Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.8 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.4 mg/m³
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:
0.113 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.9 mg/kg bw/day
DNEL related information

Local effects

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

In conclusion, the test substance IPPD showed a practically non-irritating potential to rabbit skin (Monsanto Co. 1974). This find is supported by earlier studies with human volunteers (Bayer AG 1963). A rather slight and transient eye irritation potential is noted in an eye irritation study (Monsanto Co. 1974). The test substance is not classified as skin or eye irritating.

The skin sensitisation potential of IPPD was evaluated in guinea pigs, mice and in studies with human volunteers. IPPD was sensitizing in guinea pigs and mice and was found to induce dermal sensitizing in humans; in consequence, existing classification with R 43/skin sensitizer category 1 is confirmed. According to criteria published in REACH guidance document chapter R. 8, IPPD was categorised as strong skin sensitizer.

Acute/short-term exposure systemic effects

IPPD is classified as harmful if swallowed because of an oral LD 50 of 522 mg/kg bw in rats (Hatano Research Institute 2003). The dermal acute toxicity is low indicated by dermal LD 50 > 7940 mg/kg bw in rabbits (Monsanto Co.1973). Due to the moderate oral acute toxicity, the very low dermal acute toxicity as well as the very low irritation potential of IPPD a limit exposure peaks to a factor of 8 is suggested. This approach is generally in line with the regulatory procedure in Germany (see Technical Rule for Hazardous Substances 900).

DNEL short-term systemic dermal: 0.1125 mg/kg bw/day x 8 = 0.9 mg/kg bw/day

DNEL short-term systemic inhalation: 0.8 mg/m3 x 8 = 6.4 mg/m3

DNEL long-term exposure systemic

As discussed under chapter repeated dose toxicity the subchronic feeding study (Monsanto Co 1990) is the most relevant study and is used for DNEL calculation; start point LOAEL 180 ppm (ca. 13.5 mg/kg bw/day) based on significant changes in liver weights noted in treated females.

Worker DNEL long-term systemic for oral route

Start point: LOAEL 13.5 mg/kg bw and day (subchronic feeding study in rats Monsanto Co 1990)

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

=> Corrected NOAEL 13.5 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 1*

Intraspecies differences: 5

Differences in duration of exposure (subchronic study to chronic study): 2

Dose response and endpoint specific/severity issues: 1

Quality of database: 3**

Overall factor (product of individual factors): 120

=>Worker DNEL long-term for oral route-systemic: 0.1125 mg/kg bw/day

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

** Starting point for DNEL calculation is a LOAEL, default factor of 3, according to ECHA Guidance document chapter R.8

Worker DNEL long-term systemic for dermal route

Start point: LOAEL 13.5 mg/kg bw/day (subchronic feeding study in rats Monsanto 1990).

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

=> Corrected LOAEL 13.5 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 1*

Intraspecies differences: 5

Differences in duration of exposure (subchronic study to chronic): 2

Dose response and endpoint specific/severity issues: 1

Quality of database: 3**

Overall factor (product of individual factors): 120

=>Worker DNEL long-term for dermal route-systemic: 0.1125 mg/kg bw/day

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

** Starting point for DNEL calculation is a LOAEL, default factor of 3, according to ECHA Guidance document chapter R.8

Worker DNEL long-term systemic for inhalation route

Start point: LOAEL 13.5 mg/kg bw/day (subchronic feeding study in rats Monsanto 1990).

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 LOAEC: 23.8 mg/m3

Interspecies differences: Allometric scaling: 1

Remaining interspecies differences: 1*

Intraspecies differences: 5

Differences in duration of exposure (subchronic study to chronic): 2

Dose response and endpoint specific/severity issues: 1

Quality of database: 3**

Overall factor (product of individual factors): 30

=>Worker DNEL long-term for inhalation route-systemic: 0.8 mg/m3

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

** Starting point for DNEL calculation is a LOAEL, default factor of 3, according to ECHA Guidance document chapter R.8

DNEL fertility:

There are only limited data available to assess the toxicity of reproduction of IPPD.

The data from the limited screening reproduction toxicity study (TG 421) (Duslo 2009) and the histopathological data from a 90 day feeding study (Monsanto Co. 1990) are used in a weight of evidence approach to assess the toxicity of reproduction of IPPD. Significant reduction of body weights and clinical signs were observed in males of the highest dose group (125 mg/kg bw/d). In addition, histopathological changes of prostate in mid and high dose males and insignificant changes of spermatogenesis were observed in high dose males. However, no treatment-related effects on sperm vitality and sperm morphology were noted. In addition, the histopathological evaluation of testes, prostates and seminal vesicles in the 90 day feeding study revealed no treatment-related changes in histopathology. Thus, the relevance of the histopathological changes noted in prostates and spermatogenesis is questionable.

Females of the highest dose group (125 mg/kg bw/d) showed clinical signs and abortion. The maternal toxicity observed in high dose group females was also accompanied with decreased postnatal viability of offspring and pathological changes in offspring.

