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EC number: 202-951-9 | CAS number: 101-54-2
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 7.1 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 14.2 mg/m³
DNEL related information
Local effects
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:
- 4 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 8 mg/kg bw/day
DNEL related information
Local effects
Long term exposure
- Most sensitive endpoint:
- sensitisation (skin)
Acute/short term exposure
- Most sensitive endpoint:
- sensitisation (skin)
Workers - Hazard for the eyes
Additional information - workers
Acute/short-term local effects/ Long-term exposure local effects
4-ADPA was not irritating to skin in a guideline study (TG 404) (Bayer AG 1982a). In another guideline study (Monsanto Co. 1984) the test substance showed slightly to moderate irritating effects on the skin of rabbits, which were reversible within 7 days. Transient moderate irritant effects were observed after instillation of 4-ADPA into the eyes of rabbits (Bayer AG 1982b, Monsanto Co. 1984). The conjunctival redness mean scores of 4/6 animals were > 2 (Monsanto Co. 1984), indicating an eye irrtating potential of 4-ADPA according to the GHS classification criteria; 4 -ADPA is classified as irritating to eyes (category 2) according to the classification criteria of regulation no. 1272/2008 (GHS); but this observation was not confirmed by the result of another guideline conform study. The reason for the discrepancy between the results of the two available studies is not known.
The findings from several tests with guinea pigs and mice revelaed that 4 -ADPA is a skin sensitizer in animals. In addition, the test substance has repeatedly been demonstrated to be an allergen in humans. Based on the findings in animals and humans 4-ADPA is classified as skin sensitizing. In a weight of evidence approach with the available skin sensitizing data, a strong skin sensitizing potential of 4 -ADPA is suggested.
Acute/short-term exposure systemic effects:
4-ADPA is classified as harmful if swallowed because of an oral LD50 value of 336 mg/kg bw in rats (Monsanto Co 1991b). The dermal acute toxicity is low indicated by dermal LD50 value > 5000 mg/kg bw in rabbits (Monsanto Co. 1984b).
A slight and reversilbe increase in methemoglobin was observed in cats after single oral application of 4 –ADPA at a dose of 25 mg/kg bw/day (Bayer AG 1985). The ability to induce methemoglobinemia is supported by results of a former study (Bayer AG 1957). However, the effects seen in cats at 25 mg/kg bw/day are slight and reversible. No such effects were observed in rats even at higher concentrations (up to lethal dosis, see acute oral toxicity study data). Rats are less sensitive in methemoglobin formation than cats, but strong methemoglobin formation is also detected in rats. Based on the findings of the 90-day feeding study (Singh 1986) it is concluded that effects on liver and hematological parameters are the most sensitive endpoints. Due to the moderate oral acute toxicity, the very low dermal acute toxicity and the reversible and very slight methemoglobin formation a limit exposure peaks to a factor of 2 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: 4 mg/kg bw/day x 2 = 8 mg/kg bw/day
DNEL short-term systemic inhalation: 7.1 mg/m3 x 2 = 14.2 mg/m3
DNEL long-term exposure systemic
Define starting point:
The NOAEL from a 90-day feeding study (Singh 1986) is used as starting point for DNEL derivation. The NOAEL in this 90-day feeding study with male rats was 1000 ppm (approximately 100 mg/kg bw/d). In this study, slight anemia, and changes in liver enzyme levels were seen at approximately 250 mg/kg bw/d (2500 ppm). At 5000 ppm (approximately 435 to 500 mg/kg bw/d) pathological changes in the liver were found at the histological examination, and at 7500 ppm (approximately 555 - 750 mg/kg bw/d) histopathological changes were found in the testes (degeneration of seminiferous tubes). The NOAEL in a rat carcinogenicity study with dietary exposure over 78 weeks was 1200 ppm (approximately 60 -120 mg/kg bw/d; highest dose tested).
Based on the findings from the 90 day feeding study (Singh 1986) and the supporting results from the carcinogenicity study, the NOAEL for repeated dose toxicity is assessed to be 100 mg/kg bw/d.
