Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
25
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
159 mg/m³
Explanation for the modification of the dose descriptor starting point:

No inhalation repeated dose toxicity study is available. Thus, extrapolation from OECD 408 oral studies are performed. With this the lowest NOAEL of 100 mg/kg bw/d with respect to repeated dose systemic toxicity. Adjustment of dose metric to inhalational concentration:

The REACH R.8 guidance uses an inhalation volume for rats of 0.38 m3/kg for 8 hr exposure. Thus NOAEL to NOAEC conversion: NOAEC rats = 100 mg/kg/d / 0.38 m3/kg =  263 mg/m3.

No oral absorption data are available for DIPA; hence data of TIPA are used (90% oral absorption). 100% absorption is assumed for inhaltion: NOAEC rats = 263 mg/m3 x 90/100 = 237 mg/m3.

Correction factor for increased inhalation volume during work: NOAEC worker, 8hr = 6.7 m3/ 10m3 x 237 mg/m3 = 159 mg/m3.

AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
Extrapolation to chronic exposure based on a sub-chronic toxicity study.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
Default assessment factor.
AF for intraspecies differences:
5
Justification:
Default assessment factor.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported.
On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to applay an additiona factor.
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:
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 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
Overall assessment factor (AF):
150
Dose descriptor starting point:
NOAEL
Value:
750 mg/m³
Explanation for the modification of the dose descriptor starting point:

Dermal 28 day repeated dose toxicity study is available.

AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
3
Justification:
Since the material is soluble and is unlikely to accumulate (Log Pow = -0.79) the sub-acute to sub-chronic assessment factor is considered 1.5 rather than the default factor 3 (Bitsch et. al. (2006)), Regul. Toxicol Pharmacol 46, 202-210). Combination with the default sub-chronic to chronic factor 2 leads to a correction factor of 3.
AF for interspecies differences (allometric scaling):
4
Justification:
Assessment factor for allometric scaling.
AF for other interspecies differences:
2.5
Justification:
Default assessment factor.
AF for intraspecies differences:
5
Justification:
Default assessment factor.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported.
On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to applay an additional factor.
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:
120 µg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
5
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
1
Justification:
Reduction to factor 1, if there is specific evidence that increasing exposure duration does not increase the incidence or severity of adverse effects (GD R.8.4.3.1; ECHA, Nov. 2012). During the 28 days of exposure, findings did not accumulate over time, as the frequency of occurrence and grading do not correlate with increasing number of exposure days.
AF for interspecies differences (allometric scaling):
1
Justification:
A) allometric scaling should not be applied if the effects are not dependent on metabolic rate or systemic absorption, e.g. in the case of local effects; b) In general, as long as route-to-route extrapolation is not needed, allometric scaling should also not be applied in cases where doses in experimental animal studies are expressed as concentrations (e.g., in mg/m3 in air, ppm in diet, or mg/l in the drinking water) as these are assumed to be already scaled according to the allometric principle (GD R.8.4.3.1, ECHA, Nov. 2012)].
AF for other interspecies differences:
1
Justification:
The observed slight skin irritation after repeated exposure occurs most probably due to the basic pH of the test substance (see IUCLID chapter 4.6: water solubility: 400 g/L at 20°C and pH 12.2). Therefore, no further kinetic considerations apply (GD R.8.4.3.1, ECHA, Nov. 2012).
AF for intraspecies differences:
5
Justification:
Default assessment factor.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Kinetics (absorption figures for oral, dermal and inhalation route of exposure)

No data on inhalation absorption are available. Therefore for the DNEL derivation the default as reported in the REACH guidance will be used (i.e. 100%). No oral absorption data are available for DIPA either, the specific TIPA figure will be used for DNEL derivation (i.e. 90% absorption).

Dermal absorption of DIPA is assumed to be 20% based on a study which showed that 3.5% of the dose was found in skin remote from the site of the dosing; 0.1% in liver and kidney, 0.01% in fat; 1.1% of the applied dose was found in carcass; 0.2% of the dosed radioactivity was trapped in charcoal or monoethanolamine: 1-methoxy-2-propanol solution; 14.6% of the applied radioactivity was found in excreta (urine + feces + final cage wash).

Acute toxicity

DIPA does not have to be labelled for acute toxicity and therefore derivation of a DNELacuteis not necessary.

Irritation

DIPA is classified for eye irritation (Cat. 2, H319).The available data do not allow a quantitative approach. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent eye irritation.

Sensitisation

DIPA is not considered a skin sensitiser.

Long-term toxicity

The studies which are considered for DNEL derivation of DIPA are the 28 days dermal toxicity study with rats and the 90 days oral toxicity study with rats.

Twenty-one dermal applications of DIPA over a 30 day period at dosages of 500 and 750 mg/kg bw/day resulted in slight alteration of the skin at the site of application in both male and female Fischer 344 rats. The alteration consisted of hyperkeratosis at the site of DIPA application that was consistent with irritation induced by test material application to the skin. DIPA application at a dosage of 100 mg/kg bw/day did not produce any effects in the skin at the application site. The NOAEL for dermal irritancy in this study was 100 mg/kg bw/day (this corresponds to 0.8 mg/cm2 assuming a body weight of 0.2 kg and as 25 cm2 skin was exposed) in both male and female Fischer 344 rats. No changes in body weight, feed consumption, feed efficiency, hematological parameters, serum clinical chemistry or electrolyte profiles, urinalysis parameters, terminal body weights, or organ weights (absolute or relative) indicative of systemic toxicity were observed. There were no gross or microscopic hepatic, renal or urinary bladder alteration in male or female Fischer 344 rats at any dose level tested. The NOAEL for systemic toxicity in this study was greater than or equal to 750 mg/kg bw/day, the highest dose level tested.

