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Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
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 MAPTAC, a reliable (RL=1), relevant and adequate study is available on toxicity to reproduction

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test according to OECD Guideline 422 (22 March 1996) MAPTAC was administered to 10 Sprague Dawley [Crl:CD(SD)BR] rats/sex/dose orally by gavage at dose levels of 0 (control), 100, 300 and 1000 mg a.i./kg bw/d. Males were treated for a total of 38 days including 2 weeks prior to pairing and continuously thereafter, up to the day before necropsy.

Females were dosed throughout the study including 2 weeks before pairing, thereafter during pairing, gestation and lactation periods until Day 3 post partum.

No mortality occurred in the study. No clinical signs of toxicological significance were reported. No relevant differences in body weights and food consumption were recorded in animals of both sexes compared to the control group, throughout the study.

Observation of animals at removal from the cage and in an open arena (neurotoxicity assessment) did not reveal changes attributable to the test item. Reduction in motor activity and reduced grip strength (first trial only) observed in males of the high dose group were noted at the end of treatment period when compared to controls. Considering that no differences were noted in other correlated neuromotory tests (second trial of grip strength, landing footsplay and rearing measurements in the open arena) this finding was considered incidental.

Haematology and urinanalysis revealed no changes of toxicological significance.

Some changes in clinical chemistry were noted (increase of protein (9%), albumin (7%), phosphorus (12%), calcium (5%) and decrement of chloride (2%) in high dose males; increase of phosphorus (13%) and decrease of glucose (27%) in mid-dose males; decreases of aspartate aminotransferase (up to 23%) and urea (22%) in mid and/or high dose females). However, these changes were of low severity or not dose-related, therefore considered of no toxicological relevance. Bile acids showed a 7-fold increment in high dose males. However, since only 2 animals showed high values and due to the lack of other relevant findings (e.g. liver markers), this alteration was considered of no toxicological significance.

Measurements of oestrus cycle, pre-coital intervals and copulatory index did not show differences between treated and control groups. No significant differences were observed in the number of implantation, corpora lutea, total litter size, pre-implantation loss, pre-birth loss and gestation length between control and treated groups.

A total of 6 females were found not pregnant at necropsy: 2 in the control group, 1 in the low dose group, 1 in the mid-dose group, 2 in the high dose group. The number of females with live pups on Day 4post partumwas: 8 in each of the control and high dose groups, 9 in each of the low and mid-dose groups. Clinical signs of pups were comparable between groups. At necropsy no findings related to treatment were seen in decedent pups and in pups sacrificed on Day 4 post partum.

 

At necropsy, no macroscopic or microscopic treatment-related changes were noted. In addition seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and no alterations were noted.

No relevant toxic effects were seen in parental animals up to the highest dose group of 1000 mg/kg bw/d. On the basis of the results obtained in the study, the NOAEL for both, general toxicity and reproduction/developmental toxicity was 1000 mg/kg bw/d (males/females). 

 

There are no data gaps for the endpoint toxicity to reproduction. No human data are available. However, there is no reason to believe that these results from rat would not be applicable to humans. 


Short description of key information:
Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test; oral (gavage); rat (Sprague Dawley [Crl:CD(SD)BR]), m/f (OECD guideline 422, GLP): NOAEL = 1000 mg/kg bw/d

Justification for selection of Effect on fertility via oral route:
OECD guideline 422 study, no deviations, GLP

Effects on developmental toxicity

Description of key information
A prenatal developmental toxicity study is scientifically not necessary.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
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

According to REACH regulation, Annex XI, 1, a prenatal developmental toxicity study is scientifically not necessary. The available data are sufficient for classification, labelling and risk assessment. Thus, no further testing is proposed.

MAPTAC has been screened for reproductive and developmental toxicity in a study according to OECD guideline 422. The results indicate that the substance has a low potential for adversely affecting fertility and development: There were no effects of MAPTAC on reproductive indices including number of external anomalies of delivered pups.

This is further supported by the fact that MAPTAC is rapidly metabolised in vivo and the metabolites, methacrylic acid as well as choline, demonstrate an absence of concern for specific reproductive toxicity.

Choline chloride has been evaluated in a SIDS Initial Assessment Report: “No developmental toxic effects were observed in mice after oral doses of 1250 mg/kg bw/day on gestation days 1 to 18. Doses above the levels recommended currently (4160 mg/kg bw/day and higher) and associated with maternal toxicity, did produce developmental toxic effects, but these were secondary to the maternal toxicity at the excessive doses used. The compound does not produce any significant developmental toxicity in the mouse.

For Methacrylic acid no “signs of toxicity related to embryolethality or teratogenicity were observed ” when administered to pregnant rats from day 6 to 20 of gestation as cited in US EPA, 2008.

There are no data gaps for the endpoint developmental toxicity. No human data are available. However, there is no reason to believe that these results from rat would not be applicable to humans.

 

References:

OECD SIDS 2004, Choline Chloride, SIDS Initial Assessment Report For SIAM 19, available online:www.inchem.org/documents/sids/sids/67481.pdf

US EPA, 2008 United States Environmental Protection Agency, Office of Pollution Prevention and Toxics: METHACRYLIC ACID, interim acute exposure guideline levels. Interim 10/2008; available online: http://www.epa.gov/opptintr/aegl/pubs/methacrylci_acid%20interim_de_oct_2008_c.pdf

Justification for classification or non-classification

Based on the available data, MAPTAC does not need to be classified for toxicity to reproduction, developmental toxicity and teratogenicity according to the criteria given in regulation (EC) 1272/2008 or the former European directive on classification and labelling 67/548/EEC. Thus, no labelling is required.