by dermal route used for the DNEL derivation will be 1000 mg/kg bw/d based on the 13-week study in humans.

 

Step 1) Relevant dose-descriptor:

 

NOAEL: 1000 mg/kg bw/d in humans

 

Step 2) Modification of starting point:

 

None.

 

NAELgeneral population= 1000 mg/kg bw/d

 

Step 3) Assessment factors

 

Interspecies:1

 

The dose-descriptor is based on a human study.

 

Intraspecies: 10

 

Default assessment factor for the general population.

 

Exposure duration:1

 

The dose-descriptor is based on a 3-month human study supported by a clinical studies with exposure up to 21 months. In addition, the NOAEL higher that 8910 mg/kg bw/din the 18-month dermal study in primates allows considering that the dose level of 1000 mg/kg bw/d will be safe for a long-term exposure in humans. Therefore, no assessment factor will be used to extrapolate from the 3-month exposure to the long-term exposure.

 

Dose response:1

 

Quality of database:1

 

The DNEL derivation is based on a NOAEL.

 

DNEL Value = 1000 mg/kg bw/day x 1/(1 x 10 x 1 x 1 x 1)

= 100 mg/kg bw/day

 

Remark: starting from the NOAEL of 8910mg/kg bw/d in the 18-month dermal study in primates and applying the default assessment factors (5 x 10 x 1 x 1 x 1) leads to a DNEL of 178 mg/kg bw/d.

 

Inhalation route

 

According to the results of a 13-week inhalation toxicity study compliant with the OECD TG 413 (Kenny, 2000a), the No Adverse Effects Concentration (NOAEC) for DMSO could be established at 964 mg/m3(the highest concentration attainable as vapour) for respiratory tract irritation and is higher than 2783 mg/m3(the highest concentration tested) for systemic toxicity. As the highest concentration tested didn’t induce systemic toxicity, the derivation of the DNEL from this NOAEC will lead to an underestimation of the DNEL. Therefore, the inhalation DNEL will be extrapolated from the oral toxicity studies.

 

Studies performed with several species have shown that DMSO is of low toxicity after repeated oral administration. Typical findings with prolonged treatment at high dose levels leads to changes of the refractive power of the lens in some sensitive species, decrease of the body weight gain and modifications of some haematological parameters. The ocular changes were observed at doses of 9900 mg/kg bw/d in rats for 18 months and 1100 mg/kg bw/d in dogs for 2 years (Noel et al., 1975). Similar ocular changes were not observed in monkeys following oral administration at doses of up to 8910 mg/kg bw/d for 18 months (Vogin et al., 1970), a dose level that caused marked ocular toxicity in sensitive species, and in clinical and epidemiological studies performed in humans, even after exposure to high dose levels (1000 mg/kg bw/d for 13 weeks (Brobyn, 1975), up to 2600 mg/kg bw/d for 12 weeks (Shirley et al., 1989)) and for a long period of time (1 to 45 ml/day for 1 to 21 months (Gordon, 1967)).

 

Therefore, excluding the species-specific ocular effects, the NOAELs for the other systemic effects were 3300 mg/kg bw/d in rats, 1100 mg/kg bw/d in dogs, and 2970 mg/kg bw/d in monkeys. Considering that the monkey is the most representative animal species for the evaluation of the potential toxicity of DMSO in humans, the DNEL derivation will be based on the NOAEL of 2,970 mg/kg/bw/d in monkeys (Vogin et al., 1970).

 

Step 1) Relevant dose-descriptor

 

NOAELmonkey: 2,970 mg/kg bw/d

 

Step 2) Modification of starting point:

 

The oral absorption of DMSO in monkeys is estimated to be 70% (Layman et al., 1985), therefore the oral NOAEL is equivalent an internal NOAEL of 2,079 mg/kg bw/d.

 

For a 24-hour exposure by inhalation, the equivalent NOAEC will be:

2079 mg/kg bw/d / 0.69*m3/kg bw = 3,013 mg/m3.

 

NAECgeneral population= 3,013 mg/m3

 

Step 3) Assessment factors

 

Interspecies: 2.5

 

Intraspecies: 10

 

Default assessment factor for the general population.

 

Exposure duration: 1

 

The dose-descriptor is based on an 18-month toxicity study in monkeys.

 

Dose response:1

 

The DNEL derivation is based on a NOAEC.

 

Quality of database:1

 

DNEL Value= 3,013 mg/m3x 1/(2.5 x 10 x 1 x 1 x 1)

= 120 mg/m3(37 ppm)

 

*based on a minute volume of 2.4 L/min. (REACH guidance R7c) and a mean body weight of 5 kg (http://pin.primate.wisc.edu/factsheets/entry/rhesus_macaque).

 

Oral route

 

Studies performed with several species have shown that DMSO is of low toxicity after repeated oral administration. Typical findings with prolonged treatment at high dose levels leads to changes of the refractive power of the lens in some sensitive species, decrease of the body weight gain and modifications of some haematological parameters. The ocular changes were observed at doses of 9900 mg/kg bw/d in rats for 18 months and 1100 mg/kg bw/d in dogs for 2 years (Noel et al., 1975). Similar ocular changes were not observed in monkeys following oral administration at doses of up to 8910 mg/kg bw/d for 18 months (Vogin et al., 1970), a dose level that caused marked ocular toxicity in sensitive species, and in clinical and epidemiological studies performed in humans, even after exposure to high dose levels (1000 mg/kg bw/d for 13 weeks (Brobyn, 1975), up to 2600 mg/kg bw/d for 12 weeks (Shirley et al., 1989)) and for a long period of time (1 to 45 ml/day for 1 to 21 months (Gordon, 1967)).