 

In a 90-day toxicity study (according to OECD guideline 408 and under GLP), Fischer 344 rats (10/sex/dose) were administered DIPA at 0, 100, 500 or 1000 mg/kg bw/day via their drinking water. Additional groups (10/sex) were maintained on untreated water for an additional 28 days to assess recovery from DIPA-induced effects after initially receiving the control or high-dose water (0 or 1000 mg/kg bw/day) for at least 90 days. Rats given 1000 mg/kg bw/day drank less water than lower dose groups, with a corresponding decrement in food consumption and body weight. Urine specific gravity increased, and urine volume decreased for this group as well; both were considered to be related to reduced water intake. Serum cholesterol was slightly increased, and serum phosphorous was slightly decreased in the main study group at 1000 mg/kg bw/day; neither effect was noted in the recovery group. Changes in albumin in treated groups were also observed. Absolute and relative kidney weights were increased, males were affected to a larger degree. After the 28-day recovery, the changes in kidney weights were approximately one half that present at the end of the dosing period and slight renal tubule degeneration with regeneration was seen at the end of recovery in the 1000 mg/kg bw/day group. The only effect found in the 500 mg/kg bw/day group was increased absolute and relative kidney weights for males and females, without any histopathological correlate. The mean relative kidney weights were increased about 12% and 7% relative to controls for males and females, respectively.Absolute kidney weights were increased in the 100 mg/kg bw/day male group, but these rats weighed more than the controls, and the relative kidney weights were not statistically different than controls. NOAELs of 100 and 500 mg/kg bw/day were established for males and females, respectively.

Mutagenicity and carcinogenicity

DIPA is assessed as being non-mutagenic and not carcinogenic. Based on this, no separate risk characterisation for mutagenicity and carcinogenicity is needed.

Reproduction toxicity

The one-generation study with TIPA and the OECD 422 study with MIPA are assumed to cover the endpoint effects on fertility for DIPA. As no effects on fertility were observed in these studies, no DNEL has to be derived for this endpoint.

No developmental toxicity was observed in an oral prenatal developmental toxicity study in rats with DIPA and in a rabbit study with the structural analogon picloram TIPA salt. Thus, the NOAEL for developmental toxicity was considered 1000 mg/kg bw/day. No DNEL has to be derived for developmental toxicity. There are no indications from the available data that dams are more sensitive regarding systemic effects compared to animals exposed in the repeated dose toxicity studies.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
20
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
78 mg/m³
Explanation for the modification of the dose descriptor starting point:

No inhalation repeated dose toxicity study is available. Thus, extrapolation from OECD 408 oral studies are performed. With this the lowest NOAEL of 100 mg/kg bw/d with respect to repeated dose systemic toxicity.

Using this value as a starting point for chronic DNEL derivation for workers with respect to dermal and inhalational exposure:

 

DNEL, inhalation, General Population:

Adjustment of dose metric to inhalational concentration:

The REACH R.8 guidance uses an inhalation volume for rats of 0.38 m3/kg for 8 hr exposure

An 24 h respiratory volume of 1.15 m³/kg bw for rats was used for conversion into NOAEL upon inhaltation exposure. 

No oral absorption data are available for DIPA; hence data of TIPA are used (90% oral absorption). 100% absorption is assumed for inhaltion :

NOAEC rats = 100 mg/kg d x 90 / (1.15 x 100) = 78 mg/m³

DNEL= 78 mg/m³ / (1 x 10 x 2 x 1 x 1) = 3.9 mg/m³

AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
Extrapolation to chronic exposure based on a sub-chronic toxicity study.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.
AF for intraspecies differences:
10
Justification:
Default assessment factor.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
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:
no-threshold effect and/or no dose-response information available
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:
6.3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
Value:
750 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

DNEL: 750 mg/kg d / (4 x 10 x 3 x 1 x 1) = 6.3 mg/kg bw/day

AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
3
Justification:
Since the material is soluble and is unlikely to accumulate (Log Pow = -0.79) the sub-acute to sub-chronic assessment factor is considered 1.5 rather than the default factor 3 (Bitsch et al. (2006), Regul. Toxicol Pharmacol 46, 202-210). Comination with the default sub-chronic to chronic factor 2 leads to a correction factor of 3.
AF for interspecies differences (allometric scaling):
4
Justification:
Assessment factor for allometric scaling.
AF for intraspecies differences:
10
Justification:
Default assessment factor.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately rep
orted. On this basis the quality of the database is not considered to contribute uncertainty and it is
therefore not necessary to apply an additional factor.
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:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
80
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

DNEL: 100 / (4 x 10 x 2 x 1 x 1) = 1.3 mg/kg bw/day

AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
Extrapolation to chronic exposure based on a sub-chronic toxicity study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default assessment factor.
AF for intraspecies differences:
10
Justification:
Default assessment factor.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately rep
orted. On this basis the quality of the database is not considered to contribute uncertainty and it is
therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population