Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
175 mg/m³
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
DNEL related information

Workers - Hazard via dermal route

Systemic effects

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

Workers - Hazard for the eyes

Additional information - workers

The NOAEL of 500 mg/kg/day reported in a chronic carcinogenicity study in Phthalic anhydride will be taken as the starting point for the DNEL calculation.

Potential effects on developmental toxicity were investigated in a developmental toxicity study in rats. No evidence of developmental toxicity was observed. In addition no effects were reported in repeated dose toxicity studies on the reproductive organs.Consequently potential effects on fertility and developmental toxicity are not expected and covered by the systemic DNEL.

Basis for calculation of DNEL:

Rat (Fischer 344) male/female, oral: feed

Dose: 7500, 15000 ppm= ca. 500, 1000 mg/kg bw/d

Exposure: 105 w (daily)

Method: Groups of 50 rats of each sex were administered phthalic anhydride at one of 2 doses, either 7500 or 15000 ppm (ca. 500, 1000 mg/kg bw/d) for 105 weeks. Matched controls consisted of 20 untreated rats of each sex. All surviving rats were killed at the end of the period of administration of the test chemical. All animals were checked twice daily for deaths. Observations for sick, tumor-bearing, and moribund animals were recorded daily.

Based on data on phthalic anhydride:

Systemic Effects:

The mean body weight of the high-dosed male rats were lower than those of the corresponding controls from week 13 to the end of the bioassay; mean body weight of the low-dose males and both the low- and high-dose females were essentially unaffected by administration of the test chemical.

NOAEL = 500 mg/kg bw/d (rat, m+f) (based on the reduced body weight gain (<10%) at the next higher dose (1000 mg/kg/day).

No tumors occurred in the rats of either sex at incidences that could be clearly related to the administration of the test compound. It is concluded that under the conditions of this bioassay, phthalic anhydride was not carcinogenic for F344 rats of either sex (Huff, 1984; Kluwe, 1986; NCI, 1979).

Potential effects on fertility or developmental toxicity are not expected and covered by this DNEL.

No DNEL for fertility and developmental toxicity are calculated.

Long-term inhalation route-systemic (worker) using extrapolations factors:

NOAEL (rat) oral: 500 mg/kg bw/day

For interspecies differences rat vs. human 4

500 mg/kg: 4 = 125 mg/kg bw/d

Body weight worker = 70 kg bw/person

125 mg/kg * 70 kg bw/person= 8750 mg/person/d

Respiratory volume worker = 10 m³/person (8h exposure; light activity for worker)

8750 mg/person/d: 10 m³/person = 875 mg/m³/8h

ABS (inhalation) = ABS (oral)

NOAEC worker (8h) = 875 mg/m³

For remaining interspecies differences 1 *

For extrapolation of exposure duration chronic to chronic: 1

For intraspecies differences in worker 5

For reliability of dose response 1

For quality of whole database 1

Overall factor 5

Worker DNEL long-term for inhalation route-systemic = 175 mg/m³/8h

Long-term oral route-systemic (worker) using extrapolation factors:

NOAEL (rat) oral: 500 mg/kg bw/day

For interspecies differences rat vs. human 4

For remaining interspecies differences: 1*

For intraspecies differences in worker 5

For extrapolation of exposure duration chronic to chronic: 1

For reliability of dose response 1

For quality of whole database 1

Overall factor: 20

Worker-DNEL long-term for oral route systemic = 25 mg/kg bw/d

Long-term dermal route-systemic (worker) using extrapolation factors:

NOAEL (rat) oral: 500 mg/kg bw/day

Dermal NOAEL= oral NOAEL* (ABS derm-rat)/ (ABS derm-human)

= dermal NOAEL = oral NOAEL (ABS 100%)/ (ABS 100%)

NOAEL (rat) dermal: 500 mg/kg bw/day

For interspecies differences rat vs. human 4

For remaining interspecies differences: 1*

For intraspecies differences in worker 5

For extrapolation of exposure duration chronic to chronic: 1

For reliability of dose response 1

For quality of whole database 1

Overall factor: 20

Worker-DNEL long-term for dermal route systemic = 25 mg/kg bw/d

* 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). Additionally long-term studies in 2 species (rat and mouse) are available for phthalic anhydride and the most sensitive species (with the lowest NOAEL) was used for the calculation.

Conclusion systemic DNELs

The lowest long term DNEL values for workers are:

Inhalation: 175 mg/m³/8h

Oral: 25 mg/kg bw/d

Dermal: 25 mg/kg bw/d

Due to the local irritation properties of Phthalic Acid (PA is classified as R41) the prominent toxicological effect is supposed to be the local irritation. According to the REACH TGD ´Guidance on information requirements and chemical safety assessment, Part E: Risk Characterization, May 2008´ compounds with risk of serious damage to eyes should be allocated to the moderate hazard band.

Short-term and long-term inhalation route-local (worker):

According to the REACH TGD ´Guidance on information requirements and chemical safety assessment, Part E: Risk Characterization, May 2008´ compounds with risk of serious damage to eyes are allocated to the moderate hazard band.