In conclusion, the reproduction toxicity of IPPD was evaluated in a weight of evidence approach. Based on the limited findings from the screening reproduction toxicity study and the histopathological data from the 90 day feeding study a parental and developmental toxicity NOAEL of 50 mg/kg bw and day is suggested, which based on body weight reduction and clinical signs in males at 125 mg/kg bw and clinical signs and abortion in females at 125 mg/kg bw. Developmental toxicity was indicated at 125 mg/kg bw by postnatal reduced viability index and pathological changes in offspring in the range of maternal toxicity. The NOAEL fertility of 50 mg/kg bw/day is above the suggested LOAEL systemic (13.5 mg/kg bw/and day) and thus it was concluded that the DNEL for long-term exposure covers the DNEL fertility. No additional DNEL fertility was calculated.

DNEL developmental toxicity:

The developmental toxicity of the test substance IPPD was evaluated in a developmental toxicity study (Monsanto Co. 1994). Pregnant Sprague-Dawley rats (24 per group) were used to determine the teratogenic potential of the test substance. Dosage levels of 0, 12.5, 62.5 and 125 mg/kg bw and day were administered orally by gavage as a single daily dose on day 6 through 15 of gestation. Individual clinical observations, body weight and food consumption were recorded during the study. The females were killed on day twenty of gestation, examined macroscopically and the uterine contents examined. Treatment of pregnant females with IPPD at dose level of 125 mg/kg bw/day resulted in maternal toxicity indicated by salivation, soft dark faces and decreased food consumption on day 6 to 9. No dose or treatment related differences were observed on number of live foetuses per litter, early or late resorptions, post-implantation loss, total litter weights, mean foetal weights, or total number of foetuses delivered. There was no evidence of any teratogenic effect of treatment with 2 abnormal foetuses in the control group, 2 abnormal foetuses in the low dose group (12.5 mg/kg bw/d) and 1 abnormal foetus in the mid dose group (62.5 mg/kg bw/d). There were no malformed foetuses in the high dose group (125 mg/kg bw/d). The only adverse effect noted in the foetuses and related to treatment was a retardation of ossification in the high dose group (125 mg/kg bw/d); and a low percentage of wavy ribs, 3.8% compared with 0.6% in the controls. Wavy ribs are a commonly observed effect in studies, especially in presence of maternal toxicity, and normally disappears post-natal and is not considered as a malformation but as a variation. There are no adverse effects in low and mid dose pups.

Based on the findings from this study a NOAEL maternal of 62.5 mg/kg bw/day and a NOAEL developmental toxicity of 62.5 mg/kg bw/day is suggested. The NOAEL developmental toxicity of 62.5 mg/kg bw/day is above the suggested LOAEL systemic (13.5 mg/kg bw/and day) and thus it was 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:
0.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.6 mg/m³
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:
0.06 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/kg bw/day
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high 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:
0.06 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/kg bw/day
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

In conclusion, the test substance IPPD showed a practically non-irritating potential to rabbit skin (Monsanto Co. 1974). This find is supported by earlier studies with human volunteers (Bayer AG 1963). A rather slight and transient eye irritation potential is noted in an eye irritation study (Monsanto Co. 1974). The test substance is not classified as skin or eye irritating.

The skin sensitisation potential of IPPD was evaluated in guinea pigs, mice and in studies with human volunteers. IPPD was sensitizing in guinea pigs and mice and was found to induce dermal sensitizing in humans; in consequence, existing classification with R 43/skin sensitizer category 1 is confirmed. According to criteria published in REACH guidance document chapter R. 8, IPPD was categorised as strong skin sensitizer.

Acute/short-term exposure systemic effects:

IPPD is classified as harmful if swallowed because of an oral LD 50 of 522 mg/kg bw in rats (Hatano Research Institute 2003). The dermal acute toxicity is low indicated by dermal LD 50 > 7940 mg/kg bw in rabbits (Monsanto Co.1973). Due to the moderate oral acute toxicity, the very low dermal acute toxicity as well as the very low irritation potential of IPPD a limit exposure peaks to a factor of 8 is suggested. This approach is generally in line with the regulatory procedure in Germany (see Technical Rule for Hazardous Substances 900).

DNEL short-term systemic dermal: 0.056 mg/kg bw/day x 8 = 0.5 mg/kg bw/day

DNEL short-term systemic oral: 0.056 mg/kg bw/day x 8 = 0.5 mg/kg bw/day

DNEL short-term systemic inhalation: 0.2 mg/m3 x 8 = 1.6 mg/m3

General public long-term exposure systemic

General public long-term systemic for oral route

Start point: LOAEL 13.5 mg/kg bw and day (subchronic feeding study in rats Monsanto Co 1990)

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

=> Corrected NOAEL 13.5 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 1*

Intraspecies differences: 10

Differences in duration of exposure (subchronic study to chronic): 2

Dose response and endpoint specific/severity issues: 1

Quality of database: 3**

Overall factor (product of individual factors): 240

=> General Public long-term for oral route-systemic: 0.056 mg/kg bw/day

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

** Starting point for DNEL calculation is a LOAEL, default factor of 3, according to ECHA Guidance document chapter R.8

General public long-term systemic for dermal route

Start point: LOAEL 13.5 mg/kg bw and day (subchronic feeding study in rats Monsanto Co 1990)

