Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

For DIPA, CAS no. 110-97-4, an EOGRTS is not available. In a weight of evidence according to REACH annex XI, section 1 a testing does not appear scientifically necessary, using the available toxicological data with DIPA and two analogue substances TIPA, CAS 122-20-3 and MIPA, CAS 78-96-6. For TIPA, reproductive toxicity was investigated in a one-generation study (according to FDA guidelines) in which rats were administered TIPA in the diet for 5 weeks prior to mating, during mating, gestation, lactation, and for 90 days post-weaning (offspring). The NOAEL for reproductive effects was reported 609 mg/kg bw/day for males and 700 mg/kg bw/day for females, the highest dose tested. In addition, under the conditions of an OECD 422 reproduction/developmental toxicity screening test with hydrochloride salt of MIPA, the NOAEL for reproductive performance, fertility and developmental toxicity is 1000 mg/kg bw/day for rats, the highest dose tested. Furthermore, repeated dose toxicity studies with DIPA revealed no effects on the reproductive organs up to the limit dose.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

For DIPA, CAS no. 110-97-4, an EOGRTS is not available. According to REACH annex XI, section 1 a testing does not appear scientifically necessary, because there is sufficient weight of evidence from the available toxicological data with DIPA and two analogue substances TIPA, CAS 112-20-3 and MIPA, CAS 78-96-6 leading to the conclusion, that DIPA, CAS no. 110-97-4 is not an reprotoxic substance.

In a one-generation study according to FDA guidelines, Sprague-Dawley rats (25/sex/dose) were administered TIPA in the diet at 0, 500, 2000 or 7500 ppm (approximately 0, 40, 160 or 609 mg/kg bw/d in males or 0, 44, 182 or 700 mg/kg bw/d in females) for 5 weeks prior to mating as well as during mating, gestation and lactation [1988; RL2]. Offspring (20/sex/dose) were also administered the same doses for 90 days after weaning. Prior to weaning, these rats were exposed to TIPA in utero during pregnancy of the P rats, in maternal milk during lactation, and in any diet they consumed prior to weaning. Ophthalmological, clinical chemistry, haematology and urinalysis examinations were conducted. Histopathological examination was conducted on controls and high-dose animals for all organs and on lungs, liver, kidneys and organs with lesions at the low and intermediate doses. No adverse clinical, histological, or reproductive effects (mating index, fertility index, gestation index, gestation length, percent pups born alive, viability index, lactation index, litter survival, average number of pups/litter, litter size) were noted. The NOAEL was reported to be 609 mg/kg bw/d for males and 700 mg/kg bw/d for females, the highest doses tested.

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test [2008, RL1], rats were exposed to a 65.4 % aqueous MIPA HCl solution with 100, 300 and 1000 mg/kg bw/d, corresponding to 67, 202 and 673 mg/kg bw/d organic MIPA. Only slightly reduced hemoglobin and hematocrit values were observed in the high dose male rats after 38 days of exposure, indicating a mild anemic process. No toxicity effects were observed in female rats after 45 days of exposure at all dose levels nor in the F1 pups and no developmental and fertility effects were observed. Based on the mild effects in the high dose male rats, the NOAEL for general, systemic toxicity of the test substance was set at the mid dose level (i.e. 202 mg/kg bw/d expressed as organic MIPA).

Additionally, repeated dose toxicity studies with DIPA revealed no effects on the reproductive organs up to the limit dose of 1000 mg/kg bw.

Furthermore, the data gap for the fertility toxicity was one of the concern subjects in the substance evaluation (year in CoRAP list: 2013), and the evaluating member state concluded, that there was no need for regulatory follow-up action [Substance Evaluation Conclusion document for 1,1´-iminodipropan-2ol, EC No 203-820-9, CAS No 110-97-4, Czech Republic, 28 Feb 2014].

 

Please refer to the justification for adaptation according to REACH annex XI, section 1; attached to IUCLID section 13.2: Justification for WoE: Reprotoxicity, November 2018.