Worker DNEL long-term systemic for oral route
Start point: NOAEL 100 mg/kg bw and day (subchronic feeding study, Singh 1986)
Differences in absorption Abs (oral-rat) / Abs (oral-human): 1*
=> Corrected NOAEL 100 mg/kg bw/day
Interspecies differences: Allometric scaling: 4
Remaining interspecies differences: 2.5
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: 1
Overall factor (product of individual factors): 100
=>Worker DNEL long-term for oral route-systemic: 1 mg/kg bw/day
* In vivo toxicokinetic data of 4-ADPA indicate an oral absorption rate of 80% – 88% and a dermal absorption rate of 20% (Monsanto Co 1991)
Worker DNEL long-term systemic for dermal route
Start point: NOAEL 100 mg/kg bw and day (subchronic feeding study, Singh 1986)
Differences in absorption Abs (oral-rat) / Abs (dermal-human): 4*
=> Corrected NOAEL 400 mg/kg bw/day
Interspecies differences: Allometric scaling: 4
Remaining interspecies differences: 2.5
Intraspecies differences: 5
Differences in duration of exposure (subchronic study to chronic): 2
Dose response and endpoint specific/severity issues: 1
Quality of database: 1
Overall factor (product of individual factors): 100
=>Worker DNEL long-term for dermal route-systemic: 4 mg/kg bw/day
* In vivo toxicokinetic data of 4-ADPA indicate an oral absorption rate of 80% – 88% and a dermal absorption rate of 20% (Monsanto Co 1991)
Worker DNEL long-term systemic for inhalation route
Start point: NOAEL 100 mg/kg bw and day (subchronic feeding study, Singh 1986)
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: 176.32 mg/m3
Interspecies differences: Allometric scaling: 1
Remaining interspecies differences: 2.5
Intraspecies differences: 5
Differences in duration of exposure (subchronic study to chronic): 2
Dose response and endpoint specific/severity issues: 1
Quality of database: 1
Overall factor (product of individual factors): 25
=>Worker DNEL long-term for inhalation route-systemic: 7.1 mg/m3
* In vivo toxicokinetic data of 4-ADPA indicate an oral absorption rate of 80% – 88% and a dermal absorption rate of 20% (Monsanto Co 1991)
DNEL fertility
There is no fertility study available. In a 90-day feeding study (Singh 1986) on male rats, degeneration of seminiferous tubules in the testes, accompanied by marginal changes in enzyme activities (LDH and hyaluronidase) were found at severely toxic dose level (about 7500 ppm, approximately 555-750 mg/kg bw/d). The NOAEL for testicular toxicity was determined as 5000 ppm (approximately 435 - 500 mg/kg bw/d). In early NTP (1978) carcinogenicity studies with rats and mice no histological changes in the reproductive organs of both sexes were observed up to and including the highest dose tested (corresponding to approximately 60 - 120 mg/kg bw/d for the rats; due to severe limitations in the study no reliable dose could be derived for the mice). Based on the findings of the 90-day feeding study (Singh 1986) which indicate adverse effects on the testes only at high and toxic doses and that demonstrates effects on liver and hematological parameters as most sensitive endpoints it is concluded that there is no evidence of a specific reproductive potential and that the DNEL long-term exposure covers the DNEL fertility.
DNEL developmental toxicity
Developmental toxicity (significant increased resorption, reduced foetal weight and increased foetal anomalies) was observed in two reliable gavage studies on CD rats (Monsanto Co.1989), exposed from gestational day 6 to 15 to doses that caused clear maternal toxicity (> 100 mg/kg bw/d), as evidenced by significantly decreased weight gain and food consumption. The maternal and developmental NOAELs were identified at 50 mg/kg bw/d. Based on this NOAEL of 50 mg/kg bw/d DNELs for developmental toxicity were derivated according to REACH guidance documentation chapter 8.
