Aminoguanidinium hydrogen carbonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.34 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

225

Modified dose descriptor starting point:

LOAEC

Value:

77.57 mg/m³

Explanation for the modification of the dose descriptor starting point:

Convert oral LOAEL to inhalation LOAEC: 88 mg/kg/day x [1/0.38 x rat oral absorption (50%) / human inhalation absorption (100%) x (6.7/10)] = 77.57 mg/m3

AF for dose response relationship:

3

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment.

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute study to chronic exposure value in line with Table R.8-5 of Chapter R.8 of Guidance on information requirements and chemical safety assessment .

AF for interspecies differences (allometric scaling):

1

Justification:

Differences in species addressed in calculation of dose descriptor starting point. Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment.

AF for other interspecies differences:

1

Justification:

All interspecies differences accounted for by allometric scaling.

AF for intraspecies differences:

5

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment.

AF for the quality of the whole database:

1

Justification:

Information taken from one OECD 421 study on AGBC which has been assigned a klimisch score of 1.

AF for remaining uncertainties:

2.5

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

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:

0.1 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

900

Modified dose descriptor starting point:

LOAEL

Value:

88 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Assumed dermal absorption is equal to oral absorption as a precautionary measure.

AF for dose response relationship:

3

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment.

AF for differences in duration of exposure:

6

Justification:

Extrapolation from subacute study to chronic exposure value in line with Table R.8-5 of Chapter R.8 of Guidance on information requirements and chemical safety assessment and ECETOC Guidance No. 110.

AF for interspecies differences (allometric scaling):

4

Justification:

Differences in species addressed in calculation of dose descriptor starting point. Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment.

AF for other interspecies differences:

1

Justification:

All interspecies differences accounted for by allometric scaling.

AF for intraspecies differences:

5

Justification:

Default value in Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment.

AF for the quality of the whole database:

1

Justification:

Information taken from one OECD 421 study on AGBC which has been assigned a klimisch score of 1.

AF for remaining uncertainties:

2.5

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

Based on the available data the substance is classified as Reproductive toxicant, category 2. The NOAEL of 88 mg/kg bw/day for systemic effects is based on an OECD 421 study on the test substance, The effects seen at the next highest dose of 300 mg/kg bw/day included decreased food consumption and body weight/body weight gain changes in both males and females, and decreased absolute and relative thymus weights in females only. These effects were not considered significant or severe, so there is no requirement for a specific target organ toxicity classification. The NOAEL for fertility and reproductive performance was 1000 mg/kg bw/day as no effects were seen on these parameters. The NOAEL for developmental toxicity in the F1 offspring was not determined, and a LOAEL of 88 mg/kg bw/day was calculated. Although increased pre and post-natal mortality and reduced pup weights were evident only at 1000 mg/kg bw/day dose level, dissecting aneurysms were detected in a dose-dependent fashion beginning at the lowest dose level of 88 mg/kg bw/day.

The test substance was not toxic by acute oral administration or by acute dermal administration. While dermal absorption is unlikely, it was considered equal to oral absorption in the DNEL calculation as a precautionary measure.

The substance did not show evidence or skin irritation or eye irritation, but it is considered a skin sensitizer. However, DNELs for long term systemic effects are considered sufficient to protect from local and acute effects. Therefore, local effect and acute effect DNELs were not generated.

Finally, AGBC is not considered genotoxic based on multiple in vitro assays.

All assessments factors were the default values taken from Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessments

Repeated Dose - 422 - Summary

A reproduction/ developmental toxicity screening test was carried out in order to assess the test material in accordance with the standardised guidelines OECD 421 and EPA OPPTS 870.3550 under CLP conditions.

Four groups of ten male and female Wistar Han rats were exposed by oral gavage to the test material at 0, 88, 300 and 1000 mg/kg bw/day in carboxymethylcellulose. Males were exposed for 28 days ( 2 weeks prior to mating, during mating, and up to termination) and females were exposed for up to 55 days ( 2 weeks prior to mating, during mating and gestation and during at least 4 days of lactation).

Animals were evaluated for mortality/ viability, clinical and functional observations, body weights and food consumption, clinical pathology, macroscopy at termination, organ weights and histopathology on a selection of tissues and reproduction/developmental parameters.

Severe clinical findings were observed in several females at 1000 mg/kg throughout the gestation and lactation period including paresis of hindlimbs, high stepping gait and piloerection. No clinical signs directly related to the test item were observed in any other group. The mating, fertility and conception indices, precoital time and number of corpora lutea and implantation sites were unaffected by treatment. However, the test substance adversely affected the pre-and post-natal development of offspring at 1000 mg/kg bw/day which was evident by increased pre and post- natal mortality and reduced pup weights. Furthermore, a significantly high proportion of pups, across all treatment groups had microscopic and/or macroscopic evidence of dissecting aneurysms. The mean duration of gestation varied between 22.0 and 22.8 across all dose groups. As the high dose value (22.8 days) is outside the historical control range, the prolonged duration of gestation in this dose group is considered to be treatment related.

Under the conditions of this study, the NOAEL for general systemic toxicity for males was 300 mg/kg bw/day based on decreased food consumption and body weights/ body weight gain change at 1000 mg/kg bw/day. For females the NOAEL was 88 mg/kg bw/day as they showed decreased absolute and relative thymus weights at 300 mg/kg bw/day. 

The NOAEL for fertility and reproductive performance was 1000 mg/kg bw/day as no effects were seen on these parameters.

The NOAEL for developmental toxicity in the F1 offspring was not determined, and a LOAEL of 88 mg/kg bw/day was calculated. Although increased pre-and post-natal mortality and reduced pup weights were evident only at 1000 mg/kg bw/day dose level, dissecting aneurysms were detected in a dose-dependent fashion beginning at the lowest dose level of 88 mg/kg bw/day.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Exposure to the general population is not expected based on the substance use pattern. Aminoguanidine bicarbonate is intended for use within industrial and professional use sectors only, and no uses by the general population are anticipated. As such it is considered justified not to derive a DNEL for this type of exposure.