Nitrapyrin

Toxicological Summary

Workers - 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

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Modified dose descriptor starting point:

NOAEC

Value:

8.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

= 5 mg/kg x (1/0.38)  x (100%oral rat / 100%inhal human) x (6.7/10)

AF for dose response relationship:

1

Justification:

None required. A clear NOEL is available.

AF for differences in duration of exposure:

1

Justification:

Starting point NOEL derived from a chronic toxicity study

AF for interspecies differences (allometric scaling):

1

Justification:

Not required after initial conversion of starting point from oral to inhalation

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining (TD) differences between species

AF for intraspecies differences:

5

Justification:

Default factor for variation between individual workers

AF for the quality of the whole database:

1

Justification:

None required. The data available was conducted to internationally recognised guidelines and GLP.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Modified dose descriptor starting point:

NOAEC

Value:

211 mg/m³

Explanation for the modification of the dose descriptor starting point:

Not route to route, but corrected for rat: man sRVhuman/wRV = 630 * 0.67 = 422 mg/m3 (rat and human inhalation absorption both = 100% ) and then duration (4hours to 8 hours) using  C^n x t = k, where n=1 for shorter to longer duration = (422 mg/m3 x 4 hours)/ 8 hours = 211 mg/m3

AF for dose response relationship:

1

Justification:

None required. A clear NOEL is available.

AF for interspecies differences (allometric scaling):

1

Justification:

Not required for inhalation exposure where sRV human/wRV ratio applied

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining (TD) differences between species

AF for intraspecies differences:

5

Justification:

Default factor for variation between individual workers

AF for the quality of the whole database:

1

Justification:

None required. The data available was conducted to internationally recognised guidelines and GLP.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

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:

5.6 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

180

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

AF for dose response relationship:

1

Justification:

None required. A clear NOEL is available.None required. A clear NOEL is available.

AF for differences in duration of exposure:

6

Justification:

Default factor for extrapolation from subacute to a chronic duration

AF for interspecies differences (allometric scaling):

2.4

Justification:

Default allometric scaling factor for extrapolating from rabbit to man

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining (TD) differences between species

AF for intraspecies differences:

5

Justification:

Default factor for variation between individual workers

AF for the quality of the whole database:

1

Justification:

None required. The data available was conducted to internationally recognised guidelines and GLP.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.03 mg/cm²

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Dose descriptor:

other: NOAEL

AF for dose response relationship:

1

Justification:

None required. A clear NOAEL is available

AF for differences in duration of exposure:

6

Justification:

Default factor for extrapolating from subacute to chronic duration

AF for interspecies differences (allometric scaling):

1

Justification:

Not required for local effects

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining (TD) differences between species

AF for intraspecies differences:

5

Justification:

Default factor for variation between individual workers

AF for the quality of the whole database:

1

Justification:

None required. The data available was conducted to internationally recognised guidelines and GLP.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.2 mg/cm²

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Dose descriptor starting point:

other: NOAEL

AF for dose response relationship:

1

Justification:

None required. A clear NOAEL is available.

AF for interspecies differences (allometric scaling):

1

Justification:

Not required for local effects.

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining (TD) differences between species

AF for intraspecies differences:

5

Justification:

Default factor for variation between individual workers

AF for the quality of the whole database:

1

Justification:

None required. The data available was conducted to internationally recognised guidelines and GLP.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

Justification for endpoint selection:

 

- Reproductive toxicity: effects on fertility (oral): The key study was conducted in compliance with GLP and in accordance with the OECD Guideline for the Testing of Chemicals Number 416 on the test substance.

 

- Reproductive toxicity: effects on fertility (dermal): The data obtained from oral exposure is deemed sufficient to address this endpoint.

 

- Reproductive toxicity: effects on fertility (inhalation): The data obtained from oral exposure is deemed sufficient to address this endpoint.

 

- Reproductive toxicity: developmental toxicity (oral): The key study was conducted in compliance with GLP and in accordance with the OECD Guideline for the Testing of Chemicals Number 414 on the test substance.

 

- Reproductive toxicity: developmental toxicity (dermal): The data obtained from oral exposure is deemed sufficient to address this endpoint.

 

- Reproductive toxicity: developmental toxicity (inhalation): The data obtained from oral exposure is deemed sufficient to address this endpoint.

 

- Acute toxicity: the registered substance is Harmful via the oral route (Cat.4), as the acute oral LD50 was determined to be 1066 mg/kg. The acute dermal LD50 was greater than 2000 mg/kg at 2830 mg/kg. The acute inhalation LC50 was >0.63 mg/L which was the highest dose tested.