Worker DNEL developmental toxicity for oral route
Start point: NOAEL 50 mg/kg bw and day (Developmental toxicity study, rat, Monsanto Co. 1989)
Differences in absorption Abs (oral-rat) / Abs (oral-human): 1*
=> Corrected NOAEL 50 mg/kg bw/day
Interspecies differences: Allometric scaling: 4
Remaining interspecies differences: 2.5
Intraspecies differences: 5
Developmental toxicity study comparable to OECD TG 414: 1
Dose response and endpoint specific/severity issues: 1
Quality of database: 1
Overall factor (product of individual factors): 50
=>Worker DNEL developmental toxicity for oral route-systemic: 1 mg/kg bw/day
* In vivo toxicokinetic data of 4-ADPA indicate an oral absorption rate of 80% – 88% and a dermal absorption rate of 20% (Monsanto Co 1991)
Worker DNEL developmental toxicity for dermal route
Start point: NOAEL 50 mg/kg bw and day (Developmental toxicity study, rat, Monsanto Co. 1989)
Differences in absorption Abs (oral-rat) / Abs (dermal-human): 4*
=> Corrected NOAEL 200 mg/kg bw/day
Interspecies differences: Allometric scaling: 4
Remaining interspecies differences: 2.5
Intraspecies differences: 5
Developmental toxicity study comparable to OECD TG 414: 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 dermal route-systemic: 4 mg/kg bw/day
* In vivo toxicokinetic data of 4-ADPA indicate an oral absorption rate of 80% – 88% and a dermal absorption rate of 20% (Monsanto Co 1991)
Worker DNEL develpmental toxicity for inhalation route
Start point: NOAEL 50 mg/kg bw and day (Developmental toxicity study, rat, Monsanto Co. 1989)
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: 88.16 mg/m3
Interspecies differences: Allometric scaling: 1
Remaining interspecies differences: 2.5
Intraspecies differences: 5
Developmental toxicity study comparable to OECD TG 414: 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: 7.1 mg/m3
* In vivo toxicokinetic data of 4-ADPA indicate an oral absorption rate of 80% – 88% and a dermal absorption rate of 20% (Monsanto Co 1991)
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1.74 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 3.48 mg/m³
DNEL related information
Local effects
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:
- 2 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 4 mg/kg bw/day
DNEL related information
Local effects
Long term exposure
- Most sensitive endpoint:
- sensitisation (skin)
Acute/short term exposure
- 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:
- 0.5 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1 mg/kg bw/day
DNEL related information
General Population - Hazard for the eyes
Additional information - General Population
Acute/short-term local effects/ Long-term exposure local effects
4-ADPA was not irritating to skin in a guideline study (TG 404) (Bayer AG 1982a). In another guideline study (Monsanto Co. 1984c) the test substance showed slightly to moderate irritating effects on the skin of rabbits, which were reversible within 7 days. Transient moderate irritant effects were observed after instillation of 4-ADPA into the eyes of rabbits (Bayer AG 1982b, Monsanto Co. 1984d). The conjunctival redness mean scores of 4/6 animals were>2 (Monsanto Co. 1984), indicating an eye irrtating potential of 4-ADPA according to the GHS classification criteria; 4 -ADPA is classified as irritating to eyes (category 2) according to the classification criteria of regulation no. 1272/2008 (GHS); but this observation was not confirmed by the result of another guideline conform study. The reason for the discrepancy between the results of the two available studies is not known.
The findings from several tests with guinea pigs and mice revelaed that 4 -ADPA is a skin sensitizer in animals. In addition, the test substance has repeatedly been demonstrated to be an allergen in humans. Based on the findings in animals and humans 4 -ADPA is classified as skin sensitizing. In a weight of evidence approach with the available skin sensitizing data, a strong skin sensitizing potential of 4 -ADPA is suggested.