Acute effects are investigated in an acute inhalation study. A LOAEC of 5058 mg/m3 is reported in this guideline study. No irreversible damage could be observed, no histological effects appeared and all clinic effects disappeared after 2 -3 days. Based on the low acute toxicity profile of the compound a DNEL of 10 mg/m³ is proposed to protect against local effects after inhalation, based on a factor of 500 between the DNEL and the LOAEC in animal experiments.

General Population - Hazard via inhalation route

Systemic effects

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

General Population - Hazard for the eyes

Additional information - General Population

The NOAEL of 500 mg/kg/day reported in a chronic carcinogenicity study in Phthalic anhydride will be taken as the starting point for the DNEL calculation.

Potential effects on developmental toxicity were investigated in a developmental toxicity study in rats. No evidence of developmental toxicity was observed. In addition no effects were reported in repeated dose toxicity studies on the reproductive organs.Consequently potential effects on fertility and developmental toxicity are not expected and covered by the systemic DNEL.

Basis for calculation of DNEL:

Rat (Fischer 344) male/female, oral: feed

Dose: 7500, 15000 ppm= ca. 500, 1000 mg/kg bw/d

Exposure: 105 w (daily)

Method: Groups of 50 rats of each sex were administered phthalic anhydride at one of 2 doses, either 7500 or 15000 ppm (ca. 500, 1000 mg/kg bw/d) for 105 weeks. Matched controls consisted of 20 untreated rats of each sex. All surviving rats were killed at the end of the period of administration of the test chemical. All animals were checked twice daily for deaths. Observations for sick, tumor-bearing, and moribund animals were recorded daily.

Based on data on phthalic anhydride:

Systemic Effects:

The mean body weight of the high-dosed male rats were lower than those of the corresponding controls from week 13 to the end of the bioassay; mean body weight of the low-dose males and both the low- and high-dose females were essentially unaffected by administration of the test chemical.

NOAEL = 500 mg/kg bw/d (rat, m+f) (based on the reduced body weight gain (<10%) at the next higher dose (1000 mg/kg/day).

No tumors occurred in the rats of either sex at incidences that could be clearly related to the administration of the test compound. It is concluded that under the conditions of this bioassay, phthalic anhydride was not carcinogenic for F344 rats of either sex. (Huff, 1984;

Kluwe, 1986; NCI, 1979).

Potential effects on fertility or developmental toxicity are not expected and covered by this DNEL.

No DNEL for fertility and developmental toxicity are calculated.

Long-term inhalation route-systemic (general population) using extrapolations factors:

NOAEL (rat) oral: 500 mg/kg bw/day

For interspecies differences rat vs. human 4

500 mg/kg: 4 = 125 mg/kg bw/d

Body weight general public = 70 kg bw/person

125 mg/kg * 70 kg bw/person= 8750 mg/person/d

Respiratory volume general population: 20 m³/person (24h exposure; general population)

8750 mg/person/d: 20 m³/person = 437.5 mg/m³/24 h

ABS (inhalation) = ABS (oral)

NOAEC general population (24h) = 437.5 mg/m³/24h

For remaining interspecies differences: 1*

For extrapolation of exposure duration chronic to chronic: 1

For intraspecies differences in general population: 10

For reliability of dose response 1

For quality of whole database 1

Overall factor: 10

General population DNEL long-term for inhalation route systemic = 43.75 mg/m³/24 h

Long-term oral route-systemic (general population) using extrapolation factors:

NOAEL (rat) oral: 500 mg/kg bw/day

For interspecies differences rat vs. human 4

For remaining interspecies differences: 1*

For intraspecies differences in general population 10

For extrapolation of exposure duration chronic to chronic: 1

For reliability of dose response 1

For quality of whole database 1

Overall factor: 40

General population-DNEL long-term for dermal (oral) route systemic = 12.5 mg/kg bw/d

Long-term dermal route-systemic (general population) using extrapolation factors:

NOAEL (rat) oral: 500 mg/kg bw/day

Dermal NOAEL= oral NOAEL* (ABS derm-rat)/ (ABS derm-human)

= dermal NOAEL = oral NOAEL (ABS 100%)/ (ABS 100%)

NOAEL (rat) dermal: 500 mg/kg bw/day

For interspecies differences rat vs. human 4

For remaining interspecies differences: 1*

For intraspecies differences in general population 10

For extrapolation of exposure duration chronic to chronic: 1

For reliability of dose response 1

For quality of whole database 1

Overall factor: 20

General population-DNEL long-term for dermal route systemic = 12.5 mg/kg bw/d

* 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). Additionally long-term studies in 2 species (rat and mouse) are available for phthalic anhydride and the most sensitive species (with the lowest NOAEL) was used for the calculation.

Conclusion systemic DNELs:

The lowest long term DNEL values for the general population are:

Inhalation: 43.75 mg/m³/24 h

Oral: 12.5 mg/kg bw/d

Dermal: 12.5 mg/kg bw/d

Due to the local irritation properties of Phthalic Acid (PA is classified as R41) the prominent toxicological effect is supposed to be the local irritation. For the local effects the hazard band according to REACH TGD ´Guidance on information requirements and chemical safety assessment, Part E: Risk Characterization, May 2008´ is: moderate.