 

- Skin and eye irritation/corrosion; skin sensitisation: The substance was not irritating to skin, but was irritating to the eye and showed weak sensitisation potential in an M&K study. In a repeat dose dermal toxicity study in rabbits, histopathology in the skin was considered to be symptomatic of dry skin, caused by the adsorbent properties of test material. A NOAEC of 2.2 mg/sq.cm (derived from the 100 mg/kg bw/d dose level) was set for this effect.

 

- Repeat-dose toxicity: a 1962 90-d rat dietary study and a 1989 2 year rat dietary toxicity studies are available, along with a 1989 52 week dog dietary study and a 1995 90 day dietary mouse study. NO(A)EL/LO(A)ELs were established at 5/20, 30/100 and 3/15 in the 2 year and 90 day rat and the 52 week dog studies respectively. It was not considered to be carcinogenic. The primary target organ was the liver. Dose levels in the 90 day mouse study were set too high, and a NOAEL could not be established (Lowest dose was 200 mg/kg bw/day). The rat 2 year study was selected over the dog for chronic toxicity as, after interspecies allometric respiration factors this gave the most conservative DNELs. A 15 exposure (21 day) repeat dose dermal study (rabbits) is avaialble with the systemic NOEL considered to be the top dose tested (1000 mg/kg bw/day - the limit dose). The local effects NOAEL was conservatively set at 2.2 mg/sq.cm (derived from the 100 mg/kg bw/d dose level), based on histopathology in the skin (in the absence of erythema or oedema) which was considered to be symptomatic of dry skin, most likely caused by the adsorbent properties of test material.

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

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

4.35 mg/m³

Explanation for the modification of the dose descriptor starting point:

=5 mg/kg bw/day x (1/1.15) x (100% oral rat / 100% inhal human) x (100%inhal rat / 100%inhal human)

AF for dose response relationship:

1

Justification:

None required. A clear NOEL is available.

AF for differences in duration of exposure:

1

Justification:

Starting point NOEL derived from a chronic toxicity study

AF for interspecies differences (allometric scaling):

1

Justification:

Not required after initial conversion of starting point from oral to inhalation

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining (TD) differences between species

AF for intraspecies differences:

10

Justification:

Default factor for variation between individuals in the general population.

AF for the quality of the whole database:

1

Justification:

None required. The data available was conducted to internationally recognised guidelines and GLP.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.2 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

105 mg/m³

Explanation for the modification of the dose descriptor starting point:

Not route to route, but corrected for duration (4hours to 24 hours) using  C^n x t = k, where n=1 for shorter to longer duration = (630 mg/m3 x 4 hours)/ 24 hours = 105 mg/m3.  Rat and human inhalation absorption not corrected for,  because it is assumed as 100% in both species.

AF for dose response relationship:

1

Justification:

None required. A clear NOEL is available.

AF for interspecies differences (allometric scaling):

1

Justification:

Not required as for refrence doses expressed as concentration since ventilation rate directly depends on the basal metabolic rate

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining (TD) differences between species

AF for intraspecies differences:

10

Justification:

Default factor for variation between individuals in the general population.

AF for the quality of the whole database:

1

Justification:

None required. The data available was conducted to internationally recognised guidelines and GLP.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

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:

2.8 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

360

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

AF for dose response relationship:

1

Justification:

None required. A clear NOEL is available.

AF for differences in duration of exposure:

6

Justification:

Extrapolation from sub chronic to Chronic

AF for interspecies differences (allometric scaling):

2.4

Justification:

Extrapolation from rabbit to man

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining (TD) differences between species

AF for intraspecies differences:

10

Justification:

Default factor for variation between individuals in the general population.

AF for the quality of the whole database:

1

Justification:

None required. The data available was conducted to internationally recognised guidelines and GLP.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.015 mg/cm²

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

150

Dose descriptor:

other: NOAEL

AF for dose response relationship:

1

Justification:

None required. A clear NOAEL is available

AF for differences in duration of exposure:

6

Justification:

Default factor for extrapolating from subacute to chronic duration

AF for interspecies differences (allometric scaling):

1

Justification:

Not required for local effects

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining (TD) differences between species

AF for intraspecies differences:

10

Justification:

Default factor for variation between individuals in the general population.