Acute/short-term exposure systemic effects
A slight and reversilbe increase in methemoglobin was observed in cats after single oral application of 4 –ADPA at a dose of 25 mg/kg bw/day (Bayer AG 1985). The ability to induce methemoglobinemia is supported by results of a former study (Bayer AG 1957). However, the effects seen in cats at 25 mg/kg bw/day are slight and reversible. No such effects were observed in rats even at higher concentrations (up to lethal dosis, see acute oral toxicity study data). Rats are less sensitive in methemoglobin formation than cats, but strong methemoglobin formation is also detected in rats. Based on the findings of the 90-day feeding study (Singh 1986) it is concluded that effects on liver and hematological parameters are the most sensitive endpoints. Due to the moderate oral acute toxicity, the very low dermal acute toxicity and the reversible and very slight methemoglobin formation a limit exposure peaks to a factor of 2 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: 2 mg/kg bw/day x 2 = 4 mg/kg bw/day
DNEL short-term systemic inhalation: 1.74 mg/m3 x 2 = 3.48 mg/m3
DNEL short-term systemic oral: 0.5 mg/kg bw/day x 2 = 1 mg/kg bw/day
DNEL long-term exposure systemic
Define starting point:
The NOAEL from a 90-day feeding study (Singh 1986) is used as starting point for DNEL derivation. The NOAEL in this 90-day feeding study with male rats was 1000 ppm (approximately 100 mg/kg bw/d). In this study, slight anemia, and changes in liver enzyme levels were seen at approximately 250 mg/kg bw/d (2500 ppm). At 5000 ppm (approximately 435 to 500 mg/kg bw/d) pathological changes in the liver were found at the histological examination, and at 7500 ppm (approximately 555 - 750 mg/kg bw/d) histopathological changes were found in the testes (degeneration of seminiferous tubes). The NOAEL in a rat carcinogenicity study with dietary exposure over 78 weeks was 1200 ppm (approximately 60 -120 mg/kg bw/d; highest dose tested).
Based on the findings from the 90 day feeding study (Singh 1986) and the supporting results from the carcinogenicity study, the NOAEL for repeated dose toxicity is assessed to be 100 mg/kg bw/d.
General public long-term systemic for oral route
Start point: NOAEL 100 mg/kg bw and day (subchronic feeding study, Singh 1986)
Differences in absorption Abs (oral-rat) / Abs (oral-human): 1*
=> Corrected NOAEL 100 mg/kg bw/day
Interspecies differences: Allometric scaling: 4
Remaining interspecies differences: 2.5
Intraspecies differences: 10
Differences in duration of exposure (subchronic study to chronic): 2
Dose response and endpoint specific/severity issues: 1
Quality of database: 1
Overall factor (product of individual factors): 200
=>General public DNEL long-term for oral route-systemic: 0.5 mg/kg bw/day
* In vivo toxicokinetic data of 4-ADPA indicate an oral absorption rate of 80% – 88% and a dermal absorption rate of 20% (Monsanto Co 1991)
General public long-term systemic for dermal route
Start point: NOAEL 100 mg/kg bw and day (subchronic feeding study, Singh 1986)
Differences in absorption Abs (oral-rat) / Abs (dermal-human): 4*
=> Corrected NOAEL 400 mg/kg bw/day
Interspecies differences: Allometric scaling: 4
Remaining interspecies differences: 2.5
Intraspecies differences: 10
Differences in duration of exposure (subchronic study to chronic): 2
Dose response and endpoint specific/severity issues: 1
Quality of database: 1
Overall factor (product of individual factors): 200
=>General public long-term for dermal route-systemic: 2 mg/kg bw/day
* In vivo toxicokinetic data of 4-ADPA indicate an oral absorption rate of 80% – 88% and a dermal absorption rate of 20% (Monsanto Co 1991)
General public long-term systemic for inhalation route
Start point: NOAEL 100 mg/kg bw and day (subchronic feeding study, Singh 1986)
Respiratory volume rat (sRV) general public 1/1.15: 0.87
Differences in absorption Abs (oral-rat) / Abs (inhalation-human): 1*
=> Corrected NOAEC: 87 mg/m3
Interspecies differences: Allometric scaling: 1
Remaining interspecies differences: 2.5
Intraspecies differences: 10
Differences in duration of exposure (subchronic study to chronic): 2
Dose response and endpoint specific/severity issues: 1
Quality of database: 1
Overall factor (product of individual factors): 50
=>General Public DNEL long-term for inhalation route-systemic: 1.74 mg/m3
* In vivo toxicokinetic data of 4-ADPA indicate an oral absorption rate of 80% – 88% and a dermal absorption rate of 20% (Monsanto Co 1991)
DNEL fertility
There is no fertility study available. In a 90-day feeding study (Singh 1986) on male rats, degeneration of seminiferous tubules in the testes, accompanied by marginal changes in enzyme activities (LDH and hyaluronidase) were found at severely toxic dose level (about 7500 ppm, approximately 555-750 mg/kg bw/d). The NOAEL for testicular toxicity was determined as 5000 ppm (approximately 435 - 500 mg/kg bw/d). In early NTP (1978) carcinogenicity studies with rats and mice no histological changes in the reproductive organs of both sexes were observed up to and including the highest dose tested (corresponding to approximately 60 - 120 mg/kg bw/d for the rats; due to severe limitations in the study no reliable dose could be derived for the mice). Based on the findings of the 90-day feeding study (Singh 1986) which indicate adverse effects on the testes only at high and toxic doses and that demonstrates effects on liver and hematological parameters as most sensitive endpoints it is concluded that there is no evidence of a specific reproductive potential and that the DNEL long-term exposure covers the DNEL fertility.