 

Therefore, excluding the species-specific ocular effects, the NOAELs for the other systemic effects were 3300 mg/kg bw/d in rats, 1100 mg/kg bw/d in dogs, and 2970 mg/kg bw/d in monkeys. Considering that the monkey is the most representative animal species for the evaluation of the potential toxicity of DMSO in humans, the DNEL derivation will be based on the NOAEL ofr 2970 mg/kg/bw/d in monkeys (Vogin et al., 1970).

 

Step 1) Relevant dose-descriptor

 

NOAEL of 2970 mg/kg bw/d in monkeys for a daily exposure of 18 months.

 

Step 2) Modification of starting point:

 

None.

 

Step 3) Assessment factors

 

Interspecies: 2.5 x 2

 

Intraspecies : 10

 

Default assessment factor for the general population.

 

Exposure duration : 1

 

The DNEL derivation is based on a 18-month study.

 

Dose response:1

 

The DNEL derivation is based on a NOAEL.

 

Quality of database:1

 

DNEL Value= 2970 mg/kg bw/d x 1/(5 x 10 x 1 x 1 x 1)

= 60 mg/kg bw/d

 

 

Long-term exposure, local effects

 

Inhalation route

 

Exposure of rats to ca. 1 mg/L DMSO as vapours for up to 90 days didn’t cause any irritation to the respiratory tract (see long-term exposure, systemic effects; Kenny, 2000). Irritation in the upper airways (slight inflammation and hyperplasia in the nasal epithelium and pharynx), which was slowly reversible, was only observed when rats were exposed to a DMSO aerosol (Kenny, 1999 and 2000).

 

The irritation in the upper respiratory airways was evaluated in 3 snout-only repeated-dose inhalation toxicity studies. In a 14-day study, rats were exposed to DMSO at concentrations of 0.52 mg/L as vapours and 1.39 and 5.36 mg/L as aerosols, in a 28-day study, at 0.507 mg/L as vapours and 0.132 and 1.886 mg/L as aerosols and in the 90-day study, at 0.310, 0.964 mg/L as vapours and 2.783 mg/L as aerosols.

Vapours of DMSO didn’t cause any irritation to the respiratory system in rat following 14 days to 0.52 mg/L, 28 days to 0.507 mg/L and 90 days to 0.964 mg/L. Irritation in the upper airways (slight inflammation and hyperplasia in the nasal epithelium and pharynx), slowly reversible, was observed at different concentrations of aerosols:

 

Exposure time

Non irritating concentration (mg/l)

Lowest irritating concentration (mg/l)

14 days

1.39 (aerosol, 64% < 7µm)

5.36 (aerosol, 69% < 7 µm)

28 days

1.884 (aerosol, 75% < 7 µm)

nd

90 days

0.964 (vapor)

2.793 (aerosol, 63% < 7 µm)

 

 

The irritating effects are related to thedeposit of the non-respirable fraction of the DMSO aerosol in the upper respiratory tract when the animals are exposed to very high concentrations. The NOAEC for the nasal irritation after deposition of the non-respirable fraction of a DMSO aerosol is higher than 1884 mg/m3for a 28-day exposure in rats and between 964 and 2,793 mg/m3 for a 90-day exposure.

 

Step 1) Relevant dose-descriptor:

 

The DNEL derivation will be based on the NOAEC of 1,884 mg/m3 for the nasal irritation in rats exposed for 28-days to DMSO aerosols.

 

Step 2) Modification of starting point:

 

Correction of exposure duration in study (6 hrs/day, 7 days/week) to default general population exposure (24 hrs/day, 7 days/ week).

 

NAECgeneral population= 1,884 mg/m3x 6/24 hrs

NAECgeneral population= 471 mg/m3

 

Step 3) Assessment factors

 

Interspecies: 1

 

The irritating effects of DMSO are related to the deposit of the non-respirable fraction of the DMSO aerosol in the nasal passages when the animals are exposed to very high concentrations. There are significant anatomical and physiological differences relating to the upper airways between rats and humans (REACH Guidance R7c). The relative nasal surface area (nasal cavity surface area/nasal cavity volume) is 6 times higher is rats than in humans,the respiratory rate of rats (0.29 m3/kg-day) leads to a greater burden as compared to humans (0.14 m3/kg-day) and the ratio of the nasal cavity surface area to the minute volume is 4 times higher in rats than in humans indicating an higher chance of aerosol deposition on the nasal epithelium in rats than in humans. Therefore, no additional assessment factor will be added for interspecies extrapolation from rodent to human, considering that the effects observed in rat are exaggerated and provide a “built in” safety margin.

 

Intraspecies : 10

 

Default assessment factor for the general population.

 

Exposure duration : 1

DMSO aerosols didn’t cause nasal irritation in rat following 14 days at 1,390 mg/m3, 28 days at 1,884 mg/m3and 90 days at a concentration between 964 and 2,793 mg/m3. Between 14 and 90 days of exposure, the NOAEC for the nasal irritation didn’t decrease with the increasing exposure duration. Therefore, as long as the exposure concentration is lower than the saturated vapour concentration (ca. 1,800 mg/m3based on a vapour pressure of 0.56 hPa @ 20°C), no effect is expected whatever the exposure duration.

 

Dose response:1

 

The DNEL derivation is based on a NOAEC.

 

Quality of database:1

 

DNEL Value= 471 mg/m3x 1/(1 x 10 x 1 x 1 x 1)

= 47 mg/m3(14.5 ppm)