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Administrative data

Workers - Hazard via inhalation route

Systemic effects

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

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Acute/short-term local effects/ Long-term exposure local effects

The test substance 7PPD showed a practically non-irritating potential to rabbit skin (Monsanto Co. 1973). The even very low skin irritation potential is confirmed by another skin irritation study (Monsanto Co. 1967a). A rather slight and transient eye irritation potential is noted in an eye irritation study (Monsanto Co. 1973). This finding was supported by an earlier eye irritating study, which revealed mild and transient eye irritating effects of 7PPD (Monsanto Co. 1967a) The test substance is not classified as skin or eye irritating.

For 7PPP no animal skin sensitizing data are available. A read across with 6PPD was performed. 6PPD showed clear sensitizing activities in 3 different animal experiments. All individual studies had some limitations as outlined above and reliable information on the sensitization potency of 6PPD cannot be derived from these animal experiments. Consequently, no information is available precisely quantify the sensitizing potential of 6PPD or 7PPD.

In a limited human study with 80 healthy volunteers not previously exposed to test rubber formulations, no sensitization was observed with 7PPD. No or only a low sensitization rate to 6PPD was noted in different limited human studies summarized in the OECD SIDS Initial Assessment Report for 6PPD.In human studies with 6PPD the sensitization rate was much higher in persons who had been previously sensitized to rubber samples.

Based on the above considerations no fully quantitative NOAEC can be derived for this endpoint based on the available limited animal data. However following the proposal within the REACH guidance, refined in Schaafsma et al. 2011 (Reg.Tox.Pharm. 60, 308-317), a rule of thumb value between 5 and 50 µg/cm2/day was proposed based on the classification of the compound into sensitization subcategory 1A or 1B, respectively. Since no information is available to precisely quantify the sensitizing potential of 7PPD, no valid sub-categorization can be justified and no rule of thumb value can be derived.

Taking into account all available information, including the limited human data, allocation to the moderate hazard band seems appropriate, and a qualitative risk assessment will be performed.

Acute/short-term exposure systemic effects:

The acute dermal and oral toxicity of the test substance 7PPD is very low, indicated by oral LD50 values greater than 2000 mg/kg. The acute oral LD50 value in rats is >2100 mg/kg bw (Monsanto Co. 1973, 1967a) and the dermal LD50 value in rabbits is greater than 5010 mg/kg bw (Monsanto Co. 1973, Monsanto Co. 1967a). Due to the very low acute oral and acute dermal toxicity of 7PPD a limit exposure peaks to a factor of 8 is suggested as an average for a maximum exposure interval of 15 minutes. This approach is generally in line with the regulatory procedure in Germany (see Technical Rule for Hazardous Substances 900).

DNEL short-term systemic dermal: 0.4 mg/kg bw/day x 8 = 3.2 mg/kg bw/day

DNEL short-term systemic inhalation: 3 mg/m3x 8 = 24 mg/m3

DNEL long-term exposure systemic

The data from the limited subacute 7PPD feeding study (Monsanto 1988) discussed under chapter repeated dose toxicity were used for DNEL calculation. Because of the limited data available for 7PPD, repeated dose toxicity data from 6PPD were used for supporting reasons.

Worker DNEL long-term systemic for oral route

Start point: NOAEL 20 mg/kg bw/day (subchronic, chronic and reprotox studies in rats with 6PPD,).

Differences in absorption Abs (oral-rat) / Abs (oral-human): 1

=> Corrected NOAEL 20 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 2.5

Intraspecies differences: 5

Differences in duration of exposure: 1

Dose response and endpoint specific/severity issues: 1

Quality of database: 1

Overall factor (product of individual factors): 50

=>Worker DNEL long-term for oral route-systemic: 0.4 mg/kg bw/day

Worker DNEL long-term sytemic for dermal route

The same starting point, absorption rates and assessment factors may be considered for the oral and the dermal route, therefore the same systemic DNEL applies (0.4 mg/kg bw/day).