DNEL developmental toxicity
Developmental toxicity (significant increased resorption, reduced foetal weight and increased foetal anomalies) was observed in two reliable gavage studies on CD rats (Monsanto Co.1989), exposed from gestational day 6 to 15 to doses that caused clear maternal toxicity (>= 100 mg/kg bw/d), as evidenced by significantly decreased weight gain and food consumption. The maternal and developmental NOAELs were identified at 50 mg/kg bw/d.
General public developmental toxicity for oral route
Start point: NOAEL 50 mg/kg bw and day (Developmental toxicity study, rat, Monsanto Co. 1989)
Differences in absorption Abs (oral-rat) / Abs (oral-human): 1*
=> Corrected NOAEL 50 mg/kg bw/day
Interspecies differences: Allometric scaling: 4
Remaining interspecies differences: 2.5
Intraspecies differences: 10
Developmental toxicity study comparable to OECD TG 414: 1
Dose response and endpoint specific/severity issues: 1
Quality of database: 1
Overall factor (product of individual factors): 100
=>General public DNEL developmental toxicity for oral route-systemic: 0.5 mg/kg bw/day
* In vivo toxicokinetic data of 4-ADPA indicate an oral absorption rate of 80% – 88% and a dermal absorption rate of 20% (Monsanto Co 1991)
General public developmental toxicity for dermal route
Start point: NOAEL 50 mg/kg bw and day (Developmental toxicity study, rat, Monsanto Co. 1989)
Differences in absorption Abs (oral-rat) / Abs (dermal-human): 4*
=> Corrected NOAEL 200 mg/kg bw/day
Interspecies differences: Allometric scaling: 4
Remaining interspecies differences: 2.5
Intraspecies differences: 10
Developmental toxicity study comparable to OECD TG 414: 1
Dose response and endpoint specific/severity issues: 1
Quality of database: 1
Overall factor (product of individual factors): 100
=>General public developmental toxicity for dermal route-systemic: 2 mg/kg bw/day
* In vivo toxicokinetic data of 4-ADPA indicate an oral absorption rate of 80% – 88% and a dermal absorption rate of 20% (Monsanto Co 1991)
General public developmental toxicity for inhalation route
Start point: NOAEL 50 mg/kg bw and day (Developmental toxicity study, rat, Monsanto Co. 1989)
Respiratory volume rat (sRV) general public 1/1.15: 0.87
Differences in absorption Abs (oral-rat) / Abs (inhalation-human): 1*
=> Corrected NOAEC: 43.5 mg/m3
Interspecies differences: Allometric scaling: 1
Remaining interspecies differences: 2.5
Intraspecies differences: 10
Developmental toxicity study comparable to OECD TG 414: 1
Dose response and endpoint specific/severity issues: 1
Quality of database: 1
Overall factor (product of individual factors): 25
=>General Public DNEL developmental toxicity for inhalation route-systemic: 1.74 mg/m3
* In vivo toxicokinetic data of 4-ADPA indicate an oral absorption rate of 80% – 88% and a dermal absorption rate of 20% (Monsanto Co 1991)
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