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

=> Corrected NOAEL 13.5 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 1*

Intraspecies differences: 10

Differences in duration of exposure (subchronic study to chronic): 2

Dose response and endpoint specific/severity issues: 1

Quality of database: 3**

Overall factor (product of individual factors): 240

=>General public long-term for dermal route-systemic: 0.056 mg/kg bw/day

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

** Starting point for DNEL calculation is a LOAEL, default factor of 3, according to ECHA Guidance document chapter R.8

General public long-term systemic for inhalation route

Start point: LOAEL 13.5 mg/kg bw and day (subchronic feeding study in rats Monsanto Co 1990)

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

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

=> Corrected NOAEC: 11.8 mg/m3

Interspecies differences: Allometric scaling: 1

Remaining interspecies differences: 1*

Intraspecies differences: 10

Differences in duration of exposure (subchronic study to chronic): 2

Dose response and endpoint specific/severity issues: 1

Quality of database: 3**

Overall factor (product of individual factors): 60

=>General Public DNEL long-term for inhalation route-systemic: 0.2 mg/m3

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

** Starting point for DNEL calculation is a LOAEL, default factor of 3, according to ECHA Guidance document chapter R.8

DNEL fertility

There are only limited data available to assess the toxicity of reproduction of IPPD.

The data from the limited screening reproduction toxicity study (TG 421) (Duslo 2009) and the histopathological data from a 90 day feeding study (Monsanto Co. 1990) are used in a weight of evidence approach to assess the toxicity of reproduction of IPPD. Significant reduction of body weights and clinical signs were observed in males of the highest dose group (125 mg/kg bw/d). In addition, histopathological changes of prostate in mid and high dose males and insignificant changes of spermatogenesis were observed in high dose males. However, no treatment-related effects on sperm vitality and sperm morphology were noted. In addition, the histopathological evaluation of testes, prostates and seminal vesicles in the 90 day feeding study revealed no treatment-related changes in histopathology. Thus, the relevance of the histopathological changes noted in prostates and spermatogenesis is questionable.

Females of the highest dose group (125 mg/kg bw/d) showed clinical signs and abortion. The maternal toxicity observed in high dose group females was also accompanied with decreased postnatal viability of offspring and pathological changes in offspring.

In conclusion, the reproduction toxicity of IPPD was evaluated in a weight of evidence approach. Based on the limited findings from the screening reproduction toxicity study and the histopathological data from the 90 day feeding study a parental and developmental toxicity NOAEL of 50 mg/kg bw and day is suggested, which based on body weight reduction and clinical signs in males at 125 mg/kg bw and clinical signs and abortion in females at 125 mg/kg bw. Fetotoxicity was indicated at 125 mg/kg bw by postnatal reduced viability index and pathological changes in offspring in the range of maternal toxicity. The NOAEL fertility of 50 mg/kg bw/day is above the suggested LOAEL systemic (13.5 mg/kg bw/and day) and thus it was concluded that the DNEL for long-term exposure covers the DNEL fertility. No additional DNEL fertility was calculated.

DNEL developmental toxicity

The developmental toxicity of the test substance IPPD was evaluated in a developmental toxicity study (Monsanto Co. 1994). Pregnant Sprague-Dawley rats (24 per group) were used to determine the teratogenic potential of the test substance. Dosage levels of 0, 12.5, 62.5 and 125 mg/kg bw and day were administered orally by gavage as a single daily dose on day 6 through 15 of gestation. Individual clinical observations, body weight and food consumption were recorded during the study. The females were killed on day twenty of gestation, examined macroscopically and the uterine contents examined. Treatment of pregnant females with IPPD at dose level of 125 mg/kg bw/day resulted in maternal toxicity indicated by salivation, soft dark faces and decreased food consumption on day 6 to 9. No dose or treatment related differences were observed on number of live foetuses per litter, early or late resorptions, post-implantation loss, total litter weights, mean foetal weights, or total number of foetuses delivered. There was no evidence of any teratogenic effect of treatment with 2 abnormal foetuses in the control group, 2 abnormal foetuses in the low dose group (12.5 mg/kg bw/d) and 1 abnormal foetus in the mid dose group (62.5 mg/kg bw/d). There were no malformed foetuses in the high dose group (125 mg/kg bw/d). The only adverse effect noted in the foetuses and related to treatment was a retardation of ossification in the high dose group (125 mg/kg bw/d); and a low percentage of wavy ribs, 3.8% compared with 0.6% in the controls. Wavy ribs are a commonly observed effect in studies, especially in presence of maternal toxicity, and normally disappears post-natal and is not considered as a malformation but as a variation. There are no adverse effects in low and mid dose pups.

Based on the findings from this study a NOAEL maternal of 62.5 mg/kg bw/day and a NOAEL developmental toxicity of 62.5 mg/kg bw/day is suggested. The NOAEL developmental toxicity of 62.5 mg/kg bw/day is above the suggested LOAEL systemic (13.5 mg/kg bw/and day) and thus it was concluded that the DNEL for long-term exposure covers the DNEL developmental toxicity.