Worker DNEL long-term systemic for inhalation route

Start point: NOAEL 20 mg/kg bw/day (subchronic, chronic and reprotox studies in rats with 6PPD ).

Respiratory volume rat (sRV) (worker (8 h): 1/0.38): 2.632

Differences in respiratory volume (default factor "light activity worker"): 0.67

Differences in absorption Abs (oral-rat) / Abs (inhalation-human): 1

Corrected NOAEC: 35 mg/m3

Interspecies differences: Allometric scaling: 1

Remaining interspecies differences: 2,5

Intraspecies differences: 5

Differences in duration of exposure: 1

Dose response and endpoint specific/severity issues: 1

Quality of database: 1

Overall factor (product of individual factors): 12,5

=>Worker DNEL long-term for inhalation route-systemic: 3 mg/m3

DNEL fertility

There are no fertility and developmental toxicity study data for 7PPD available. A read across approach was conducted with 6PPD for risk assessment. Similarities of 7PPD and 6PPD in chemical structure, physico-chemical properties and in mammalian toxicity were discussed (for more details see chapter repeated dose toxicity, data matrix, analogue approach chapter summary and discussion). Based on the similarities in chemical structures, physico-chemical properties and mammalian toxicity between 7PPD and 6PPD it is assumed that the read across with study data from 6PPD is sufficient for hazard assessment. Based on the analogue read across approach the data from the 6PPD fertility and developmental toxicity studies are used for hazard assessment.

Read across approach with 6PPD

The effects of 6PPD on fertility were evaluated in a reproduction toxicity screening study (OECD TG 421) (Biosafety Research Center 2001) and an early three-generation study (Monsanto 1980). No adverse effects of 6PPD on the reproductive organs of male and female rats were noted. In addition, no adverse effects on reproduction performance were indicated up to the highest concentrations evaluated. Based on the data from the reproduction toxicity screening study a NOAEL fertility of 100 mg/kg (highest dose tested) is suggested. In the reproduction toxicity screening study the parental LOAEL was indicated by an increase in liver weights (18 %) at 25 mg/kg bw/day. Because the mild effects noted at 25 mg/kg bw/day were not confirmed by other repeated dose toxicity studies with even longer exposure it was considered that the systemic NOAEL is 20 mg/kg bw day and respective DNEL of 6PPD covers also the parental toxicity. No additional DNEL fertility was calculated.

DNEL developmental toxicity

Read across approach with 6PPD

The developmental toxicity of the test substance 6PPD was evaluated in a teratology study with Sprague-Dawley rats (Monsanto Co. 1987). 6PPD administered to pregnant rats during the period of major organogenesis, was neither teratogenic nor embryo/fetotoxic at dose levels of up to 250 mg/kg/day. An increase in clinical signs of maternal animals occurred at dose levels of 100 and 250 mg/kg/day in a dose-dependent manner. The 50 mg/kg/day dosage was considered a NOAEL for any maternal effect. In a preliminary reproduction toxicity screening study (Biosafety Research Center 2001) parental toxicity was indicated at 25 mg/kg bw/day, which based on liver effects. However this is considered to be covered with the systemic NOAEL (20 mg/kg bw day) and respective DNEL.No abnormal findings related to 6PPD were noted for external examination, clinical signs, growth or necropsy of the offspring up to the highest dose evaluated (100 mg/kg bw/day). Based on the findings of the screening study a NOAEL for developmental toxicity of 100 mg/kg bw/day are suggested.