Effects on developmental toxicity

Description of key information

In an OECD guideline 414 developmental toxicity study, pregnant female rats were administered DIPA via oral gavage on gestation days 6 to 20. The maternal and developmental NOAEL were both 1000 mg/kg bw/day, the highest dose tested. Read-across to the developmental toxicity data for the structural analogue TIPA: An OECD414 with Picloram TIPA salt and sub-chronic dose range finder with TIPA also revealed no adverse developmental effects in rabbits.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Twenty-five female Sprague-Dawley rats were administered DIPA at 0, 100, 300 or 1000 mg/kg bw/day via oral gavage on gestation days 6 to 20 in an OECD guideline 414 study (Johnson, 2007; RL2). Half of the offspring had visceral examinations conducted by dissection under a low power stereomicroscope for evidence of visceral alterations. No treatment-related effects were reported regarding the incidence of fetal alterations at dose levels up to 1000 mg DIPA/kg bw/day. Fetal alterations were noted to occur sporadically, however, they were of low incidence, showed no dose response, and were therefore not considered to be treatment-related. The reported NOAEL for maternal and developmental toxicity was 1000 mg/kg bw/day.

For DIPA, CAS no. 110-97-4, a PNDTS in a second species is not available. According to REACH annex XI, section 1 a testing does not appear scientifically necessary, because this endpoint is covered with the read-across to the developmental toxicity data for the structural analogue TIPA: An OECD414 with Picloram TIPA salt and sub-chronic dose range finder with TIPA also revealed no adverse developmental effects in rabbits but showed, that there is a MTD (maximal tolerable dose) for the dams below the limit dose.

A teratogenicity study with rabbits was performed with Picloram TIPA salt (a structural analogue of TIPA, see additional read-across justification for developmental toxicity, 2nd species in the IUCLID section 13), according to OECD414 and GLP compliant [Dow, 1992; RL1]. The study was conducted in two phases. In Phase I, groups of 18 inseminated New Zealand White rabbits were administered the test substance by oral gavage on GD7-19 at targeted dose levels of 0, 180, 538 or 1000 mg/kg bw/d. Phase II of this study was conducted as a repeat of Phase I to determine whether the increased resorption rate and certain fetal observations in Phase I were reproducible and/or attributed to treatment. In Phase II, an additional dose group of 54 mg/kg bw/d was added at the low end to establish a no-observed-effect level. On GD28, all surviving animals were necropsied and liver, kidneys and gravid uterine weights were recorded. The ovaries were examined for corpora lutea and the uterus was examined for implantations and resorptions. Fetuses were removed, weighed, sexed and examined for external, visceral and skeletal alterations. Maternal toxicity was observed in rabbits given 538 or 1000 mg/kg bw/d, as evidenced by decreased feed consumption accompanied by higher incidences of decreased feces, soft feces, perineal soiling and decreased body weight gain (Phase I and II). In addition, an increased incidence of high-dose dams aborting (one in Phase I and two in Phase II) was also interpreted to represent maternal toxicity. No other adverse maternal or embryonal/fetal effects attributed to treatment were observed at any dose level. The test substance was not teratogenic at any dose level tested. In conclusion, the maternal no-observed-adverse-effect level (NOAEL) was 180 mg/kg bw/d. Corrected for molecular weight this is equivalent to 79.56 mg/kg bw/d for TIPA. The no-observed-effect level (NOEL) for embryonal/fetal toxicity or teratogenicity of the test substance was 1000 mg/kg/d, the highest dose level tested; equivalent to 440 mg TIPA/kg bw/d.

Supportingly, in a short‐term repeated dose study [2016; RL2] TIPA was administered dissolved in drinking water for 21 days to groups of 3 - 5 female New Zealand White rabbits, via daily gavage. Animals were exposed to either 0 or 1000 mg/kg bw/d. In the dose group (1000 mg/kg bw/d) all 5 females showed reduced food consumption and lost body weight throughout the study. These animals also had reduced faeces or diarrhoea. Two rabbits died on the 3rd and 5th treatment day, respectively. The deceased animals showed no other preterminal clinical signs of toxicity, nor were there any specific necropsy findings. In conclusion, if additional testing for developmental toxicity would be performed with TIPA, the dose‐selection for this study would be in the range of 500 mg/kg bw/d (half of the lethal dose), which is comparable to the converted dose of 440 mg TIPA/kg bw/d from the OECD414 rabbit study with Picloram TIPA salt (where no developmental toxic effects were observed).

Please refer to the justification for adaptation according to REACH annex XI, section 1; attached to IUCLID section 13.2: Justification for WoE: Reprotoxicity, November 2018.

Additionally, the justification for the read-across from Picloram TIPA salt to TIPA is attached to IUCLID section 13.2: Justification for RA: Developmental Toxicity, 2nd species, November 2018.

Mode of Action Analysis / Human Relevance Framework

No information available.

Justification for classification or non-classification

Based on the available studies, there is no indication that DIPA can cause effects on fertility or developmental toxicity. Therefore, DIPA does not need to be classified according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.