AF for the quality of the whole database:

1

Justification:

None required. The data available was conducted to internationally recognised guidelines and GLP.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.1 mg/cm²

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

other: NOAEL

AF for dose response relationship:

1

Justification:

None required. A clear NOAEL is available.

AF for interspecies differences (allometric scaling):

1

Justification:

Not required for local effects

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining (TD) differences between species

AF for intraspecies differences:

10

Justification:

Default factor for variation between individuals in the general population.

AF for the quality of the whole database:

1

Justification:

None required. The data available was conducted to internationally recognised guidelines and GLP.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.05 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

5 mg/kg bw/day

AF for dose response relationship:

1

Justification:

None required. A clear NOEL is available.

AF for differences in duration of exposure:

1

Justification:

A chronic study is utilised to predict a chronic value. No extrapolation required.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor from rat to man

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining (TD) differences between species

AF for intraspecies differences:

10

Justification:

Default factor for variation between individuals in the general population.

AF for the quality of the whole database:

1

Justification:

None required. The data available was conducted to internationally recognised guidelines and GLP.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.15 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

AF for dose response relationship:

1

Justification:

None required. A clear NOEL is available.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor from rat to man

AF for other interspecies differences:

2.5

Justification:

Default factor for remaining (TD) differences between species

AF for intraspecies differences:

10

Justification:

Default factor for variation between individuals in the general population.

AF for the quality of the whole database:

1

Justification:

None required. The data available was conducted to internationally recognised guidelines and GLP.

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - General Population

Justification for endpoint selection:

 

- Reproductive toxicity: effects on fertility (oral): The key study was conducted in compliance with GLP and in accordance with the OECD Guideline for the Testing of Chemicals Number 416 on the test substance.

 

- Reproductive toxicity: effects on fertility (dermal): The data obtained from oral exposure is deemed sufficient to address this endpoint.

 

- Reproductive toxicity: effects on fertility (inhalation): The data obtained from oral exposure is deemed sufficient to address this endpoint.

 

- Reproductive toxicity: developmental toxicity (oral): The key study was conducted in compliance with GLP and in accordance with the OECD Guideline for the Testing of Chemicals Number 414 on the test substance.

 

- Reproductive toxicity: developmental toxicity (dermal): The data obtained from oral exposure is deemed sufficient to address this endpoint.

 

- Reproductive toxicity: developmental toxicity (inhalation): The data obtained from oral exposure is deemed sufficient to address this endpoint.

 

- Acute toxicity: the registered substance is Harmful via the oral route (Cat.4), as the acute oral LD50 was determined to be 1066 mg/kg. The acute dermal LD50 was greater than 2000 mg/kg at 2830 mg/kg. The acute inhalation LC50 was >0.63 mg/L which was the highest dose tested.

 

- Skin and eye irritation/corrosion; skin sensitisation: The substance was not irritating to skin, but was irritating to the eye and showed weak sensitisation potential in an M&K study. In a repeat dose dermal toxicity study in rabbits histopathology in the skin was considered to be symptomatic of dry skin, caused by the adsorbent properties of test material. A NOAEC of 2.2 mg/sq.cm (derived from the 100 mg/kg bw/d dose level) was set for this effect.

 

- Repeat-dose toxicity: a 1962 90-d rat dietary study and a 1989 2 year rat dietary toxicity studies are available, along with a 1989 52 week dog dietary study and a 1995 90 day dietary mouse study. NO(A)EL/LO(A)ELs were established at 5/20, 30/100 and 3/15 in the 2 year and 90 day rat and the 52 week dog studies respectively. It was not considered to be carcinogenic. The primary target organ was the liver. Dose levels in the 90 day mouse study were set too high, and a NOAEL could not be established (lowest dose was 200 mg/kg bw/day). The rat 2 year study was selected over the dog for chronic toxicity as, after interspecies allometric respiration factors this gave the most conservative DNELs. In the rat teratogenicity study (gavage, corn oil vehicle) the NOAEL/LOAEL for maternal systemic effects was 15/50 mg/kg bw/day based on reduced body weight gain and this gives the most conservative acute/short-term risk assessment for the general population. A 15 exposure (21 day) repeat dose dermal study in rabbits is available with the systemic NOEL considered to be the top dose tested (1000 mg/kg bw/day - the limit dose). The local effects NOAEL was conservatively set at 2.2 mg/sq.cm (derived from the 100 mg/kg bw/d dose level), based on histopathology in the skin (in the absence of erythema or oedema) which was considered to be symptomatic of dry skin, most likely caused by the adsorbent properties of test material.