In conclusion, based on the findings from the more recent study a NOAEL developmental toxicity of 100 mg/kg bw/day is suggested for 6PPD. Because the mild maternal toxic effects noted at 25 mg/kg bw day were not confirmed by other repeated dose toxicity studies with even longer exposure it was suggested that the systemic NOAEL (20 mg/kg bw day) and respective DNEL covers the maternal toxicity. The NOAEL developmental toxicity is above the systemic NOAEL and thus it can be concluded that the DNEL for long-term exposure covers the DNEL developmental toxicity.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.6 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.6 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Acute/short-term local effects/ Long-term exposure local effects

The test substance 7PPD showed a practically non-irritating potential to rabbit skin (Monsanto Co. 1973). The even very low skin irritation potential is confirmed by another skin irritation study (Monsanto Co. 1967a). A rather slight and transient eye irritation potential is noted in an eye irritation study (Monsanto Co. 1973). This finding was supported by an earlier eye irritating study, which revealed mild and transient eye irritating effects of 7PPD (Monsanto Co. 1967a) The test substance is not classified as skin or eye irritating.

For 7PPP no animal skin sensitizing data are available. A read across with 6PPD was performed. 6PPD showed clear sensitizing activities in 3 different animal experiments. All individual studies had some limitations as outlined above and reliable information on the sensitization potency of 6PPD cannot be derived from these animal experiments. Consequently, no information is available precisely quantify the sensitizing potential of 6PPD or 7PPD.

In a limited human study with 80 healthy volunteers not previously exposed to test rubber formulations, no sensitization was observed with 7PPD. No or only a low sensitization rate to 6PPD was noted in different limited human studies summarized in the OECD SIDS Initial Assessment Report for 6PPD.In human studies with 6PPD the sensitization rate was much higher in persons who had been previously sensitized to rubber samples.

Based on the above considerations no fully quantitative NOAEC can be derived for this endpoint based on the available limited animal data. However following the proposal within the REACH guidance, refined in Schaafsma et al. 2011 (Reg.Tox.Pharm. 60, 308-317), a rule of thumb value between 5 and 50 µg/cm2/day was proposed based on the classification of the compound into sensitization subcategory 1A or 1B, respectively. Since no information is available to precisely quantify the sensitizing potential of 7PPD, no valid sub-categorization can be justified and no rule of thumb value can be derived.

Taking into account all available information, including the limited human data, allocation to the medium hazard band seems appropriate, and a qualitative risk assessment will be performed.

 

Acute/short-term exposure systemic effects

The acute dermal and oral toxicity of the test substance 7PPD is very low, indicated by oral LD50 values greater than 2000 mg/kg. The acute oral LD50 value in rats is >2100 mg/kg bw (Monsanto Co. 1973, 1967a) and the dermal LD50 value in rabbits is greater than 5010 mg/kg bw (Monsanto Co. 1973, Monsanto Co. 1967a). Due to the very low acute oral and acute dermal toxicity of 7PPD a limit exposure peaks to a factor of 8 is suggested as an average for a maximum exposure interval of 15 minutes. This approach is generally in line with the regulatory procedure in Germany (see Technical Rule for Hazardous Substances 900).

DNEL short-term systemic dermal: 0.2 mg/kg bw/day x 8 = 1.6 mg/kg bw/day

DNEL short-term systemic oral: 0.2 mg/kg bw/day x 8 = 1.6 mg/kg bw/day

DNEL short-term systemic inhalation: 0.7 mg/m3x 8 = 5.6 mg/m3

General public long-term exposure systemic

General public long-term systemic for oral route

Start point: NOAEL 20 mg/kg bw/day (subchronic, chronic and reprotox studies in rats with 6PPD,).

Differences in absorption Abs (oral-rat) / Abs (oral-human): 1

=> Corrected NOAEL 20 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 2.5

Intraspecies differences: 10

Differences in duration of exposure: 1

Dose response and endpoint specific/severity issues: 1

Quality of database: 1

Overall factor (product of individual factors): 100

=> General Public long-term for oral route-systemic: 0.2 mg/kg bw/day

General public long-term systemic for dermal route

The same starting point, absorption rates and assessment factors may be considered the oral and the dermal route, therefore the same systemic DNEL applies (0.2 mg/kg bw/day). However given the potentially highly potent sensitizing properties exposure has to be minimized below the value of 2.5 µg/cm2/day.

General public long-term systemic for inhalation route

Start point: NOAEL 20 mg/kg bw/day (subchronic, chronic and reprotox studies in rats with 6PPD).

Respiratory volume rat (sRV) general public 1/1.15: 0.87

Differences in absorption Abs (oral-rat) / Abs (inhalation-human): 1

=> Corrected NOAEC: 17 mg/m3

Interspecies differences: Allometric scaling: 1

Remaining interspecies differences: 2.5

Intraspecies differences: 10

Differences in duration of exposure: 1

Dose response and endpoint specific/severity issues: 1

Quality of database: 1

Overall factor (product of individual factors): 25

=>General Public DNEL long-term for inhalation route-systemic: 0.7 mg/m3

DNEL fertility

There are no fertility and developmental toxicity study data for 7PPD available. A read across approach was conducted with 6PPD for risk assessment. Similarities of 7PPD and 6PPD in chemical structure, physico-chemical properties and in mammalian toxicity were discussed (for more details see chapter repeated dose toxicity, data matrix, analogue approach chapter summary and discussion). Based on the similarities in chemical structures, physico-chemical properties and mammalian toxicity between 7PPD and 6PPD it is assumed that the read across with study data from 6PPD is sufficient for hazard assessment. Based on the analogue read across approach the data from the 6PPD fertility and developmental toxicity studies are used for hazard assessment.

Read across approach with 6PPD

The effects of 6PPD on fertility were evaluated in a reproduction toxicity screening study (OECD TG 421) (Biosafety Research Center 2001) and an early three-generation study (Monsanto 1980). No adverse effects of 6PPD on the reproductive organs of male and female rats were noted. In addition, no adverse effects on reproduction performance were indicated up to the highest concentrations evaluated. Based on the data from the reproduction toxicity screening study a NOAEL fertility of 100 mg/kg (highest dose tested) is suggested. In the reproduction toxicity screening study the parental LOAEL was indicated by an increase in liver weights (18 %) at 25 mg/kg bw/day. Because the mild effects noted at 25 mg/kg bw/day were not confirmed by other repeated dose toxicity studies with even longer exposure it was considered that the systemic NOAEL (20 mg/kg bw day) and respective DNEL of 6PPD covers also the parental toxicity. No additional DNEL fertility was calculated.

DNEL developmental toxicity

Read across approach with 6PPD

The developmental toxicity of the test substance 6PPD was evaluated in a teratology study with Sprague-Dawley rats (Monsanto Co. 1987). 6PPD administered to pregnant rats during the period of major organogenesis, was neither teratogenic nor embryo/fetotoxic at dose levels of up to 250 mg/kg/day. An increase in clinical signs of maternal animals occurred at dose levels of 100 and 250 mg/kg/day in a dose-dependent manner. The 50 mg/kg/day dosage was considered a NOAEL for any maternal effect. In a preliminary reproduction toxicity screening study (Biosafety Research Center 2001) parental toxicity was indicated at 25 mg/kg bw/day, which based on liver effects. However this is considered to be covered with the systemic NOAEL (20 mg/kg bw day) and respective DNEL. No abnormal findings related to 6PPD were noted for external examination, clinical signs, growth or necropsy of the offspring up to the highest dose evaluated (100 mg/kg bw/day). Based on the findings of the screening study a NOAEL for developmental toxicity of 100 mg/kg bw/day are suggested.

In conclusion, based on the findings from the more recent study a NOAEL developmental toxicity of 100 mg/kg bw/day is suggested for 6PPD. Because the mild maternal toxic effects noted at 25 mg/kg bw day were not confirmed by other repeated dose toxicity studies with even longer exposure it was suggested that the systemic NOAEL (20 mg/kg bw day) and respective DNEL covers the maternal toxicity. The NOAEL developmental toxicity is above the systemic NOAEL and thus it can be concluded that the DNEL for long-term exposure covers the DNEL developmental toxicity.